Mahoney is an Editorial Assistant at Healio She received her BA in English from the University of Vermont in Burlington and is a member of Phi Beta Kappa.  Mahoney worked as a freelance journalist and as a reporter for NewsXPartners and the NXP Writer’s Syndicate speaking with leaders in the commercial wellness space.  she can be found spending time with family and friends or puzzling.  Hybrid closed-loop systems outperformed other types of subcutaneous insulin treatment for diabetes but some systems were more efficient than others according to results published in Diabetes/Metabolism Research and Reviews including multiple daily injection therapy standalone insulin pumps and sensor augmenting pumps there are no head-to-head trials directly comparing the different systems,” Sergio Di Molfetta, PhD assistant professor at University of Bari Aldo Moro and endocrinologist in the Endocrinology Unit of the Policlinico Consorziale University Hospital of Bari although these systems are similar in overall structure the researchers noted they include different algorithms which may lead to disparate glycemic outcomes This inspired the researchers to perform a systematic review and network meta‐analysis to compare the safety and efficacy of seven commercially available alternative HCL systems: MiniMed 670G and MiniMed 780G (Medtronic); t:slim X2 with Control-IQ technology (Tandem Diabetes Care); CamAPS Fx (CamDiab Ltd.); Diabeloop Generation 1 (DBLG‐1; Diabeloop) and Diabeloop for highly unstable diabetes (DBLHU; Diabeloop); and Omnipod 5 (Insulet Corporation) The researchers identified 28 randomized controlled trials that compared how 2,446 adults adolescents and/or children with type 1 diabetes responded to an HCL compared with another type of subcutaneous insulin therapy treatment and reported 24-hour time in range (TIR) as an endpoint The eligible trials examined five HCL systems (MiniMed 670G duration of intervention and age of the participants were similar The primary endpoint of the analysis was TIR with the comparators grouped as subcutaneous insulin therapy without continuous glucose monitoring (SIT); subcutaneous insulin therapy with continuous glucose monitoring (SITCGM); and low-glucose suspension or predictive low-glucose suspension (LGSPLGS) Di Molfetta and colleagues found that all the HCL systems significantly increased TIR compared with SIT MiniMed 780G had the greatest improvement in TIR (mean difference [MD] = 21.59%; 95% CI followed by Control IQ (MD = 16.49%; 95% CI the improvement in TIR was significantly greater with HCL systems compared with LGSPLGS (except for DBLG1) and SITCGM and with MiniMed 780G compared with the other HCL systems the researchers found that all the HCL systems decreased time below range compared with SIT DBLG1 achieved the greatest reduction in time below range compared with SIT with an MD of –3.69% (95% CI followed by MiniMed 670G (MD = –2.9%; 95% CI 3.73 to 1.27) and CamAPS Fx (MD = –2.0%; 95% CI Reduction of time below range with HCL systems was numerically greater than with LGSPLGS and with SITCGM All the HCL systems significantly decreased time above range and all but DBLG1 significantly reduced mean glucose compared with SIT and SITCGM MiniMed 780G achieved the greatest reductions in time above range (MD = 18.82%; 95% CI 24.3 to 13.34) and mean glucose (MD = 26 mg/dL; 95% CI risk for hypoglycemia and diabetic ketoacidosis was similar between patients using HCL systems and patients using other types of insulin therapy Subgroup analyses also revealed that “Minimed 780G was even more effective in improving TIR in studies with baseline HbA1c greater than or equal to 8%,” Di Molfetta told Healio “HCL systems with purely predictive algorithms achieved greater improvement in TIR in studies with mean age of participants younger than 18 years and shorter diabetes duration (lower than 10 years) and therefore are possibly more effective in these subgroups of patients.” The researchers noted several limitations to this study including low certainty of evidence for many comparisons and their inability to apply these results to patients with type 2 diabetes pregnant women and other “special” populations with diabetes “MiniMed 780G is probably the most effective system for improving TIR while DBLG1 is the most effective in reducing time below range,” Di Molfetta told Healio “The MiniMed 780G's algorithm combines elements from proportional-integral derivative model predictive control and fuzzy logic control and delivers autocorrection boluses up to one every 5 minutes on the top of basal insulin regulation it is possibly more efficient in tackling hyperglycemia the DBLG1 algorithm allows a higher hypoglycemia threshold to be set for insulin delivery and further recommends calibrated preventive sugaring when hypoglycemia is predicted despite basal rate reduction,” Di Molfetta said “We believe that our results may be useful for clinicians facilitating patient-tailored decision-making,” he added results from clinical trials should be part of the decision process for orienting toward certain systems rather than toward others based on glycemic goals and patient clinical characteristics.” can be reached at sergio.dimolfetta@policlinico.ba.it Get the latest news and education delivered to your inbox The email address associated with your Healio account is: If you would like to edit or change the email address that your subscriptions and alerts are sent to You'll receive reminders to complete your saved activities from Healio CME Prefect Emeritus of the Congregation for the Causes of Saints Angelo Amato grew up in a family dedicated to shipbuilding He was the eldest of four children and began his education at the Nautical Institute of Bari he changed course by entering the Salesian aspirant of Torre Annunziata he made his first religious profession and moved to Rome to study at the Pontifical Salesian Athenaeum He made his perpetual profession in 1962 and was ordained a priest on December 22 Amato continued his education at the Pontifical Gregorian University where he received a doctorate in theology in 1974 he was sent to Greece to further his knowledge of Orthodox theology residing at the Vlatadon Monastery in Thessaloniki he attended classes and researched the sacrament of penance in Greek Orthodox theology Amato taught Christology at the Pontifical Salesian University where he held the positions of dean and vice-rector He was also a consultant to various Vatican congregations and a member of the theological-historical commission for the Great Jubilee of the Year 2000 he was appointed secretary of the Congregation for the Doctrine of the Faith and consecrated archbishop by Pope John Paul II in 2003 Benedict XVI appointed him Prefect of the Congregation for the Causes of Saints and created him a cardinal in 2010 He participated in the 2013 conclave that elected Pope Francis and continued as Prefect until 2018 Cardinal Amato was a key figure in the beatification and canonization of many religious figures including the diocesan phase of the beatification process of Don Tonino Bello in 2013 remembered him as a man of faith and tireless pastor standing out for his dedication to the Church and the people of God His life and work leave an indelible mark on the history of the Catholic Church Conclave 2025: More Voters Than Ever to Elect Francis’ Successor On the Road to the Conclave: The Church Prepares to Elect the New Pope on May 7 What are the Congregations before the Conclave Tweets by Pontifex AreaB Gallery in Milan is hosting an exhibition that explores the relationship between nature and art through the contrasting visions of two contemporary artists-Antonio Bardino (Alghero is curated by Giuseppe Frangi and presents a series of works that confront the natural subject from two divergent but complementary perspectives range between painting and sculpture and are made in different sizes Bardino and De Molfetta’s works relate to the natural element as a material that becomes a vehicle for expressing a broader and sometimes ambiguous vision of reality Their approach merges into a reflection on artifice and the transformative power of art where nature itself becomes a metaphor for a world that slips between reality and fiction between the controlled and the uncontrollable.Uniting the two poetics is the expressive force of the signs that characterize their respective works: Bardino’s brush and De Molfetta’s touch manage to convey a vital energy that strikes the viewer De Molfetta’s sculptures and Bardino’s paintings are united by their ability to go beyond the surface of their subject engaging the viewer in an experience that awakens new emotional and interpretive paths which will be accompanied by a catalog published by Vanillaedizioni with a text by curator Giuseppe Frangi Visiting hours are Monday through Thursday from 10 a.m and Saturdays the exhibition can be visited by appointment known for his pictorial research that explores nature with an approach bordering on hyperrealism offers in this exhibition a cycle of works that seem to transform the environment into a place suspended between the natural and the surrealist His large canvases bring the viewer into a close encounter with the natural subject transformed into something beyond mere observation An emblematic example of this tension is the work Resistances of 2024 whose shapes and details appear as realistic as they are artificial challenging visual perception and inviting the viewer to confront the intensity and vitality of a nature bursting out of pictorial space Bardino’s work is characterized by an intense exploration of matter and form the artist succeeds in constructing an image that plays on the boundary between the natural and the artificial using the sculptural brush that defines every detail of his works with almost surgical precision His pictorial research focuses mainly on those aspects of nature that are more impervious seem to move away from it to enter a new dimension If Bardino plays with painting to create sculpture in two dimensions Francesco De Molfetta responds with pictorial sculpture using ceramics to construct forms that seem to come straight out of the imagination are the result of an analysis of the natural element that pushes him to treat ceramics with an expressive freedom rare for this material traditionally associated with more static and austere forms transformed into an almost living material the natural and imaginary worlds intermingle: on a clod of grass almost surrealistic in its unrealistic glazed green a scene takes place that evokes the world of the Smurfs This contrast between the solid material of ceramics and the imagery that animates it is one of the most fascinating features of his research De Molfetta uses ceramics as an expressive language that allows him to bring to life fantastic creatures that seem to escape from reality and project themselves into a dreamlike dimension enriched with surprising details that make them fascinating and disturbing at the same time as if each object had its own soul and its own will to transform into something else The interplay between fantasy and reality is always present in his work in a continuous shift of meaning that invites the viewer to confront an unexpected vision of nature Antonio Bardino was born in Alghero in 1973 and initially trained at the F His artistic career was enriched by his frequentation but especially for his deep inclination toward experimentation marked a turning point in Bardino’s life and artistic research lending a pataphysical and conceptual imprint to his production A significant event of their collaboration is the pataphysical baptism on Nov which represented the young artist’s entry into a new creative universe of meaning games and parallel worlds Bardino devoted himself to experiments in various fields of art but it was mainly in his pictorial works that his language evolved to Udine marks a turning point in his research fueled by the exploration of themes of nature and contemporary interiors Bardino’s work is distinguished by the intense relationship he establishes with the natural world treated with a hyperrealism that does not renounce a certain artificial tension become a symbol of an elusive and not totally controllable nature creating a tension between order and chaos Bardino has participated in numerous awards and competitions including the Premio Lissone and the Premio Combat and has been a finalist in prestigious events such as the Premio Celeste and the Premio Rugabella He has exhibited in numerous galleries both in Italy and abroad consolidating his position in the field of contemporary painting Francesco De Molfetta was born in Milan in 1979 and began his artistic career in a rather eclectic way His art was discovered by the well-known gallery owner Franco Toselli one of the main protagonists of the Arte Povera movement who introduced him to the most important art circuits since the early 2000s with exhibitions in Italy and abroad at major international art fairs as well as in museums and private galleries in Europe and around the world a highlight for De Molfetta was his participation in an exhibition at the L.A MOCA (Museum of Contemporary Art in Los Angeles) where he exhibited in a context dedicated to the New Pop and Surrealist art scene This encounter with the American public sanctioned the international recognition of his work Among his best-known works is the provocative sculpture Lourdes Vuitton a work that mocks religion and consumer society which was exhibited at the Sacred Art Biennial De Molfetta is known for his irreverent and ironic approach pushing the boundaries of contemporary art through the fusion of tradition and innovation and his work explores themes such as identity The artist has collaborated with prestigious brands creating works that question popular culture and its symbols His participation in major international art events such as the Tolentino Biennale and the Milan Triennale has consolidated his presence on the contemporary scene He has also directed and written short films that have won awards including one that won the Ambrogino d’Oro as best short film about the city of Milan De Molfetta exhibited a solo room at the Milan Triennale Museum one of Italy’s most important cultural institutions and has been involved in numerous exhibitions in museum settings and galleries around the world He teaches Aesthetics of Contemporary Art at the Humanitarian Society in Milan This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page As former Angels communications director Eric Kay sits in prison for a 22-year sentence his appeal filed this week asks to vacate the conviction and indicates he could have accepted a much more lenient punishment Kay was convicted for providing the drugs that killed Angels pitcher Tyler Skaggs in 2019 His appellate attorney alleged in the brief that his trial attorney “belittled” him and threatened to withdraw from the case if he accepted a plea offer that could have had him released in 5-to-10 years Kay’s appellate attorney filed an appeal to overturn his February 2022 conviction The 70-page document argued that the evidence was “legally insufficient” to support the jury’s guilty verdict It also stated that the government’s closing statement was “repeatedly improper.” Skaggs died at age 27 from a fentanyl overdose on July 1, 2019, in his Southlake, Texas, hotel room. The Angels had traveled to the area earlier that evening in advance of a series against the Rangers The jury deliberated for fewer than two hours and found that Kay provided the fentanyl-laced pills that killed Skaggs and that Skaggs would have lived but for ingesting the fentanyl The jury also decided based on a preponderance of evidence that Kay provided those pills in Tarrant County distribution of a controlled substance resulting in death and conspiracy to possess with intent to distribute controlled substances Each charge carries a 10-year federal mandatory minimum sentence Means imposed a 22-year sentence in October after hearing recordings of Kay criticizing Skaggs on the phone in the days following his conviction Kay is currently serving his sentence at FCI Englewood in Colorado and is scheduled for release in 2041 indicates that Kay’s prison term could have been significantly reduced if he accepted a plea He could have served even less time with good behavior It also would have avoided the spectacle of a trial which included numerous former Angels players testifying “His counsel belittled him for considering it and threatened to withdraw from the case,” Kay’s appellate attorney Brett Ordiway wrote in the brief Molfetta spoke to The Athletic on Wednesday and adamantly disagreed with the assertion in the brief “It didn’t happen that way,” Molfetta said that I threatened not to be his lawyer anymore Molfetta acknowledged that he did get frustrated with Kay but said he couldn’t discuss the details because of attorney-client privilege He said it didn’t have to do with whether or not he should take the deal and was related more to the timing of making a decision on the matter He said he did advise Kay that it was the right decision to go to trial “Tyler Skaggs had a problem long before he ever met Eric Kay,” Molfetta said You try cases and you live with the jury and the decision and you’ve got to move on “But I am alarmed … the jury didn’t look at one exhibit My only fear in all of this was where I was trying the case Molfetta said he’s rooting for Kay to win his appeal despite the disconnect between the two following Kay’s conviction Kay’s other trial attorney, Reagan Wynn, had his law license suspended on an unrelated matter shortly after Kay’s conviction The court appointed an attorney for Kay’s sentencing The brief cited his attorneys “abandon(ing) him” as a factor in requesting a vacation of Kay’s conviction but did not use ineffective counsel as a reason to overturn the verdict is more related to a lack of evidence and alleged false statements made by the prosecuting attorneys But it was always going to be an uphill climb to garner an acquittal at trial A Pew Research study published in 2019 stated that only 2 percent of federal criminal defendants go to trial And just 17 percent of those trials result in an acquittal Ordiway said in the appeal brief that the United States Court of Appeals for the Fifth Circuit should overturn the conviction and grant an acquittal The government will have 30 days to respond to the appeal and then Kay will have three weeks to respond to the government’s response Both sides will typically request extensions The court will then decide whether to hear oral arguments on the brief That would likely come in the fall if the court consents to hear arguments It can also make a judgment on an appeal based solely on the briefs Appeals of federal court convictions are successful about 7 percent of the time, according to The Appellate Law Firm, citing a 2015 study Kay’s brief states the government failed to prove that he had anything to give that he gave anything to Skaggs and that fentanyl was the but-for cause of Skaggs’ death It claims that a rational jury could not conclude that Kay distributed anything in the state of Texas The government needed to prove through a preponderance of evidence (more likely than not) that he distributed the pills in Texas The brief also argued the government’s case was “devoid of evidence” that Kay conspired with anyone to distribute the controlled substances The government argued during the trial that Kay flew to Texas with the team then brought the fentanyl-laced pills to Skaggs’ hotel room Text messages between the two in the minutes before Skaggs died were critical evidence in the case The government also enlisted several former Angels players to testify that Kay also provided them with illegal drugs at their request Ordiway also cited six allegedly “improper” remarks made by the prosecution in the closing arguments that “cast serious doubt on the correctness of the verdict.” This included a statement that Kay was Skaggs’ only drug source This was despite both former Angels teammate Matt Harvey and a separate former friend of Skaggs acknowledging they provided drugs to Skaggs “Because the evidence is legally insufficient to support the jury’s guilty verdicts this Court should enter a judgment of acquittal,” Ordiway wrote in his conclusion because the Government’s closing argument was repeatedly improper this Court should reverse the district court’s judgment and remand this case for a new trial.” the result here could bring significant implications for the Angels The team is being sued by Skaggs’ family as part of a wrongful death lawsuit in California The two parties in that case are scheduled for a jury trial to begin on Oct Evidence of a criminal conviction can be used in related civil cases (Photo of Eric Kay from 2022: LM Otero / Associated Press) Sam Blum is a staff writer for The Athletic covering the Los Angeles Angels and Major League Baseball he was a sports reporter for the Dallas Morning News he covered Auburn for AL.com and the University of Virginia for The Daily Progress in Charlottesville Christian Molfetta, who has degrees from Stanford University and the University of Michigan, signed a minor-league contract with the Detroit Tigers is scheduled to report to minor-league spring training in Lakeland He has been assigned to Double-A Erie and will likely begin the 2024 season with the SeaWolves "It seems to me like the Tigers have a new wave of momentum going," Molfetta said Thursday help out as best I can and then see what happens The whole thing I've always wanted in my baseball career is the opportunity to see what will happen B1G WEEK: Michigan football kicks off Rose Bowl week at Disneyland, with 'one-track mind' on Alabama Molfetta spent the past three seasons with the Los Angeles Angels after signing as an undrafted free agent competing in 13 games for Double-A Rocket City in 2021 60 games for High-A Tri-City in 2022 and 11 games for Triple-A Salt Lake in 2023 He spent most of the 2023 season on the development list meaning he practiced and caught bullpens with Triple-A Salt Lake but wasn't active for games He hit .129 with three walks and nine strikeouts across 34 plate appearances in 11 games The Angels released Molfetta at the end of September "No one is going into the season wanting to ride the development list the whole year and get like 30 at-bats," Molfetta said "I played with so many guys that have some unbelievable experience I felt like the experience and the development that I got was invaluable compared to the year before." [ MUST LISTEN: Make "Days of Roar" your go-to Detroit Tigers podcast, available anywhere you listen to podcasts (Apple, Spotify) ]  In the Angels' organization, Molfetta developed a relationship with Dylan Axelrod. The Tigers recently hired Axelrod, who spent the past four seasons in player development with the Angels, as their new pitching performance and integration coordinator a former MLB pitcher with a strength and conditioning background will facilitate the collaboration between the strength and conditioning coaches the pitching coaches and the pitchers in the Tigers' organization "He is a great dude and a great baseball mind," Molfetta said "He is very analytical and very data driven OUT OF NOWHERE: Tigers lefty Andrew Magno emerges as under-the-radar reliever to watch in 2024 The best season of Molfetta's baseball career took place in Ann Arbor the sixth-year college catcher ended up playing a full season at third base to fill a need on the roster because of a preseason injury 23 walks and 30 strikeouts across 46 games It was by far the most games he played in a single season during his college career "(Head coach Erik) Bakich really allowed me to be myself on the field I just fell in love with the game again at Michigan and I tried to carry that over into pro ball Molfetta was recruited to play for Michigan as a graduate transfer by pitching coach Chris Fetter. He has a relationship with Fetter, who left the Wolverines in November 2020 to become the Tigers' pitching coach There's also a relationship with former Tigers third baseman Brandon Inge who played 13 MLB seasons and has worked for the Wolverines as a volunteer assistant since 2021 Tigers manager A.J. Hinch played college baseball at Stanford in the mid-1990s and graduated with a degree in psychology before embarking on his seven-year MLB player career and his ongoing 10-year MLB managerial career Stanford is where Molfetta played his first five seasons in college but he played in just 70 games with 174 total plate appearances in those five years compared to 46 games and 211 plate appearances in one year at Michigan I'm excited to meet some new guys and develop even further," Molfetta said "I don't know how long my opportunity is going to be and I don't know what that opportunity is going to look like until the season starts but I'm just excited for spring training." DOUBLE-A CATCHER: Switch-hitting catcher Eliezer Alfonzo raked in Venezuela. Can he help Tigers in future? a .187 hitter with one home run in 84 minor-league games feared his baseball career would come to end after the Angels released him He is stoked to join the Tigers on a minor-league deal That's noteworthy because Molfetta could work in many different industries He has a Bachelor of Arts degree from Stanford in science He has a Master of Science degree from Michigan in sport management "Stanford is a great place to come from," Molfetta said "but there are a lot of guys that go into pro ball out of Stanford that pull the chute pretty early because they have so many opportunities Contact Evan Petzold at epetzold@freepress.com or follow him @EvanPetzold Please select what you would like included for printing: Copy the text below and then paste that into your favorite email application This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply Service map data © OpenStreetMap contributors according to caretaker trainer Eric Campana.James Broadhurst29 August 2024IN-form chaser Molfetta Cruise will be tested when he takes on a qualify field which includes Barbeque Man and the red-hot Crumble Monelli in the 488m Free To All at Mandurah this Saturday according to caretaker trainer Eric Campana Treeby-based Campana has temporarily taken over the training duties for Molfetta Cruise on behalf of his neighbour who is about to leave for a lengthy trip to Italy Molfetta Cruise picked up his first win for Campana last weekend when he led all-the way to score over 488m in 27.09 Molfetta Cruise notched a PB time of 26.94 and the 51 race veteran is chasing as well as ever with three wins and two runner-up placings in his past five attempts "The dog's been going really well and he's come into my kennel so I can keep him racing while Nick is away," Campana explained "We've got the heats of the (Group 2) Mandurah Cup next weekend so we'll put him in that series and see how he goes "He's has only been in the kennel a couple of weeks but he's been good for me so far MOLFETTA CRUISE takes out the first heat of the Distance Potential for trainer NICK MINUTILLO. pic.twitter.com/PikRcnkQoq "We'll send him around and hope he stays sound, that's the main thing."  Molfetta Cruise is suited from box seven in Saturday's race but Campana is wary of the firepower he'll be up against, in particular from Crumble Monelli as that greyhound has roared back into top nick following a mid-year slump. Crumble Monelli has won his past four races and his victory in last weekend's The Peter Thomas Final (488m) was especially ominous because he finally showed the electric early toe that carried him to so much success last year, including in the inaugural The Sandgroper. The blue brindle speedster was rocket propelled out of the traps with a blistering 5.51 first section before rolling on to a conformable victory in 27.07. "(Molfetta Cruise) definitely wants to be out wide so I'm happy enough with the draw but when you're taking on dogs like Crumble Monelli and Barbeque Man you have to be at the top of your game," Campana said.  "You just can't afford to give these sort of dogs five lengths down the back, it's impossible to pick them up.  "If he can stay in touch early he's a chance but I'm not sure if I'm backing him, well see. "We'd like to win obviously but if he runs top three I'll be happy."  Volume 12 - 2021 | https://doi.org/10.3389/fendo.2021.667784 This article is part of the Research TopicNIKE: Neuroendocrine Tumors, Innovation in Knowledge and EducationView all 11 articles Medullary thyroid carcinoma is a rare neuroendocrine neoplasm that originates from thyroid C cells the tumor recurs at locoregional or metastatic level the immune checkpoint inhibitors have provided promise for changing the cancer treatment paradigm through the application of new approaches that enhance the body’s natural antitumor defenses The aim of this review is to summarize and discuss available data on efficacy and safety of the Food and Drug Administration-approved immune checkpoint inhibitors in patients with medullary thyroid carcinoma we found 7 useful data sources (one single-case report one short article with very preliminary data Despite the lack of published evidence regarding the use of immune check point inhibitors it must be considered that all the ongoing registered clinical trials saw first light in the last three years thus indicating a growing interest of researchers in this field will help to clarify whether this class of drugs may represent a new weapon in favor of patients with medullary thyroid carcinoma Medullary thyroid carcinoma (MTC) is a rare neuroendocrine neoplasm (NEN) that originates from thyroid C cells Surgery, with complete resection of the tumor, is the only curative approach (1). However, in many patients, the tumor displays an aggressive behavior, resulting in persistence or locoregional and distant disease recurrence. In this setting, the management remains challenging (1, 2) Tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib have shown to improve progression-free survival (PFS), and are currently available as approved agents for the treatment of progressive MTC. However, both drugs may cause grade III or IV adverse events (AEs), classified according to the Common Terminology Criteria for Adverse Events of the National Cancer Institute (3, 4) In 2020, the new generation TKIs selpercatinib and praseltinib gained the Food and Drug Administration (FDA) approval in patients with advanced/metastatic rearranged during transfection (RET) gene-mutant MTC who require systemic therapy, therefore widening the spectrum of available therapies. However, also for these drugs severe AEs have been reported (5, 6) Therapeutic options also include radionuclide therapy, such as peptide receptor radionuclide therapy (i.e. lutetium-177 and yttrium-90 labeled somatostatin analogs) (7), and iodine-131-metaiodobenzylguanidine (8) radionuclide therapy is not approved for MTC treatment immunotherapy has provided promise for changing the cancer treatment paradigm through the application of new approaches that enhance the body’s natural antitumor defenses Figure 1 Mechanisms of action for FDA-approved immune checkpoint inhibitors Table 1 FDA-approved immune checkpoint inhibitors by the reactivation of T cell-mediated tumor rejection the inhibition of PD-1/PD-L1 binding in cancer can promote T cell activation and proliferation ultimately leading to cytotoxicity in tumors MTC is reported to exhibit low PD-L1 expression in both tumor cells and tumor-infiltrating immune cells (17–19) and no microsatellite instability, irrespective of the presence/absence of either desmoplasia, lymph node metastases and/or RET mutation (18, 20) The aim of this review is to summarize and discuss available data on efficacy and safety of FDA-approved ICIs in patients with MTC We performed a literature search in the international online databases (PubMed and Embase) using the following terms: “immune checkpoint inhibitors” “medullary thyroid carcinoma” “multiple endocrine neoplasia type 2” By using the same keywords adopted for reviewing published articles, we conducted an in-depth search in the ClinicalTrials.gov registry The initial literature search revealed a total of 108 published articles two of which were pertinent to the study objectives asymptomatic grade 3 rise in lipase) ultimately led to mandatory treatment discontinuation A subsequent analysis of a patient’s lymph node (resected post-vaccination) revealed that the tumor was PD-L1 positive Very preliminary results of a phase II trial evaluating nivolumab plus ipilimumab in patients with aggressive thyroid cancer (NCT03246958) are also available (26) 7 patients with progressive MTC and prior TKI failure were included in an exploratory cohort of the study and assessed for radiographic response based on RECIST v1.1 criteria Lack of partial response is reported for all the 7 patients no safety information is provided for MTC as a single cohort (please see the Registered Clinical Trials section for more comprehensive description of the trial design) We found 37 registered clinical trials (RCTs), five of which fully matched the aim of this review (Table 2) Table 2 Registered clinical trials evaluating FDA-approved immune checkpoint inhibitors in medullary thyroid carcinoma NCT03753919 (A Phase II Study of Durvalumab (MEDI4736) Plus Tremelimumab for the Treatment of Patients With Progressive Refractory Advanced Thyroid Carcinoma - The DUTHY Trial) is a prospective exploratory phase II study whose aim is to evaluate the following outcomes in patients affected by advanced thyroid cancer (estimated enrollment: 46 patients) Primary outcomes are PFS rate at 6 months and overall survival (OS) rate at 6 months; secondary outcomes comprise overall response rate (ORR) and response status after start of study treatment patients are divided in three cohorts: i) advanced radioiodine-refractory differentiated thyroid carcinoma (DTC) Hürtle cell and poorly-differentiated thyroid carcinoma (Cohort 1); ii) advanced MTC (Cohort 2); iii) anaplastic thyroid cancer (ATC) (Cohort 3) Each cohort is planned to receive durvalumab plus tremelimumab (anti-CTLA-4 antibody not yet approved by FDA) every 4 weeks up to 4 cycles followed by durvalumab alone every 4 weeks until progression with the estimated study completion date being July 2021 The present study status is “Recruiting” NCT04514484 (Pilot Trial of Nivolumab Plus Cabozantinib for Advanced Solid Tumors in Patients With HIV Infection) is a phase I trial that aims at defining in HIV-positive patients with advanced/metastatic solid cancer (estimated enrollment: 18 patients) the incidence of dose limiting toxicities during cycle 1 of therapy with cabozantinib and nivolumab (primary outcome) Secondary outcomes include the assessment of immune status (CD4 and CD8 cell counts) at each time point from baseline changes in serum markers of immune activation patients ≥18 years old receive cabozantinib on days 1-28 and nivolumab on day 1 Cycles repeat every 28 days for up to 1 year or 1 year after a partial response is achieved or 6 months after a complete response is achieved in the absence of disease progression or unacceptable toxicity The estimated study completion date is November 2025 The present study status is “recruiting” NCT03072160 (Phase II Trial of Pembrolizumab in Recurrent or Metastatic Medullary Thyroid Cancer) is a phase II single center clinical trial aimed to determine in patients having or not having undergone previous vaccine therapy (estimated enrollment: 15 patients in each cohort) whether a PD-1 inhibitor may allow for a decline in calcitonin levels or radiographic response (primary outcome); secondary outcomes include impact of previous therapeutic cancer vaccine on response rates evaluation of immune responses in each cohort All patients will receive pembrolizumab 200 mg every 3 weeks The study started in June 2017 and was completed in November 2019 and indeed the present study status is “completed” very preliminary results appeared in the Study Results section of the ClinicalTrials.gov registry Thirteen patients were enrolled in the cancer vaccine arm (2/13 patients completed the trial) and 4 patients were enrolled in the control arm (none completed the trial) Disease progression was observed in 1/13 patients of the first arm NCT03012620 (Secured Access to Pembrolizumab for Patients With Selected Rare Cancer Types) is a phase II multicenter study which aims to investigate the efficacy and safety of pembrolizumab in 7 different cohorts of patients with unresectable/locally advanced/metastatic rare cancers for which no other treatment options are available (estimated enrollment: 350 patients) and ORR/PFS/OS in subgroups of subjects with high versus low expression of PD-L1 cohort 4 features rare thyroid cancer patients of ≥18 years are planned to receive pembrolizumab 200 mg on day 1 of every 21-day cycle The study started in July 2017 and its estimated completion date is December 2023 an increasing attention to the possibility of treating MTC with ICIs and indeed we found 5 ongoing RCTs with FDA-approved drugs that collectively involve nearly 500 patients with solid tumors As an additional sign of interest, two trials investigating camrelizumab, a novel PD-1 inhibitor recently approved in China for the treatment of relapsed/refractory classical Hodgkin lymphoma (27, 28) are also intended to recruit patients with MTC the NCT04612894 (The Efficacy and Safety of Anti-PD-1 Antibody Camrelizumab Combined With Apatinib for Neoadjuvant Therapy in Locally Advanced Thyroid Cancer: a Phase II Study) and NCT04521348 (A Phase II Study to Explore the Safety and Efficacy of Multiple Target Kinase Inhibitor (mTKI) Combined With Anti-Programmed Death-1(PD-1) Antibody in the Treatment of Advanced Thyroid Cancer) trials A number of different new scenarios could be opened by combinations or sequential schemes with other anti-tumor treatment modalities Systemic chemotherapy has been proposed to exert synergistic effects when combined with PD-1/PD-L1 blocking drugs in non-small-cell lung carcinoma (33). Indeed, chemotherapeutic agents may affect antitumor immunity both indirectly stimulating the immune system through immunogenic death of tumor cells, and directly regulating immune cell subsets, thereby reducing immunosuppression in the tumor microenvironment (TME) (34) Second- or third-line treatment with ICIs has become increasingly common for patients with advanced disease who have already received other types of anticancer therapies (35) The therapeutic potential of FDA-approved atezolizumab, avelumab, ipilimumab and pembrolizumab has also been investigated in NENs other than MTC (39, 40) thereby confirming a strong interest for ICI therapy in this subset of tumors Despite the lack of evidence regarding the use of ICIs in MTC it should be considered that all the aforementioned RCTs saw first light in the last three years and hopefully from additional ones in the next future will help clarify whether these drugs may represent a new weapon in favor of patients with MTC and determine their position in the treatment algorithm AC and AF were responsible for the supervision All authors contributed to the article and approved the submitted version This work was supported by the Italian Ministry of Education University and Research (MIUR): PRIN 2017Z3N3YC The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest This review is part of the ‘Neuroendocrine Tumors Innovation Knowledge and Education’ project led by AC and AF which aims at increasing the knowledge on NET cytotoxic T-lymphocyte-associated protein 4; DoR Medullary Thyroid Carcinoma beyond Surgery: Advances Endocr Relat Cancer (2019) 26(9):R499–518 Endocrinol Metab Clin North Am (2019) 48(1):285–301 PubMed Abstract | CrossRef Full Text | Google Scholar Vandetanib in Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized Cabozantinib in Progressive Medullary Thyroid Cancer 5. 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Sergio Di Molfetta, cy5kaW1vbGZldHRhQGxpYmVyby5pdA== ‡These authors share first authorship Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Why does a small city in Italy have two teams in the same semi-professional league? This was my first question when I discovered that there was to be a city derby in the lowly Eccellenza Puglia division of Italian football As I entered the hospitality section and while eating a Neapolitan speciality accompanied with a traditional espresso I started speaking to fans and staff alike to help me understand why and how this has come to be Its history is varied and the locals are proud of past achievements but over the last few years The original association has been dissolved and then re-founded under a different name on multiple occasions due to financial and legal reasons all the while jumping from league to league as they start over and over again This sadly though is not unique to Molfetta In the lower and upper reaches of Italian football this has become far too common an occurrence But what is less common is a city starting a rival The current owner of Molfetta Sportiva is broadly speaking an unpopular figure due to his extreme hands on approach He runs the club from top to bottom and he seems to have control on every aspect of its running from fitness regimes to match day tactics to ticket prices it’s doubtful he works completely by himself and none of us are privy to what happens behind closed doors he seems to have the final say on all matters of importance who feel that such control in the modern game is unnecessary and maybe even fool hardy There is also a feeling that Molfetta Sportiva is no longer a club over which its fans have any influence and their opinion on matters is not heard a protest club called Molfetta Calcio was founded to try and make the people of Molfetta feel involved again and in turn to make them feel valued Molfetta Calcio aims to create a family friendly atmosphere with a temporary children’s area set-up on match-days with all citizens encouraged to come and be part of the day most of the information above I gained from speaking to locals and my own experiences Other people may have a different attitude and interpretation of events But what cannot be argued was the tension and electricity in the air for the first ever all Molfetta Debry Molfetta Calcio vs Molfetta Sportiva 1917 – November As the two teams came out there was a feeling of intrigue and curiosity their club song was played loudly over the PA system to pockets of applause and cheers The teams started to play and the fans were quiet for the most part But within the first 10 minutes a Molfetta Calcio player was sent off Screams and shouts filled the ground as the player walked off the field of play breaking any form of peace within the stadium the heavens opened and heavy rain drenched players and fans alike The first-half carried on in a balanced manner even with it being 10 against 11 a Molfetta Sportiva player struck a cross come shot which bounced off the left glove of the opposing goalkeeper and fell into the net almost hoping the referee would find a reason to disallow such a fortunate goal And with that the half came to a conclusion The second-half commenced and the action and conditions were similar to the first half Molfetta Calcio continued to push forward forcing Molfetta Sportiva’s goalkeeper into a number of fine saves But all of this impetus left space at the back leading to the next flash point of the game a second yellow for a Molfetta Calcio player leading to his marching orders Another unpopular but correct decision from the referee leaving the home team with nine men Rather than look to kill-off the game with a second goal Molfetta Sportiva dropped deeper in an attempt to frustrate their rivals This tactic invited pressure and Molfetta Calcio threw men forward in hope of scoring an unlikely equaliser And the pressure very nearly told when the home struck the post in the latter stages However their efforts were in vain and in the last few seconds things went from bad to worse for the new boys on the block as Molfetta Calcio sent off for stamping on another player It had been a true local derby in every sense of the word and Molfetta Sportiva had won its first ever edition There was almost a delayed reaction from the players in celebrating a first famous victory as the crowd’s frustration turned into fury The referee and his assistants quickly made their way off the pitch to a number of jeers and gestures As players and staff were walking down a staircase into the changing rooms agitating an already raucous crown further As players and coaches from both sides tried to act as peacemakers It was not clear what happened next but a small part of the crowd suddenly went wild with rage directing their venom towards one particular Molfetta Sportiva player who started to walk with purpose towards the spectators in question the music over the PA was increased to a deafening volume to drown out any chants or insults that were now raining down from the stands The other players of Molfetta Sportiva grabbed their teammate and forced him down the staircase ending the whole spectacle It was a game that will live long in the memory and if there wasn’t history for a rival in the truest sense before this game As I was walking back towards the car-park the over-riding feeling of the whole event was anger anger that a small city felt the need to create a protest club and that people were becoming less and less united one can’t help but feel this situation may not be for the greater good of Molfetta Comment * document.getElementById("comment").setAttribute( "id" "a51ede1cda7b83eef0ba2b740aa69135" );document.getElementById("bfea0afb7f").setAttribute( "id" and website in this browser for the next time I comment Δdocument.getElementById( "ak_js_1" ).setAttribute( "value" Continues to Expose Unscrupulous "Cancellation" Companies Preying on Timeshare Owners 2020 /PRNewswire/ -- Diamond Resorts® vacation ownership and entertainment industries has filed a lawsuit against a ring of so-called timeshare "exit" companies for allegations of fraudulent business practices and false advertising The 13 defendants are based in Florida and Nevada and include Timeshare Freedom Group The lawsuit alleges that the defendants use false and misleading advertising to convince timeshare owners to stop making payments on their timeshare contracts while charging the unsuspecting victims thousands — sometimes tens of thousands — of dollars in upfront fees in exchange for no legitimate service The Diamond Resorts complaint outlines how these Defendants falsely present their timeshare exit services as a "legal" solution This lie is supported by the use of lawyers and "law firms" to inaccurately suggest the active involvement of a licensed attorney the "exit" services offered by these companies amount to nothing more than instructing timeshare owners to cease making payments These companies do not deliver on their promises to help timeshare owners out of their contracts but instead charge thousands of dollars to drive owners into financial jeopardy and foreclosure Diamond Resorts is warning its owners not only about the illusory services offered by these companies but also about the deceptive way in which they collaborate to mislead and profit off of timeshare owners the timeshare cancellation ring operates as follows: About Diamond Resorts Diamond Resorts® offers destinations events and experiences to help members make a habit of breaking from the routine From unforgettable getaways to exclusive concert series to VIP receptions and dinners reconnect and remind each other what matters most customer service and flexibility means members can return to a favorite resort book a cruise to explore new countries or attend a once-in-a-lifetime event with the same level of confidence and anticipation With access to a world of entertainment and activities a Diamond membership ensures that people are always looking forward to vacation http://www.diamondresorts.com Do not sell or share my personal information: Pope Francis made a brief trip to southern Italy on Friday to commemorate the 25th death anniversary of a popular Italian bishop known for his pastoral zeal and works of peace The Pope flew to the towns of Alessano and Molfetta associated with Bishop Tonino (Antonio) Bello of Molfetta-Ruvo-Giovinazzo-Terlizzi whose cause for beatification was opened in 2007 The Pope left from Rome's Ciampino Airport to the Galatina military airport from where he boarded a helicopter to Alessano the town where Bishop Tonino was born and later buried Pope Francis visited the tomb of the bishop and met some of his relatives Pope Francis flew north to the port town of Molfetta He celebrated Mass in the cathedral and then headed back to Rome After attending school in his hometown from 1940 to 1945 he entered the seminary in Ugento and then at the Pius XI Regional Pontifical Seminary in Molfetta He then proceeded to Bologna for higher studies and completed his theology course at the Benedict XV Ponticial Seminary After his priestly ordination Bello was appointed vice-rector at the seminary of Ugento He later studied at Rome’s Pontifical Lateran University from where he obtained a doctoral degree He then served as an assistant to the Catholic Action organization rector of the seminary and administrator of the Sacred Heart parish of Ugento and parish priest in Tricase Pope John Paul II appointed him Bishop of Molfetta and Ruvo Bishop Bello renounced all signs of power and tried to help the most disadvantaged He ensured Caritas groups were established in every parish founded a community to help people with addictions and Venezuela where he visited immigrants from his diocese Bishop Bello is greatly known for his work with Pax Christi He was appointed the president of Pax Christi Italy in 1985 An outspoken critic of the Gulf War and other conflicts he led a group from Italy across the Adriatic to Sarajevo where he headed a peace march Bishop Bello envisaged the Church in “apron” evoking the image Christ at the Last Supper who tied a towel (apron) around his waist and got down on his knees to wash the feet of his disciples in a symbolic gesture of humble loving service Bishop Bello preferred to take a bus and often used a bicycle since he felt cars added to air pollution He died of stomach cancer in Molfetta on 20 April 1993 Pope Francis visited Alessano and Molfetta exactly on the 25th anniversary of the death of Bishop Tonino Bello Thank you for reading our article. You can keep up-to-date by subscribing to our daily newsletter. Just click here 2023 at 7:55 pm PT.css-79elbk{position:relative;}Jose Luisvallad Trujillo who has been in custody since his arrest in January 2018 was acquitted of attempted murder and a lesser charge jurors considered CA — A 50-year-old Orange County man was acquitted Tuesday of attempted murder in the shooting of a neighbor he sparred with over trash cans and parking He was also facing sentencing enhancements for the personal use of a firearm inflicting great bodily injury and discharge of a firearm causing great bodily injury and his clients in the city pitched in to cover his defense according to his attorney Michael Molfetta said "He's a handyman for two families in Laguna Beach and they paid for me," Molfetta said Jurors deliberated for about four hours before reaching verdicts in the 2100 block of South Orange Avenue in Santa Ana Molfetta argued his client acted in self-defense Trujillo had an ongoing conflict with Christian Cuellar over the placement of trash cans and parking Deputy District Attorney Neal Albright said in court papers Cuellar lived with his mother in the front house at 2114 S and the defendant lived in a back home at 2116 S Trujillo was getting ready to drive with his girlfriend and two children to school when the two got into a conflict over a trash can Trujillo grabbed a hatchet and swung it at Cuellar emerged with an AK-47 and shot Cuellar in the leg Trujillo ordered his girlfriend and the two children out of the car and drove away Trujillo told police that his neighbor had previously touted an association with a street gang and had threatened him Cuellar waved a gun at him and on that morning had made a motion with his hand miming a gun pointing at the defendant Molfetta said his client purposely shot Cuellar in the leg to avoid killing him "He purposely put one in his leg to stop him from advancing," Molfetta said Cuellar "is a complete waste of human skin In the past he "threw a knife at my client "And he threatened to shoot his kids with a motion of his hand." The defense attorney said one of the police investigators testified during the trial that he had never heard about the allegation of gang affiliation for the alleged victim "Law enforcement did absolutely nothing to look into if this kid was in MS-13," Molfetta said "They made a determination at the time and their narrative never swayed." Molfetta questioned Cuellar about a tattoo on his arm that read "La Vida Loco," he said "He said he just likes Ricky Martin," Molfetta said "I said name another song of his and he couldn't do it .. very emotional" when the verdict was announced Metrics details Mast cells (MCs) are multifaceted innate immune cells often present in the tumor microenvironment (TME) Several recent findings support their contribution to the transition from chronic inflammation to cancer MC-derived mediators can either favor tumor progression This apparent controversial role likely depends on the plastic nature of MCs that under different microenvironmental stimuli can rapidly change their phenotype and functions the exact effect of unique MC subset(s) during tumor progression is far from being understood Using a murine model of colitis-associated colorectal cancer we initially characterized the MC population within the TME and in non-lesional colonic areas by multicolor flow cytometry and confocal microscopy Our results demonstrated that tumor-associated MCs harbor a main connective tissue phenotype and release high amounts of Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α This MC phenotype correlates with the presence of high levels of Stem Cell Factor (SCF) and IL-33 inside the tumor we investigated the effect of SCF and IL-33 on primary MC cultures and underscored their ability to shape MC phenotype eliciting the production of pro-inflammatory cytokines Our findings support the conclusion that during colonic transformation a sustained stimulation by SCF and IL-33 promotes the accumulation of a prevalent connective tissue-like MC subset that through the secretion of IL-6 and TNF-α maintains a pro-inflammatory microenvironment the final redout may depend on the environment in which MC differentiates it is not only the tissue site but also the disease status that influences MC heterogeneity MCs have been also identified in different tumors, suggesting their contribution to cancer initiation and progression [28] a comprehensive description of how the intestinal tumor microenvironment (TME) shapes MC phenotypes and effector functions Using a mouse model of chemical-induced inflammatory colorectal cancer herein we report that CRC microenvironment is characterized by high amounts of SCF and IL-33 During the development of cancer under the action of SCF CTMCs accumulate in colonic lesions and despite a dramatic down-modulation of c-kit they are still capable of producing high amounts of pro-inflammatory cytokines when IL-33 and SCF were used in combination to stimulate primary MC cultures they can interact to additively provoke the production of pro-inflammatory cytokines Acute colitis and colonic adenomas were induced as schematized in Fig. S1A A Representative histochemical Toluidine Blue staining for MCs in the colon paraffin-embedded sections of untreated mice (Healthy) in the inflamed colon (Colitis) and inside the AOM/DSS-induced colorectal tumors (Tumor) acquired with 20× objective (Healthy and Colitis) or 10× and 40× (insert) objectives (Tumor) B Lamina propria cells were isolated by enzymatic digestion from colon of DSS-induced colitis mice (Colitis) and colon of untreated mice (Healthy) C Upon AOM administration and 4 cycles of DSS treatment colorectal tumors/polyps (Tumor) were dissected and tumor-infiltrating cells were isolated by enzymatic digestion Cells isolated from the tumor-free colonic counterpart of AOM/DSS treated mice were used as control (Tumor-free) C MCs were identified as c-kit/FcεRI double positive cells gated on CD45+/CD19−/CD3−/NK1.1−/CD11b− cells Representative dot plots (left panels) and number of MCs expressed as mean ± SD of the mice analyzed are shown (right panels) Each vertical bar is representative of 3 independent experiments with at least 2 mice/group D Cells were stimulated with PMA/Ionomycin for 2 h and the expression of TNF-α and IL-6 was analyzed on c-kit+FcεRI+ MCs by flow cytometry A representative dot plot is shown on the left The right histograms show the percentage of cytokine-positive MCs upon PMA/Ionomycin stimulation The percentages of IL-6/TNF-α double positive MCs are also shown Each graph is representative of 2 independent experiments with 5 mice/group Each symbol represents data obtained from an individual mouse and the same group of mice are indicated with the same symbol Paired Student’s t test **p < 0.01 and *p < 0.05 E Immunofluorescence of colon paraffin-embedded sections from AOM/DSS treated mice were stained with anti-MCP1 (upper panels) or anti-MCP4 (lower panels) Abs followed by Alexa Fluor 488 secondary Abs (green) Nuclei were counterstained with DAPI (blue) The frequencies of MCs positive for mMCP1 and mMCP4 proteases analyzed in 20 fields randomly acquired from three independent experiments with a total of 3 mice/group are shown (right panels) and classified as Tumor-free or Tumor based on normal or aberrant crypt architecture Unpaired Student’s t test *p < 0.05; **p < 0.01 MCs showing an activated phenotype and expressing mMCP4 expand in colonic lesions of AOM/DSS mice A SCF and IL-33 levels were analyzed by ELISA using lysates of colon tissues obtained from untreated mice (Healthy) DSS-treated mice (Colitis) and AOM/DSS treated mice (Tumor-free and Tumor) Cytokine concentrations are expressed as picograms of cytokine per microgram of total proteins in the tissue sample Means ± SD of three independent experiments are shown One-way ANOVA *p < 0.05; **p < 0.01; ****p < 0.0001 B Expression of c-kit and IL-33R was analyzed on AOM/DSS-induced colorectal tumors/polips (Tumor) compared with the tumor-free colonic counterpart (Tumor-free) colon of DSS-induced colitis mice (Colitis) and colon of untreated mice (Healthy) Mean fluorescence intensity (MFI) ± SD of the different analyzed mice are shown Each vertical bar is representative of two (IL-33R) or three (c-kit) independent experiments with at least 2 mice/group One-way ANOVA ***p < 0.001; ****p < 0.0001 MCs were differentiated in vitro from bone marrow precursors in the presence of IL-3 alone (30 ng/ml) or in combination with SCF (25 ng/ml) c-kit and IL-33R was analyzed by flow cytometry Representative histograms are shown in the upper panels while means +/- SD of three independent experiments are shown in lower panels B c-Kit expression levels were analyzed by real-time PCR c-Kit mRNA levels in BMMC differentiated with IL-3 alone was arbitrary set to 1 and results shown as fold change Interestingly, BMMCs differentiated in IL-3 alone and then subjected to short-term exposure with 25 ng/ml SCF showed a progressive loss of c-kit surface expression accompanied by a slight decrease in total protein levels (Fig. S4) likely due to a partial degradation of engaged receptor complexes (data not shown) MCs differentiated in the presence of IL-3 and SCF and then deprived of SCF overnight partially restored c-kit surface expression (data not shown) Regardless, c-kit downmodulation induced upon BMMC differentiation in the presence of SCF is accompanied by a defect in response to IgE and multivalent antigen stimulation both in term of degranulation and cytokine production (Fig. S5) SCF affects MC phenotype inducing c-kit downmodulation and a concomitant hypofunctional MC state in response to FcεRI engagement The presence of SCF during MC differentiation also induced a predominant connective-like phenotype characterized by high transcriptional levels of mMCP4, 5 and 6, while MCs differentiated in the presence of IL-3 showed a significant higher expression of mMCP1 transcripts, as revealed by RT-PCR (Fig. S6) BMMCs (A) were differentiated from BM-precursors cultured in the presence of IL-3 alone or in combination with SCF, as indicated in Fig. 4 while PDMC (B) were differentiated from isolated peritoneal committed MCs cultured in the presence of IL-3 (30 ng/ml) and SCF (25 ng/ml) for 10 days BMMCs and PDMC were stimulated with the indicated doses of IL-33 for 48 h and the expression levels of mMCP1 and mMCP4 mRNA transcripts were evaluated by real-time PCR A The amount of mRNA expressed in unstimulated BMMC differentiated with IL-3 alone was arbitrary set to 1 Means ± SD of three independent experiments are shown as fold change One-way ANOVA *p < 0.05; **p < 0.01; ***p < 0.001 B The amount of mRNA expressed in unstimulated PDMC was arbitrary set to 1 an increase in mMCP5 and mMCP6 expression levels were also seen on both BMMC and PDMC cultures (data not shown) these results demonstrate the capability of IL-33 to induce a connective tissue-like MC phenotype and suggest a combined action of SCF and IL-33 in shaping MC plasticity in vivo Next, we evaluated the capability of SCF and IL-33 to stimulate cytokine production in MC primary cultures (Fig. 5). BMMC differentiated in IL-3 + SCF and PDMC primary cultures were starved overnight from SCF and then stimulated with 100 ng/ml of IL-33 or SCF alone or in combination for 6 h in the presence of Brefeldin A TNF-α and IL-6 expressions were analyzed by flow cytometry on permeabilized cells Means ± SD of three independent experiments are shown as percentage of cells positive for the indicated cytokines One-way ANOVA *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 Those soluble factors can provoke a superimposable production of cytokines from both BMMC cultures regardless the hypofunctional state in response to FcεRI engagement previously observed on IL-3/SCF differentiated BMMCs PDMCs were able to produce higher amounts of cytokines compared to BMMC cultures in response to both stimuli used alone or in combination they responded very well to IL-33 stimulation alone producing high amount of IL-6 we found that the combined treatment with SCF and IL-33 increased cytokine production over the individual stimuli in all 3 types of primary MC cultures and that the most accentuated additive effect was observed for TNF-α BMMC and PDMC both differentiated in IL-3 (30 ng/ml) and SCF (25 ng/ml) were starved overnight from SCF prior stimulation with 100 ng/ml of IL-33 and/or SCF for 15 min Cells were lysed and equal amounts of total proteins were separated on gels run in parallel (SDS-PAGE) Levels of phosphorylated and total proteins were analyzed by western blot The pERK and ERK (PDMC) immunoblots are from the same gels but lanes were non-continuous Densitometric analysis of phosphorylated proteins was performed by FIJI software and normalized with the total protein amount Quantitative changes in protein phosphorylation upon different stimuli of three or five (for IkBα) different independent experiments are shown in the graphs All together these results demonstrate that IL-33 and SCF could activate selective biochemical pathways on primary MC cultures and suggest that their combined action is necessary to provoke a huge production of pro-inflammatory cytokines no data are available on SCF-dependent recruitment of a selective MC subset To investigate whether SCF neutralization reduces the accumulation/expansion of MCP4+ MC subset, mice were treated (i.p.) with isotype control IgGs (Ctrl-Ig) or SCF-neutralizing antibody before the beginning of the last DSS cycle, as schematically depicted in Fig. 7A. A Schematic representation of anti-SCF neutralizing Ab administration in vivo injected three times with anti-SCF or control Ab (100 μg/mouse) starting from the fourth DSS cycle Treated and control mice were sacrificed at 13 weeks from AOM administration B Colon paraffin-embedded sections from AOM/DSS mice treated with Ctrl-Ig or anti-SCF neutralizing antibodies as described in (A) were stained with anti-MCP4 Ab followed by Alexa Fluor 488 secondary Abs (green) Nuclei were counterstained with DAPI (blue) and images were acquired with a Zeiss LSM980 confocal microscopy using a 20× objective The frequencies of MCs positive for mMCP4 protease were analyzed in 20 fields randomly acquired from tumor lesions and shown as mean ± SD cells/field Number of adenomas and colon lengths are shown in (C) Graphs are representative of two independent experiments with a total of 5 mice/group B RNA-Scope assay for cytokines combined with immunofluorescence for MC proteases highlights cytokine production by mucosal and connective MC subsets The two MC subsets were immunostained for mMCP1 or mMCP4 while IL-6 and TNF-α mRNA expression was quantified by RNA-scope A Percentage of the two MC subsets (mMCP1 and mMCP4) negative or positive for the indicated cytokines was calculated on the basis of the following four-grade scoring system: score 0 Means ± SD of three independent experiments (30 cells/each exp) are shown Paired Student’s t test: *p < 0.05; **p < 0.01 B Low magnification images (20×) show MCs positive for mMCP1 or mMCP4 proteases (green) in transformed colon paraffin-embedded sections of AOM/DSS treated mice High magnification images (63x) show mMCP1 or mMCP4 MCs (green) double positive for IL-6 (white dots) and TNF-α (red dots) mRNA expression Means ± SD of two independent experiments (30 cells/each exp) are shown as percentage of MCs double positive for IL-6 and TNF-α mRNA expression (scores from 1 to 3) Altogether our findings suggest that the presence of SCF and IL-33 in CRC tissues favor the accumulation of a connective tissue-like MC phenotype which through the production of IL-6 and TNF-α contribute to the establishment of an inflammatory tumor microenvironment whether the MC phenotype is altered by the TME remains to be elucidated and the exact role of unique MC subset during tumor progression is far from being understood using a murine model of intestinal-type colon cancer we report the presence of high levels of SCF and IL-33 in the TME which coincides with the accumulation of TAMCs with a connective-like phenotype that through the production of TNF-α and IL-6 contributes to a pro-inflammatory environment Moreover, by combining in situ RNA hybridization with immunofluorescence, we firstly demonstrated that mMCP4+ MCs are the main subset responsible for cytokine production in tumor lesions (Fig. 8) The chronic exposure of TAMCs to both soluble factors likely explains the dramatic down-modulation of c-kit and the up-regulation of IL-33R that we have reproducibly observed (Fig. 2B) future in vivo experiments are required to further underscore the exact role of SCF and IL-33 in MC proliferation and/or MC progenitor recruitment and differentiation during CRC progression by generating primary cultures from bone marrow- or peritoneal-derived MC precursors we further investigated whether and how SCF and IL-33 regulate MC phenotype and functions SCF alone in addition to a strong phosphorylation of ERK1/2 observed on both BMMC and PDMC cultures, appears to be able to activate the PI3kinase pathway and to selectively induce STAT3 phosphorylation (Fig. 6) A plausible interpretation of our findings is that the amplified cytokine production observed by the combined action of SCF and IL-33 depends on the activation of common or unique but convergent signaling pathways All together our results underscore the ability of SCF in combination with IL-33 to shape phenotype and function of MCs that through the secretion of IL-6 and TNF-α may contribute to chronic inflammation and disease in the intestinal microenvironment no conclusive data exist about the role of a specific MC subset in the carcinogenesis process emphasizing the need to examine the impact of MCs and their proteases from different perspectives an open area of investigation remains if a common progenitor will generate distinct phenotypic and functional MC subsets and/or whether differentiated MCs may exhibit distinct features based on their responsiveness to SCF IL-33 and/or other specific microenvironment signals A deep dissection of MC phenotypic and functional plasticity could offer potential therapeutic targets during CRC progression Female C57BL/6J mice were purchased from Charles River (Wilmington MA) and were of 4- to 6-week old by the time of use weighing 20–25 g All animals were housed in ventilated cages (no more than 5 mice per cage) under specific pathogen‐free conditions and in a controlled environment (12-h daylight cycle lights off at 18:00) with free access to food and water Acute colitis was induced by feeding the mice with 2.5% (wt/vol) dextran sulfate sodium (DSS) (molecular weight 40,000 Da; Merck-Life Sciences Monitoring of the percent loss of body weight from day 0 was used to follow the disease course Four cycles of DSS allow the development of intestinal adenomas with a number of colonic tumors ranging from 5 to 12 adenomas Thirteen weeks later mice were sacrificed by cervical dislocation after anesthesia For blocking experiments, mice were i.p. injected with anti-SCF neutralizing antibody (AB-455-NA R&D Systems) or normal goat control IgG (AB-108-C R&D Systems) (100μg/mouse) three times every 10 days starting one day before the fourth DSS cycle (see Fig. 7A) All animal studies were conducted in accordance with all relevant ethical regulations for animal testing and research including the Italian code for the care and use of animals for scientific purposes The Italian Ministry of Health approved the use of animals for the induction of experimental colitis and colorectal cancer with DSS and AOM/DSS (Authorization n the large intestine was cut longitudinally along the main axis rolled up and immediately fixed in 4% PFA for 24 h Rolled colons were then extensively washed with PBS and embedded in paraffin deparaffinized in xylene and hydrated through a graded series of alcohol to water Staining with hematoxylin and eosin (Dako Agilent Pathology solutions CA) was performed under standard conditions Dehydration steps were performed with increasing concentrations of ethanol Sections were mounted with Entellan anhydrous mounting medium (Merck Life Sciences) and images were acquired using a Leica DM1000 microscope Negative controls were processed in the same manner but without primary antibody slides were dewaxed and rehydrated and stained with 0.5% w/v toluidine blue (Merck Life Sciences) in 1% Sodium chloride for 2–3 min and washed with distilled water Slides were dehydrated and mounted in Entellan mounting medium rehydrated and antigen-retrieval was performed in citrate buffer for 20 min at 100 °C Sections were incubated overnight at 4 °C with rat anti-mouse MCP1 Ab (E-bioscience) diluted in 5% normal goat serum or with goat anti-mouse MCP4 Ab (Abcam United Kingdom) diluted in 1% normal donkey serum after blocking with 10% of normal goat serum or normal donkey serum for 1 h AlexaFluor 488-conjugated goat anti-rat or AlexaFluor 488-conjugated donkey anti-goat (Thermo Scientific) Ab was used to reveal mMCP1 and mMCP4 AlexaFluor 647-conjugated donkey anti-goat Ab was used to reveal mMCP4 After counterstaining with DAPI (Thermo Scientific) for 15 min sections were mounted with Prolong Diamond antifade mounting solution (Thermo Scientific) Imaging was carried out with an inverted Olympus IX73 microscope equipped with a X-Light V3 spinning disk (Crestoptics Italy) using a Prime BSI Express Scientific CMOS camera Images of the entire tissue sections were collected as 2048 × 2048 pixel files by using a UPLANFL 20×/0.45NA objective (Olympus Japan) and MetaMorph V7.8.0 software (Molecular Devices CA) and then processed with Fiji ImageJ software The number of MCs was automatically analyzed in each image using Fiji software images were acquired with Zeiss LSM980 confocal microscope using a 20×/0.8NA objective (Zeiss RNAscope was performed using RNAscope Multiplex Fluorescent V2 Assay (ACDBio MN) combined with immunofluorescence according to the manufacturer’s instructions sections were deparaffinized and hydrated followed by Hydrogen Peroxide treatment for 10 min at room temperature To improve RNA exposure tissues were immersed in 1X antigen retrieval 20 min 100 °C in the steamer and transferred to 100% ethanol for 3 min Protease plus solution was incubated for 30 min at 40 °C before RNA probes (Mm-TNFα Amplification steps were performed following the manufacturer’s instructions and TNF-α mRNA signal was revealed by HRP-C1 incubation 15 min at 40 °C followed by Opal690 fluorophore 30 min at 40 °C while IL-6 signal was revealed by HRP-C2 followed by Opal570 fluorophore All incubations were performed in a pre-warmed HybEZHumidity Control Tray mMCP1 and mMCP4 immunofluorescent staining was performed on the same sections Slides were then counterstained with DAPI and mounted with Prolong Diamond mounting medium Confocal images were acquired with a Zeiss LSM980 confocal microscope using a 63×/1.35NA oil-immersion objective (Zeiss The pinhole was set at one Airy unit and 3 sequential scans were created to avoid overlapping spectra Z-stack acquisition (0.2 μm step) was performed based on mMCP1/MCP4 signal at 4 μs/pixel with 2 frames averaging and bidirectional scanning All quantified images were acquired by using identical confocal settings Projected images were generated from unprocessed z-stacks and puncta count was performed using Fiji ImageJ software (NIH) Regions of interest (ROI) were created based on mMCP1/MCP4 signals and the number of puncta in each ROI was automatically analyzed Cytokine-producing cells were identified according to a scoring system described in the ACDBio protocol the four-grade scoring system was defined as: score 0 Cells with score 0 were considered negative for cytokine expression Score from 1 to 3 is a measure of increased cytokine production Cells were considered double positive for IL-6 and TNF-α expression if at least two dots of each cytokine/cell were revealed cut longitudinally upon flushing the luminal contents and incubated in 5 mM EDTA and 10 mM Hepes at 37 °C for 30 min to remove the epithelial layer Lamina propria leukocytes were isolated by mechanical dissociation and enzymatic digestion in RPMI medium containing 0.5 mg/ml DNase I and 0.25 mg/ml Liberase TL (Merck Life Sciences) for 30 min at 37 °C and strained (100-µm filter) Leukocytes were enriched using 40% Percoll (Merck Life Sciences) Tumor-infiltrating leukocyte were isolated with the same protocol except for EDTA/Hepes step The following Abs were used for flow cytometric analysis: anti-CD3-FITC; anti-CD19-FITC; anti-NK1.1-FITC; anti-cKit-APC (clone 2B8); anti-cKit-PE (clone 2B8); anti-FcεRIα-PE-Cy7 anti-FcεRIα-Pacific blue (all from Biolegend MA); anti-CD11b-FITC and anti-CD45-PerCP-Cy5.5 (from Thermo Scientific); anti-IL-33R PE (BD Biosciences Dead cells were excluded using APC-H7-conjiugated Fixable viability Dye (Thermo Scientific) isolated cells were treated with Cell Stimulation Cocktail (ThermoFisher) stained for cell surface markers and then fixed and permeabilized using the Cytofix/cytoperm kit (BD Biosciences) before intracellular staining with anti-TNF-α-PE-Cy7 and anti-IL-6-APC Samples were acquired by FacsCantoII and Flow cytometric analysis was performed with FlowJo 10 software (BD Bioscience) and a 1 cm of tissue was homogenized in 500 μl PBS containing protease inhibitors (Thermo Scientific) and Triton X-100 at the final concentration of 1% thawed and centrifuged at 13,000 rpm 15 min 4 °C to remove particulates Protein concentration was assessed by Bradford assay MN) were used to quantify IL-33 and SCF according to the manufacturer’s instructions Bone marrow cells were isolated from femurs of C57BL/6 mice and supplemented with 10% Fetal Calf Serum (FCS) 1% glutamine and with 30 ng/mL recombinant murine IL-3 (Peprotech United Kingdom) alone or together with 25 ng/mL recombinant murine SCF (Peprotech) at 37 °C under 5% CO2 Cultures were passaged every 3 days by resuspending the pelleted cells in fresh culture medium at a concentration of 1 × 106/ml BMMC purity was evaluated by flow cytometry as the percentage of FcεRI and cKit double-positive cells using anti-cKit-APC-H7 (BD Biosciences) and anti-FcεRIα-Pacific blue (Biolegend) Abs BMMCs were used at a purity of more than 90% To differentiate MCs from peritoneal precursors peritoneal cavity lavage with 5 ml of cold PBS was performed to euthanized WT mice then cultured 1 × 106/ml cells in complete RPMI medium nonadherent cells were removed and fresh culture medium was added to adherent cells The same procedure was repeated twice a week for two weeks MC purity was evaluated by flow cytometry and cultures more than 90% double positive for FcεRI and c-Kit were used for in vitro experiments primary MC cultures were starved overnight in RPMI complete medium supplemented with 15 ng/ml IL-3 and then treated with 100 ng/ml of IL-33 and/or SCF alone or in combination in the presence of Brefeldin A 5 μg/ml (Merck Life Sciences) for 6 h at 37 °C fixed and permeabilized using Cytofix/Cytoperm kit (BD Biosciences) and then stained with anti-TNFα-PECy7 and IL-6-APC Abs Immunoreactive bands were visualized on the nitrocellulose membranes using horseradish-peroxidase-linked/coupled donkey anti-rabbit or sheep anti-mouse IgG (GE Healthcare CA) based on manufacturer’s instructions and exposed to Invitrogen iBrightTM Imaging Systems (Thermo Scientific) anti-pp44/42 (ERK1/2) (T202/Y204) and anti-P44/42 (ERK1/2) (all from Cell Signaling MA); anti-Ikb-α (Santa Cruz Biotechnologies Densitometric analysis was performed using FIJI Image J software BMMCs were sensitized with 1 μg/mL IgE for 1 h at 37 °C in complete media Cells were washed twice with Tyrode’s buffer (10 mM Hepes buffer pH 7.4 5.6 mM glucose and 0.1% bovine serum albumin) and plated in 96-well plates at 3 × 106/mL in 100 μL of Tyrode’s buffer Cells were then treated with DNP-HSA (100 and 1000 ng/mL) for 30 min at 37 °C The enzymatic activity of β-hexosaminidase in supernatants and cell pellets was measured with p-nitrophenyl N-acetyl-D-glucosaminide (NAG) in 0.1 M sodium citrate for 30 min at 37 °C The release of the product 4-p-nitrophenol was detected by absorbance at 405 nm Student’s t test and one-way ANOVA followed by Tukey’s multiple-comparisons tests were used to quantify statistical deviation between experimental groups *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 All data generated or analyzed during this study are included in this published article and its supplementary information files Mast cells signal their importance in health and disease Protective and pathological roles of mast cells and basophils Regulation of mouse and human mast cell development Regulation of mast-cell and basophil function and survival by IgE Regulation of the pleiotropic effects of tissue-resident mast cells Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family Mast cells as sensors of cell injury through IL-33 recognition IL-33 and thymic stromal lymphopoietin in mast cell functions Interleukin 33 is a guardian of barriers and a local alarmin Murine mast cells secrete and respond to interleukin-33 Interleukin-33 exacerbates allergic bronchoconstriction in the mice via activation of mast cells The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells IL-33 induces a hyporesponsive phenotype in human and mouse mast cells IL-33 fine tunes mast cell degranulation and chemokine production at the single-cell level Yin-Yang of IL-33 in Human Skin Mast Cells: Reduced Degranulation but Augmented Histamine Synthesis through p38 Activation Developmental origin and functional specialization of mast cell subsets Mast cell secretory granules: armed for battle Protease phenotype of constitutive connective tissue and of induced mucosal mast cells in mice is regulated by the tissue Phenotypic and functional plasticity of cells of innate immunity: macrophages Expression profiling of constitutive mast cells reveals a unique identity within the immune system Delayed expulsion of the nematode Trichinella spiralis in mice lacking the mucosal mast cell-specific granule chymase Mouse mast cell tryptase mMCP-6 is a critical link between adaptive and innate immunity in the chronic phase of Trichinella spiralis infection Mast cells as targets for immunotherapy of solid tumors Role of mast cells in colorectal cancer development Chemically induced mouse models of acute and chronic intestinal inflammation KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes IL-33/ST2 pathway contributes to metastasis of human colorectal cancer c-Kit as a Novel Potential Therapeutic Target in Colorectal Cancer IL-33 activates tumor stroma to promote intestinal polyposis Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer Syk-dependent regulation of Hrs phosphorylation and ubiquitination upon FcεRI engagement: impact on Hrs membrane/cytosol localization Immune complexes exposed on mast cell-derived nanovesicles amplify allergic inflammation an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines IL-33 induces IL-13 production by mouse mast cells independently of IgE-FcepsilonRI signals SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment basophils and eosinophils: From allergy to cancer Mast cell-tumor interactions: molecular mechanisms of recruitment intratumoral communication and potential therapeutic targets for tumor growth Decreased susceptibility of mast cell-deficient Kit(W)/Kit(W-v) mice to the development of 1 2-dimethylhydrazine-induced intestinal tumors Mast cells infiltrating inflamed or transformed gut alternatively sustain mucosal healing or tumor growth Mast cell modulates tumorigenesis caused by repeated bowel inflammation condition in azoxymethane/dextran sodium sulfate-induced colon cancer mouse model A protective role of mast cells in intestinal tumorigenesis Mast Cell-Dependent CD8+ T-cell Recruitment Mediates Immune Surveillance of Intestinal Tumors in ApcMin/+ Mice Mast cells inhibit colorectal cancer development by inducing ER stress through secreting Cystatin C Mast cell-T cell axis alters development of colitis-dependent and colitis-independent colorectal tumours: potential for therapeutically targeting via mast cell inhibition The controversial role of intestinal mast cells in colon cancer Mast cells are an important cellular source of tumor necrosis factor α in human intestinal tissue Mast cells are an essential hematopoietic component for polyp development Prevention of colitis-associated carcinogenesis with infliximab Mast cells promote small bowel cancer in a tumor stage-specific and cytokine-dependent manner Cell intrinsic deregulated ß-catenin signaling promotes expansion of bone marrow derived connective tissue type mast cells KIT as a master regulator of the mast cell lineage IL-33/ST2 axis promotes mast cell survival via BCLXL Interleukin-33 promotes the proliferation of mouse mast cells through ST2/MyD88 and p38 MAPK-dependent and Kit-independent pathways Differential expression of secretory granule proteases in mouse mast cells exposed to interleukin 3 and c-kit ligand Synovial fibroblasts promote the expression and granule accumulation of tryptase via interleukin-33 and its receptor ST-2 (IL1RL1) Effects of chronic treatment with the c-kit ligand on immunoglobulin E-dependent anaphylaxis in mice Genetically mast cell-deficient Sl/Sld mice acquire anaphylactic responsiveness but the congenic normal mice do not exhibit augmented responses Stem cell factor programs the mast cell activation phenotype novel mediators of SCF-induced signalling and potential targets for c-Kit-driven diseases Prognostic significance of cell infiltrations of immunosurveillance in colorectal cancer Tumor-infiltrating tryptase+ mast cells predict unfavorable clinical outcome in solid tumors mast cells positive to tryptase and microvascular density in colo-rectal cancer patients: possible biological-clinical significance Notch3 contributes to T-cell leukemia growth via regulation of the unfolded protein response Lipid raft-dependent FcepsilonRI ubiquitination regulates receptor endocytosis through the action of ubiquitin binding adaptors The Ubiquitin-proteasome pathway regulates Nectin2/CD112 expression and impairs NK cell recognition and killing Download references The authors thank the Center for Life Nano- & Neuro-Science (CLN2S) of the Istituto Italiano di Tecnologia (IIT where the fluorescent images were collected This work was supported by grants from the Italian Association for Cancer Research (AIRC IG 2020-ID 24955-P.I: Paolini Rossella; MFAG-21311; 5×1000-21147) and the Istituto Pasteur Italia-Fondazione Cenci Bolognetti (2020-366) Gianluca Scarno is Supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship Present address: Leibniz Institute for Immunotherapy-Division of functional immune cell modulation Present address: Human Oncology and Pathogenesis Program These authors contributed equally: Mario Lecce Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Department of Biology and Biotechnologies “Charles Darwin” and EP performed most experiments with the assistance of GP MM and TS helped with immunofluorescence and RNAscope experiments on tissue sections analyzed and interpreted the data with the collaboration of EDS RP wrote the manuscript with the assistance of RM All authors had the opportunity to discuss the results and comment on the manuscript The authors declare no competing interests The Italian Ministry of Health approved the use of animals for the induction of experimental colitis and colorectal cancer with DSS and AOM/DSS (Authorization no Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41419-023-06139-7 Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. 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Or sign-in if you have an account It’s always enlightening to discover and explore how today’s garden designs are evolving and moving in new directions A lecture by two renowned landscape architects on Oct 28 at Vancouver’s Robson Square was a great opportunity to learn more about some new ecological landscape trends Subscribe now to read the latest news in your city and across Canada Create an account or sign in to continue with your reading experience SALA Garden Design Lecture committee and their sponsors bring in notable designers from around the world to share new perspectives with our local landscape architect community as well as with landscape architect students and those already established in the industry who live in Switzerland and work throughout Europe gave a leading-edge presentation on the new design benefits of connecting nature and the changing climate to each project This could well be the future of garden design Start your day with a roundup of B.C.-focused news and opinion By signing up you consent to receive the above newsletter from Postmedia Network Inc The next issue of Sunrise will soon be in your inbox Interested in more newsletters? Browse here. Both Strode and De Molfetta bring a lot to the table in terms of horticultural architecture. She practises not only as an architect but also lectures and teaches landscape architecture in Italy, Switzerland and the U.S. Federico, in addition to his landscape architectural skills, has worked for the Lisbon Botanical Garden and for the Arnold Arboretum in the U.S. I enjoyed the opportunity to speak with them a few days after their lecture to get a better sense of how they approach their design process. I asked Strode about the opportunities for landscape architect students. She talked about the diversity of her students, both in age and demographics, and she pointed out she is seeing a good number of international students and slightly more females than males, which follows a similar trend in North American universities. We also talked about the important role of landscape architecture in our communities, and she spoke very eloquently on the significant value good design brings to any landscape. Strode pointed out that the many layers of communication, between all parties involved in any broader community project, is vital. Dialogue is so important. Asking the right questions and listening to all points of view provide a better understanding of the core values and goals of each project. Strode and De Molfetta are very much leading-edge when it comes to incorporating ecological design and adapting to a rapidly changing climate. One of the many challenges they face is the public’s acceptance of less-structured, ecological design, as opposed to a more traditional, neat and tidy look. During their lecture, they didn’t have enough time to talk about the pollinator and wildlife connection to their work, so I asked De Molfetta how this factor played a role. He explained that, if their design was implemented in the way they proposed, any wildlife inhabiting the edge of their designed plantings, whether along the perimeters of a forest or grasslands, they would find a great new place to reside and would begin populating the new landscaping. When starting a new project, De Molfetta noted that one of the first issues he looks at is drainage. With more extreme weather patterns, he believes this is an essential first step. Understanding how and where water flows is critical and capturing it for use in the landscape is very much a part of their design. As the climate becomes warmer, tree canopy cover is also a very important issue. Strode and De Molfetta are a very special team. They are guiding landscape architecture in a new direction. They not only design and adapt their designs on-site but revisit their sites over time to see the results of their incredible planning process. They harmonize sites by bringing together the culture and ecology of each area and by adapting it to the new reality of our changing climate. It was a brilliant lecture and a delight to meet this incredibly talented couple. transmission or republication strictly prohibited This website uses cookies to personalize your content (including ads), and allows us to analyze our traffic. Read more about cookies here. By continuing to use our site, you agree to our Terms of Use and Privacy Policy You can manage saved articles in your account and the suggestion that Skaggs pitched in a game while high But it was more of a tease of what is to come Tuesday when Harvey is scheduled to testify The former All-Star is expected to face blistering questions about his own history of drug use Molfetta did not suggest Monday that Harvey gave Skaggs the drugs that contributed to his death But the defense team wants to establish that Skaggs got opioids from multiple sources for years and might have gotten that July 2019 supply from someone besides Kay the former Angels communications director who is on trial for Skaggs' death The revelation about Harvey came on what was by far the most eventful day of the week-old trial the jury heard from a friend of Skaggs' named Chris Leanos The government brought Leanos to testify that he was not in California in the days before the trip to Texas on which Skaggs died intending to eliminate Leanos as a potential source of the drugs Skaggs took when he died Leanos also testified that he once saw what appeared to be a drug transaction between Kay and Skaggs at a team charity event at Disneyland after which Skaggs disappeared into a men's room Leanos said the transaction looked "odd" and that he guarded the door until Skaggs emerged he said he believed Kay had given Skaggs drugs and Skaggs had used them But Leanos left plenty of land mines for the prosecution testified that he received a text from Skaggs "a week or two" before the pitcher's death with a request for oxycodone that he does not sell opioids and that he told Skaggs to stay away from them because of the danger he told Skaggs' family about the text and then deleted it at the request of Skaggs' stepbrother Molfetta asked Leanos how many times since 2018 he had sold each drug in his repertoire "That's 240 to 250 drug transactions in last three years yet you get a deal from the government that says you can sit and admit to literally killing anybody" -- at which point the government objected Leanos has not been accused of killing anyone Molfetta repeated that Leanos hypothetically could admit to murder on the stand and not be prosecuted "And they wanted you to talk about that one transaction at the house of the mouse "And that I was out of town" when Skaggs left for Texas Leanos also admitted to bringing small amounts of cocaine and MDMA to Skaggs' 2018 bachelor party in Las Vegas at Skaggs' request police detective testified that when Kay was interviewed the day Skaggs died he lied about both having been in Skaggs' room and Skaggs' history of drug use • The government introduced extensive evidence of Kay's seeking opioids through the online marketplace app OfferUp in which he repeatedly said he wanted to avoid anything with fentanyl • The government also established numerous Venmo payments from Skaggs and pitcher Garrett Richards to Kay • After the government established that Leanos could not have gotten from Arizona to Anaheim in time to meet Skaggs before the team flight took off the defense raised the possibility that Leanos had a window to meet him at Long Beach Airport Drug Enforcement Administration agent said they had not investigated that possibility The "Ben R" who exchanged texts with Skaggs the day before he died a woman who had sent a selfie during a mildly flirtatious exchange She testified that she did not have an "inappropriate relationship" with Skaggs and that she did not know why he had her listed as "Ben R" in his contacts Kay's assistant in 2019 and his replacement as communications director testified that in the days after Skaggs' death an intoxicated Kay confessed that he had been with Skaggs the night he died Chodzko said Kay told him that he did not use that night and that whatever drugs Skaggs had were already in his room when Kay arrived he told team president John Carpino what had happened and then took Kay to a rehabilitation facility Harvey is expected to tell jurors that he did provide Skaggs with drugs on occasion but not the ones that contributed to his death Harvey was on the team's injured list and did not make the trip to Texas The day ended with an unusual rebuke of the government The last witness was a cardiologist who was on the stand for 20 minutes to say that Skaggs did not die from a heart issue but prosecutors apparently were concerned that jurors could be confused by lines in Skaggs' autopsy that said he had some thickening in his heart Previous testimony established that it was perfectly normal for a professional athlete but tomorrow are you going to bring another doctor to say he didn't die of cancer And then a nephrologist to say it wasn't his kidneys?" He admonished them that if they run out of their allotted 20 hours of time they won't get more and "it will be your own fault." The defense rested Wednesday after presenting a brief case and closing arguments are scheduled for Thursday morning 10 women and two men will decide whether the government proved that Kay distributed the opioid fentanyl Before wrapping its case, the defense called a fifth player to the stand to testify about his own drug use, free-agent pitcher Blake Parker who played with the Angels for one season in 2018 was in tears when he took the stand in the afternoon although he was composed when questioning began He said he had received oxycodone pills from Kay but couldn't remember if Skaggs introduced the two men "I don't remember who told me that he was 'the man,'" Parker said Defense attorney Michael Molfetta asked Parker several times if he remembered telling police that Kay felt pressured to provide drugs to the players "Do you remember a conversation with Mr Kay about his desire to stop doing drugs?" Molfetta said "Do you remember him saying it's hard to do because 'those guys keep banging on me for more pills?'" Molfetta asked "What I remember is it was more that he didn't want to get involved with the people he had to get involved with to get the pills." Molfetta continued to press Parker about what he said to police that he stopped asking Kay for pills once he knew Kay was trying to get clean I don't want to put him in a bad spot so why would I try to get him to get me something he didn't want to use himself,'" Parker said The morning began with testimony from Skaggs' stepbrother whom the defense called to ask about Skaggs' early use of oxycodone and the allegation that Ramos deleted texts from Skaggs' phone after the pitcher died The defense had trouble tracking him down last week and when Ramos took the stand he said that an aggressive form of multiple sclerosis made it hard for him to remember past events Molfetta asked Ramos repeatedly if he remembered providing Skaggs with oxycodone to help wean the pitcher off Percocet in 2013 testified last week that her son told family members he had "an issue" with the opioid painkiller that year Ramos answered Molfetta's questions as literally as possible he did not "buy" Skaggs pills to help him wean off Percocet "I helped Tyler wean off with the pills he gave me that he said he was taking." Ramos apparently told a grand jury that he gave Skaggs half of a round blue pill twice a day in order to help him break his Percocet habit but said Wednesday he couldn't remember saying that despite getting a chance to review his grand jury testimony the defense submitted the relevant lines from that grand jury testimony into evidence Both said Skaggs did tell them that at some point but that they believed he did not end up going out Sign up for the Morning Brief email newsletter to get weekday updates from The Weather Channel and our meteorologists.​ Climate change is sending green monk parakeets to the Italian countryside leading them to take over in droves and wreak havoc on the environment The South American birds are not native to Italy, but were released by pet owners and escaped from aviaries decades ago The birds have thrived in the Italian climate becoming a marvel of Rome as well as the city of Molfetta But now, as the climate tropicalizes, the birds are on the move, causing issues in cities and countrysides such as Bari, Bisceglie, Giovinazzo, Palese, Santo Spirito and beyond (​MORE: Delicious Disaster: Crabs Invade Italy) The damage is most evident at Puglia almond groves, where the parakeets feast on the nuts, which are already facing historically low production due to climate change Fruit farmers have felt the impact of the birds as well The birds also pose a health threat to livestock and humans with the potential to transmit diseases such as psittacosis (known as “parrot fever”) a University of Kent project dedicated to the study of invasive parrots in Europe Italy isn’t the only country to play host to these unwelcome invaders. Hoards of monk parakeets have caused issues in Brooklyn, Chicago, New Orleans, Madrid, Barcelona and parts of Mexico, as well as other locales. And monk parakeets aren’t the only parrot species taking over, though a 2021 study found monk parakeets to be the most destructive invasive parrot species to crops They are also one of the most successful invasive bird species (​MORE: Alabama Teen, Teacher Find 30-Million-Year-Old Whale Skull) Europe’s parakeet invasions are expected to worsen as climate change creates a warmer climate. A warmer climate facilitates the spread of invasive parakeet species, and agricultural adaptations to climate change will mean a focus on producing more crops that the birds happen to thrive on, such as corn, nuts and sunflowers In recent years, Madrid has made an effort to cull the monk parakeet population, facing an outcry from activists. ParrotNet’s research pays special attention to the monk parakeet and notes that culling is an unpopular solution because of the public’s affinity for the green birds The parakeet population in Italy’s countryside has only recently gained traction with organizations that support farm workers and agriculture, such as Coldiretti Puglia. The problem has become a major talking point in the region within the last month, with government officials speaking out in hopes of a solution to the growing problem Senior editor Nicole Bonaccorso works as weather.com's photo editor and writes about breaking news The Weather Company’s primary journalistic mission is to report on breaking weather news the environment and the importance of science to our lives This story does not necessarily represent the position of our parent company We recognize our responsibility to use data and technology for good We may use or share your data with our data vendors The Weather Channel is the world's most accurate forecaster according to ForecastWatch, Global and Regional Weather Forecast Accuracy Overview Sign up for the Morning Brief email newsletter to get weekday updates from The Weather Channel and our meteorologists.​ The South American birds are not native to Italy, but were released by pet owners and escaped from aviaries decades ago But now, as the climate tropicalizes, the birds are on the move, causing issues in cities and countrysides such as Bari, Bisceglie, Giovinazzo, Palese, Santo Spirito and beyond (​MORE: Delicious Disaster: Crabs Invade Italy) The damage is most evident at Puglia almond groves, where the parakeets feast on the nuts, which are already facing historically low production due to climate change The birds also pose a health threat to livestock and humans with the potential to transmit diseases such as psittacosis (known as “parrot fever”) Newcastle’s Disease and avian influenza (​MORE: Alabama Teen, Teacher Find 30-Million-Year-Old Whale Skull) Europe’s parakeet invasions are expected to worsen as climate change creates a warmer climate. A warmer climate facilitates the spread of invasive parakeet species, and agricultural adaptations to climate change will mean a focus on producing more crops that the birds happen to thrive on, such as corn, nuts and sunflowers and notes that culling is an unpopular solution because of the public’s affinity for the green birds The parakeet population in Italy’s countryside has only recently gained traction with organizations that support farm workers and agriculture, such as Coldiretti Puglia. The problem has become a major talking point in the region within the last month, with government officials speaking out in hopes of a solution to the growing problem Senior editor Nicole Bonaccorso works as weather.com's photo editor and writes about breaking news The Weather Company’s primary journalistic mission is to report on breaking weather news \\nGreen Parakeets Overwhelm Parts Of Italy The Society was incorporated in the State of New Jersey on October 31 Ann’s Parish up to 1938 when the feast was moved to an open field in Moonachie returning back to St With the arrival of a new Statue in 1948 the Society then switched affiliations to St Francis Church where the Statue currently resides under the leadership of President Corrado DePinto and Chairman Anthony Cilento (Honorary President,) arranged to buy the property at 332 Adams St. Over the years the Society’s membership has swelled and contracted but the goal was always to produce the best Feast possible The decade between the mid-sixties through the late seventies seemed to be the height of popularity Buses of the Faithful would come to the celebrations Many dignitaries from Molfetta would come to Hoboken to add to the celebration we have enjoyed the company of the Papal Nuncio to the United Nations During the 1980’s Hoboken was changing and no longer was a first destination for immigrants The Italian community began to move out to the suburbs and the crowds that were once a certainty no longer could be counted upon The Feast was traditionally held on Labor Day week-end Many in the Molfettese Community chose to stay “Down the Shore” thereby diminishing the tradition further During these years a handful of Societa’ members kept the Tradition going Without these members our Tradition would have gone the way of other Hoboken feasts namely; Santa Febronia Our Lady of Mount Carmel and Our Lady of Montevergine which was the last of the feasts not emanating directly from a church The few most responsible members were; Vincenzo “Jimmy” DePinto During this time the only other Feast was that of Saint Ann which was experiencing a rebirth of interest the festival had grown in popularity and success Many in the Molfettes community would ask rhetorically “Why can’t we be as successful?” It was around 1996 when a few new younger gentlemen began to join the Society With the cooperation of the “old guard” a few changes were implemented to try to bring the Feast to the Level of success that it once enjoyed The first changed happened in 1998 when the week-end of the Feast was changed to the following week after Labor Day When this failed to turn the tide it was decided to remodel the entire Feast to attract patrons from outside of the Molfettese Community It was agreed to move the festival to Sinatra Park and promote it as The Hoboken Italian Festival in honor of Madonna Dei Martiri It was hoped that it would attract crowds and sponsors The entire plan was based on attracting a different audience each of the 4 nights All of this was planned so that Saturday would be “our day,” with the Mass and Procession and fireworks on the Hudson Trying to be as true to the Feast in Molfetta as possible the Procession went right up to a waiting boat where the statue was loaded along with the faithful and cruised in the Hudson River just like it is does in Molfetta That day in 1999 was truly a turning point for the Feast ensuring that it will go on for many years to come It was estimated that over 45,000 people attended gratification was the enormous turn out of Molfettese who came back “I have not seen my Madonna on the water since I was little back in Molfetta.” Since that watershed year the festival has grown in success and the Societa’ has enjoyed a rebirth of members ensuring the future of this Beautiful Tradition Welcome to IPE Real Assets. This site uses cookies. Read our policy CBRE Global Investors has acquired the company owning the Gran Shopping Mongolfiera Molfetta in Italy from Orion Capital Managers and HB Capital The asset was purchased on behalf of the CBRE European Shopping Centre Fund II (ESCF II) from the Orion Income Return Partners fund Although financial details were not disclosed the asset is understood to have been sold by Orion for a price in excess of its acquisition price from developer Foruminvest in 2013 of €135 mln The shopping centre is located in Molfetta north of the town of Bari and has a catchment area of over 250,000 inhabitants 'Gran Shopping Mongolfiera Molfetta is a leading shopping destination with high and stable occupancy rates driven by strong tenant demand We are very pleased to have been able to secure this acquisition for ESCF II,' commented Alberico Radice Fossati including a mall and hypermarket (which is not part of the transaction) and is fully let to international tenants that include Zara It is the dominant shopping destination within the area and has 2,500 parking spaces 'The fund concentrates on buying assets that are dominant within their catchment area and provide an attractive combination of stable income streams and growth potential; Mongolfiera is an excellent example of this,' said Toby Smith 'It is also one of the final acquisitions for the fund which is expected to have 12 assets under management in total with a total Fund GAV of c.€1.3 bn when fully invested,' added Smith Date: 1 March 2018 Location: Dentons - Italy PropertyEU's latest Italian morning discussion panel is hosted by Dentons in Milan on 1 March 2018. Come to this time-efficient briefing hear the view of market-leading experts and get to ask your own questions Attendance is free but registration is essential Click here for informaton on the speakers and to secure your place Copyright © 1997–2025 IPE International Publishers Limited Site powered by Webvision Cloud Volume 10 - 2019 | https://doi.org/10.3389/fimmu.2019.02557 This article is part of the Research TopicMolecular Strategies Aimed to Boost NK Cell-based Immunotherapy of CancerView all 11 articles Efficient clearance of transformed cells by Natural Killer (NK) cells is regulated by several activating receptors Expression of these receptors as well as their specific “induced self” ligands is finely regulated during malignant transformation through the integration of different mechanisms acting on transcriptional the release of activating ligands in the extracellular milieu through protease-mediated cleavage or by extracellular vesicle secretion represents some relevant cancer immune escape processes covalent modifications including ubiquitination and SUMOylation also contribute to negative regulation of NKG2D and DNAM-1 ligand surface expression resulting either in ligand intracellular retention and/or ligand degradation All these mechanisms greatly impact on NK cell mediated recognition and killing of cancer cells and may be targeted to potentiate NK cell surveillance against tumors Our mini review summarizes the main post-translational mechanisms regulating the expression of activating receptors and their ligands with particular emphasis on the contribution of ligand shedding and of ubiquitin and ubiquitin-like modifications in reducing target cell susceptibility to NK cell-mediated killing Strategies aimed at inhibiting shedding of activating ligands and their modifications in order to preserve ligand expression on cancer cells will be also discussed Natural Killer (NK) cell activation is tuned by the integration of signals derived from inhibitory receptors for Major Histocompatibility Complex (MHC) class I molecules and from activating receptors that bind either non self-molecules associated to pathogens or self-molecules up-regulated in stress conditions including malignant transformation (1, 2) DNAM-1 belongs to the immunoglobulin receptor family and is expressed not only on NK cells but also on monocytes, T cells, and subsets of B cells (14, 20, 21). It binds to Nectin2/CD112 and PVR/CD155 both members of the Nectin/Nectin-like family of adhesion molecules (22–24) and it associates with the integrin LFA1 to transduce intracellular signals Natural cytotoxicity receptors comprise NKp46, NKp44, and NKp30 immunoglobulin-like receptors that are not exclusively expressed on NK cells but also on innate lymphoid cells (ILCs) of group 1 (ILC1) and a subset of ILC3, γδ T cells, and a population of cytotoxic T lymphocytes (25, 26). Only ortholog of NKp46 is expressed in mice (26) NKp30 and NKp46 associate with the signal transducing adaptors CD3ζ and FcεRIγ while NKp44 mainly signals through the DAP12 adapter. Splicing variants of NKp44 and NKp30 endowed with inhibitory signal capability have been described and are associated with worst prognosis in cancer patients (9, 27) NCRs interact with several ligands that are either pathogen-encoded or self-molecules and include cell surface and intracellular proteins that reach the surface in infected or transformed cells (28) the ligands expressed on tumor cells have not been fully identified yet Each NCR has the ability to recognize a specific configuration of heparan sulfate proteoglycans expressed in the context of tumor microenvironment, and this binding can modulate receptor function (28) Ligands for NKp30 include B7-H6 belonging to the B7 family and only expressed on tumor cells, the intracellular protein HLA-B associated transcript 3 (BAT3), also known as BAG6, and galectin-3 (29–31) The first two ligands bind to and activate NKp30 while the released form of galectin-3 inhibits anti-tumor NKp30 function NKp46 recognize viral ligands including hemagglutinins as well as tumor ligands of still unknown identity Most of the above mentioned NK cell activating ligands, including NKG2DLs and B7-H6, are absent in normal cells but their expression is induced upon neoplastic transformation, thus rendering tumor cells more susceptible to NK cell-mediated killing (29, 36–41) On the other hand, PVR and Nectin2 are expressed on healthy cells (21) but their amount is up-regulated on epithelial and hematological tumor cells promoting NK cell cytotoxicity (7, 42–44) Post-translational mechanisms controlling NK cell-mediated recognition of tumor cells and DNAM1 ligand expression is prevented by post-translational mechanisms on target cell surface (right) Release of B7-H6 and NKG2D ligands on exosomes is also depicted In addition to regulate ligand expression on tumor cell ubiquitin modification also provides a signal for internalization and trafficking of NKG2D and CD16 on NK cells (left) CD16 is also downmodulated by metalloproteinase-mediated shedding Mechanisms regulating DNAM-1 and NCR (NKp30) downmodulation are currently unknown (B) Therapeutic strategies aimed to prevent post-translational mechanisms affecting activating ligand and receptor expression Generation of soluble ligands relies on different mechanisms including alternative splicing, exosome secretion and proteolytic cleavage. Soluble PVR isoforms are generated by alternative splicing (59) and have an inhibitory effect on DNAM-1 mediated tumor immunity (54). In addition, alternative splicing gives rise to ULBP-4/5 secreted ligands that can impair NK cell target recognition in vitro (60, 61) In regard to NKp30Ls, the nuclear protein BAG6 is secreted on exosomes and stimulates NK cell activity (69), whereas the cell surface ligand B7-H6 can be released in its soluble form associated to exosomes or through protease-mediated cleavage (57, 70, 71). Although several stress conditions can increase exosome secretion from cancer cells (72–75) it is still uncertain whether the release of NKG2DLs or B7-H6 through exosome-like vesicles could result in the diminution of their expression on the cell surface Differently from the exosome-mediated release the proteolytic cleavage of NKG2DLs and B7H6 has been associated to a reduction of cell surface ligands thus its inhibition could be accomplished as a promising approach to keep the ligands on cancer cell surface and to promote anti-cancer immune response Recent evidences reveal a role for ubiquitination and SUMOylation in the regulation of NK cell ligand expression on tumor cells Ubiquitination and SUMOylation are reversible modifications whereby Ub and small Ub-like modifier (SUMO), respectively, are covalently bound to a target protein through the action of enzymes frequently up-regulated during malignant transformation (92–95) proteins undergo different fate depending on the type of modification Proteins modified by poli-Ub chains are generally targeted to proteasomal degradation (95) whereas the addition of single Ub molecules to one or more lysine residues promote non-degradative fates including regulation of membrane protein endocytosis (96). SUMOylated substrates undergo conformational changes that in turn modify their interaction with other proteins or their enzymatic activity without inducing a degradative fate (94) Little is currently known about the role of these modifications in the regulation of NK cell ligand expression during malignant transformation these results support a negative role for the Ub pathway in the regulation of NKG2DL expression Inhibition of Ub and SUMO pathways increases Nectin2 and PVR surface expression and renders tumor cells more sensitive to NK cell-mediated killing Although these findings are currently limited to NKG2D and DNAM-1 ligands they provide novel insights into the mechanisms underlying activating ligand expression in diseased cells and reveal novel potential targets for therapeutic intervention Tumor progression also implies the inability of NK cells to kill tumor cells as consequence of ligand mediated down-regulation of activating receptors (Figure 1A) However, receptor down-regulation may be affected by the presence of soluble or membrane-bound ligands as well as by their affinity and/or avidity (19) A decreased in NCR expression levels was observed in NK cells derived from patients affected by myeloid leukemia and other tumors upon the interaction with their respective ligands (8, 107) Reduced NKp30 surface expression has been also detected on NK cells derived from ovarian carcinoma and neuroblastoma patients as a result of chronic stimulation either with B7-H6-expressing tumor cells or soluble B7-H6 (55, 56, 108). Moreover, the presence of soluble BAG6 has been associated with a low transcriptional levels of different NKp30 isoforms (58, 109) DNAM-1 engagement, by membrane-bound ligands but not their soluble counterpart, is also followed by receptor down-modulation and impairment of NK cell functions in patients affected by different tumors including MM, ovarian carcinoma and AML (44, 110, 111) the mechanisms underlying these effects are still undefined For other activating receptors including NKG2D and CD16 mechanisms of ligand-induced down-modulation have been elucidated NKG2D stimulation by ligands expressed on tumor cells as well as by soluble ligands promotes receptor endocytosis and the decrease of NKG2D-dependent functions (46, 76, 112–115). In regard to released ligands, those associated to exosomes show a higher avidity and a more efficient ability to induce receptor down-regulation compared to shed ligands (66, 67) In humans, internalization of ligand-engaged NKG2D receptors requires DAP10 ubiquitination and is followed by lysosomal degradation (116). However, MICA is more efficient than ULBP2 in promoting receptor ubiquitination (114) Altogether these results demonstrate that activating receptor expression is modulated in tumor microenvironment by the interaction with ligand-expressing cells thus impairing NK cell ability to counteract tumor development ADAMs inhibitors have been largely unsuccessful in clinical trials but they remain a viable and desirable therapeutic target based on preclinical studies Strategies aimed at inhibiting ADAM17-mediated CD16 cleavage from the surface of NK cells could be also promising. Beyond the usage of inhibitors, recent advances in generating function-blocking antibodies of ADAM17 are emerging. The monoclonal antibody MEDI3622 has been shown to block CD16A cleavage from activated human NK cells allowing to an increased IFNγ production in the course of ADCC (136) Proteasome inhibitors can change the fate of ubiquitinated ligands. Bortezomib (Velcade) and Carfilzomib (Kyprolis) have been already used as chemotherapeutic drugs for relapsed MM patients (137–139) and for the treatment of mantle cell lymphoma (140) In line with our findings (106), previous reports demonstrated that low doses of bortezomib increase NK cell activating ligand, including Nectin2 (141–143) Whether those drugs can directly affect ligand expression stabilizing ubiquitinated Nectin2 and/or SUMOylated PVR is currently unknown Regarding the SUMO pathway, the FDA-approved drug Topotecan has been shown to affect SUMOylation in glioblastoma multiforme (144). Moreover, natural compounds including ginkgolic acid and tannic acid (145, 146) have been found to possess anti-cancer activities by targeting the SUMO pathway (147) All of these compounds hold great promise to be developed into novel and efficient anti-cancer drugs several activating ligands are subjected to protease-mediated cleavage with a consequent dramatic reduction of their surface expression A similar effect is also achieved upon ubiquitination or SUMOylation of NKG2D and DNAM-1 ligands which are retained intracellularly and/or degraded the Ub pathway may also contribute to down-regulate the surface expression of activating receptors all these post-translational mechanisms act to reduce NK cell-mediated surveillance against tumors and represent potential targets for therapeutic intervention Several inhibitors have been developed and their use in combination with conventional therapies represent a useful tool to potentiate NK-cell mediated recognition and killing of tumor cells and elaboration of the final version of the manuscript This work was supported by grants of Italian Association for Cancer Research (AIRC Investigator Grant cod 16014 and AIRC 5x1000) and Sapienza University (RM1181642771A58E) Controlling natural killer cell responses: integration of signals for activation and inhibition doi: 10.1146/annurev-immunol-020711-075005 NK cells and cancer: you can teach innate cells new tricks NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy Accelerated tumor growth in mice deficient in DNAM-1 receptor DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors Enhanced in vivo growth of lymphoma tumors in the absence of the NK-activating receptor NKp46/NCR1 NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors NKp30 expression is a prognostic immune biomarker for stratification of patients with intermediate-risk acute myeloid leukemia Combination immune therapies to enhance anti-tumor responses by NK cells Natural killer (NK) cells and anti-tumor therapeutic mAb: unexplored interactions New prospects on the NKG2D/NKG2DL system for oncology Recognition of tumors by the innate immune system and natural killer cells NKG2D receptor and its ligands in host defense Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation Regulation of ligands for the NKG2D activating receptor doi: 10.1146/annurev-immunol-032712-095951 NKG2D and its ligands: “one for all a novel adhesion molecule involved in the cytolytic function of T lymphocytes DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112) Molecular mechanisms of natural killer cell activation in response to cellular stress Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis The natural cytotoxicity receptors in health and disease NKp44 triggers NK cell activation through DAP12 association that is not influenced by a putative cytoplasmic inhibitory sequence Regulation of the functions of natural cytotoxicity receptors by interactions with diverse ligands and alterations in splice variant expression The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells a soluble inhibitory ligand of human NKp30 plays an important role in tumor escape from NK cell attack Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44 A subset of HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44 Natural killer cells control tumor growth by sensing a growth factor Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin doi: 10.1002/1521-4141(200104)31:4<1076::AID-IMMU1076>3.3.CO;2-P Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia MICA/NKG2D-mediated immunogene therapy of experimental gliomas The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112) DNAX accessory molecule-1 mediated recognition of freshly isolated ovarian carcinoma by resting natural killer cells and NKp46 in the natural killer cell-mediated killing of myeloma cells The DNA damage response: a common pathway in the regulation of NKG2D and DNAM-1 ligand expression in normal Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma Soluble MICA as an independent prognostic factor for the overall survival and progression-free survival of multiple myeloma patients MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer Soluble MICB in malignant diseases: analysis of diagnostic significance and correlation with soluble MICA Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention Differential clinical significance of individual NKG2D ligands in melanoma: soluble ULBP2 as an indicator of poor prognosis superior to S100B Increased soluble CD155 in the serum of cancer patients Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients B7-H6-mediated downregulation of NKp30 in NK cells contributes to ovarian carcinoma immune escape Metalloprotease-mediated tumor cell shedding of B7-H6 the ligand of the natural killer cell-activating receptor NKp30 NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D a soluble isoform of the UL16-binding protein RAET1E produced by tumor cells Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity Immunoassays for scarce tumour-antigens in exosomes: detection of the human NKG2D-Ligand in tetraspanin-containing nanovesicles from melanoma Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion Differential mechanisms of shedding of the glycosylphosphatidylinositol (GPI)-anchored NKG2D ligands Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes A GPI anchor explains the unique biological features of the common NKG2D-ligand allele MICA*008 RIG-I activation induces the release of extracellular vesicles with antitumor activity an endogenous ligand for the NK cell activating receptor NKp30 reveals the identity of two different soluble isoforms during normal human pregnancy a ligand for the natural killer cell-activating receptor NKp30 Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: role of HSP70/TLR2/NF-kB axis Restoring Anticancer immune response by targeting tumor-derived exosomes with a HSP70 peptide aptamer Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells Cancer exosomes as conveyors of stress-induced molecules: new players in the modulation of NK cell response Proteolytic release of soluble UL16-binding protein 2 from tumor cells Tumor-associated MICA is shed by ADAM proteases Cutting edge: the metalloproteinase ADAM17/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein The membrane type matrix metalloproteinase MMP14 mediates constitutive shedding of MHC class I chain-related molecule A independent of A disintegrin and metalloproteinases Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the “a disintegrin and metalloproteases” 10 and 17 Generation of soluble NKG2D ligands: proteolytic cleavage exosome secretion and functional implications Cutting an NKG2D ligand short: cellular processing of the peculiar human NKG2D ligand ULBP4 Matrix metalloproteinase inhibitors in cancer therapy: turning past failures into future successes ADAMs in cancer cell proliferation and progression Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide Radiation-induced matrix metalloproteinases limit natural killer cell-mediated anticancer immunity in NCI-H23 lung cancer cells Targeting NKG2D and NKp30 ligands shedding to improve NK cell-based immunotherapy The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA MICA-129 dimorphism and soluble MICA are associated with the progression of multiple myeloma mediates its recruitment to membrane microdomains and promotes its shedding doi: 10.1146/annurev-biochem-060310-170328 Sumoylation: a regulatory protein modification in health and disease doi: 10.1146/annurev-biochem-061909-093311 doi: 10.1146/annurev-biochem-061516-044859 Ubiquitination and endocytosis of the high affinity receptor for IgE Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity Posttranslational regulation of the NKG2D ligand Mult1 in response to cell stress Stress-regulated targeting of the NKG2D ligand Mult1 by a membrane-associated RING-CH family E3 ligase Intracellular retention of the NKG2D ligand MHC class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity Brief residence at the plasma membrane of the MHC class I-related chain B is due to clathrin-mediated cholesterol-dependent endocytosis and shedding Activation of liver X receptor up-regulates the expression of the NKG2D ligands MICA and MICB in multiple myeloma through different molecular mechanisms A short half-life of ULBP1 at the cell surface due to internalization and proteosomal degradation UPR decreases CD226 ligand CD155 expression and sensitivity to NK cell-mediated cytotoxicity in hepatoma cells Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions Circulating innate immune markers and outcomes in treatment-naive advanced non-small cell lung cancer patients Primary human tumor cells expressing CD155 impair tumor targeting by down-regulating DNAM-1 on NK cells Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance c-Cbl regulates MICA- but not ULBP2-induced NKG2D down-modulation in human NK cells Regulation of NKG2D expression and signaling by endocytosis Ubiquitin-dependent endocytosis of NKG2D-DAP10 receptor complexes activates signaling and functions in human NK cells Tyrosine kinase-dependent ubiquitination of CD16 zeta subunit in human NK cells following receptor engagement doi: 10.1002/(SICI)1521-4141(199910)29:10<3179::AID-IMMU3179>3.0.CO;2-9 Anti-CD20 therapy acts via FcgammaRIIIA to diminish responsiveness of human natural killer cells Obinutuzumab-mediated high-affinity ligation of FcgammaRIIIA/CD16 primes NK cells for IFNgamma production Ubiquitination and degradation of Syk and ZAP-70 protein tyrosine kinases in human NK cells upon CD16 engagement Downregulation of Fc gamma receptor IIIA alpha (CD16-II) on natural killer cells induced by anti-CD16 mAb is independent of protein tyrosine kinases and protein kinase C CD56(dim)CD16(+) NK cells downregulate CD16 following target cell induced activation of matrix metalloproteinases NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17) Membrane-type 6 matrix metalloproteinase regulates the activation-induced downmodulation of CD16 in human primary NK cells Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy Genotoxic stress induces senescence-associated ADAM10-dependent release of NKG2D MIC ligands in multiple myeloma cells Enzymatic inhibition of MICA sheddase ADAM17 by lomofungin in hepatocellular carcinoma cells The ADAMs family of proteases as targets for the treatment of cancer Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin's lymphoma cell models A disintegrin and metalloproteinases 10 and 17 modulate the immunogenicity of glioblastoma-initiating cells Modulation of NKG2D-ligand cell surface expression enhances immune cell therapy of cancer IL-2-activated haploidentical NK cells restore NKG2D-mediated NK-cell cytotoxicity in neuroblastoma patients by scavenging of plasma MICA Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity High-resolution glycosylation site-engineering method identifies MICA epitope critical for shedding inhibition activity of anti-MICA antibodies Anti-ADAM17 monoclonal antibody MEDI3622 increases IFNgamma production by human NK cells in the presence of antibody-bound tumor cells Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives Proteasome inhibitors: an expanding army attacking a unique target Proteasome inhibitor-based therapy for treatment of newly diagnosed multiple myeloma Targeting ubiquitination for cancer therapies Low-dose bortezomib increases the expression of NKG2D and DNAM-1 ligands and enhances induced NK and gammadelta T cell-mediated lysis in multiple myeloma ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype Translating the anti-myeloma activity of Natural Killer cells into clinical application Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate A gene-expression screen identifies a non-toxic sumoylation inhibitor that mimics SUMO-less human LRH-1 in liver Small-molecule inhibitors targeting protein SUMOylation as novel anticancer compounds Santoni A and Paolini R (2019) Post-translational Mechanisms Regulating NK Cell Activating Receptors and Their Ligands in Cancer: Potential Targets for Therapeutic Intervention Received: 24 July 2019; Accepted: 15 October 2019; Published: 31 October 2019 Copyright © 2019 Molfetta, Zingoni, Santoni and Paolini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Rossella Paolini, cm9zc2VsbGEucGFvbGluaUB1bmlyb21hMS5pdA== MORE INFORMATION VATICAN CITY (CNS) — The church needs courageous men and women like Italian Bishop Antonio Bello of Molfetta who imitated Jesus’ closeness to the poor and the downtrodden Visiting the birthplace of the beloved bishop affectionately known as “Don Tonino,” the pope said Bishop Bello’s life and ministry “remind us to not theorize closeness to the poor but to be close to them as Jesus did.” “Don Tonino did not do this because it was convenient or because he was seeking approval but because he was moved by the Lord’s example we find the strength to rid ourselves of the garments that get in the way so that we can dress ourselves in service which is the only priestly vestment recorded in the Gospel,’” he said April 20 Pope Francis arrived in the morning by helicopter in the town of Alessano located in the southern Italian province of Lecce the pope carried a bouquet of white lilies and yellow sunflowers and laid them in front of the bishop’s tomb Surrounded by palm trees and an olive tree adorned with rosaries and multicolored peace flags Pope Francis spent nearly five minutes praying silently He also prayed in front of the tomb of the bishop’s parents Don Tonino spent his first years of priestly ministry as vice rector of a seminary while collaborating with the Catholic charitable organization After he was named bishop of Molfetta in 1982 by St Bishop Bello not only served the poor of his diocese but also worked to promote peace often rallying against wars in the Persian Gulf and Bosnia-Herzegovina He served as president of Pax Christi Italy The Vatican approved the opening of Bishop Bello’s sainthood cause in 2007 Pope Francis rode in a small white golf cart and greeted thousands of men Standing in front of an image of the bishop the pope said Bishop Bello did not remain “with his hands in his pockets” but worked tirelessly to promote peace “with the conviction that the best way to prevent violence and every kind of war meant taking care of the needy and promoting justice.” the shops where communion is handcrafted,” he said he had a “healthy allergy toward titles and honors” and instead chose to free himself “from the signs of power to make way for the power of signs.” let us allow ourselves to be transported by his youthful Christian zeal let us listen to his urgent invitation to live the Gospel without concession It is a strong invitation given to each one of us Pope Francis boarded a helicopter to Molfetta where he celebrated an outdoor Mass in the diocese Bishop Bello served for nearly 10 years Pope Francis recalled the bishop’s devotion to the Eucharist and the word of God Christians who are nourished by the Eucharist “also share the Lord’s mentality and are called to “no longer live for themselves but for others.” “dreamed of a Church hungry for Jesus and intolerant of all worldliness a Church that ‘knows how to perceive the body of Christ in the uncomfortable tabernacles of misery Site developed by     Copyright © Yedioth Internet the twins on last night's controversial — "American Idol" on Fox will be at Newburgh Free Academy — at 6 p.m tomorrow to take part in the One Soul Talent Show For more information contact 562-2469 or 562-2506 — If you can't wait until tomorrow to see the twins turn into "Access — Hollywood" at 7:30 tonight on NBC originally from New Windsor — and graduates of Newburgh Free Academy were featured during a segment — of American Idol last night The judges were split on what to do with — the twins — The Molfetta’s received two votes to stay — from Randy Jackson and Paula Abdul Simon Cowell and guest judge Gene — Simmons both voted against them After a small argument between the — judges Paula and Randy stormed out of view from the cameras The — Molfetta's had no choice but to accept the negative decision — During the preview scenes for tonight's show it — looks as if one of the twins will be appearing again in the Las Vegas — audition — Check back this evening for more details on our American idols from — Germain Lussier analytics and third-party cookies.By continuing to browse On June 4th, the Italian Cultural Institute of Tirana presented Antonio Molfetta’s performance during the 6th edition of the Albania Guitar Festival The concert festival aims to spread culture and musical education to younger generations The Festival sees activities taking place  across all  Albanian cities with a calendar of events that take place all year round and a comprehensive programme of concerts The Italian guitarist Antonio Molfetta discovered his interest in guitars at an early age A casual “encounter” with the music played by the great Spanish guitarist Andrés Segovia encouraged him to undertake classical guitar lessons with passion and determination; Vito Fiore was his first teacher and several important teachers from the world guitar scene followed until he completed his studies at the “G Verdi” Conservatory of Milan and specialised at the prestigious Accademia Musicale Chigiana in Siena under the guidance of  Oscar Ghiglia His achievements include first place at the first international competition “City of Lodi” His concerts and numerous master classes have led him to perform in Germany he has devoted himself to the study of jazz guitar improvisation and composition under Nuccio D’Angelo and  Giuseppe Continenza he has been the Artistic Director of prestigious guitar festivals such as  “The Art of the Guitar” “Guitar Week” and the Mesagne “International Guitar Festival” he works with the “Università Libera Età Natalia Ginsburg” in Carpi where he gives courses in “history and guide to listening to music” and teaches classical guitar at the “Carpi Guitar International” Guitar Academy For more information, go to iictirana.esteri.it The Sanremo Giovani World Tour (SGWT) is a collaborative project between the Ministry of Foreign Affairs and RAI born in.. in collaboration with the Compagnia della Luna organises the story-concert 'La musica è pericolosa' (Music.. an unprecedented concert will be broadcast showcasing young opera talents in two.. One year after the death of Ennio Morricone the great Italian composer known and loved by audiences around the world.. Four events with some of the most famous Italian and Spanish artists who meet for the first time thanks to.. To mark the prestigious exhibition 'De Chirico Magische Wirklichkeit' ('De Chirico Magical Reality') being hosted by the Hamburg Kunsthalle from.. JP and Rich Molfetta didn't let their "American Idol" rejection get them down Paula and Randy dismissed the former New Windsor residents from the popular TV show won the chance to represent the East Coast in the worldwide music festival called Emergenza It had to endure five rounds of competitions beginning late last year They were crowned "NY Manhattan (USA)" champions on June 28 at Webster Hall in Manhattan and will now be flown to Germany to compete against 14 bands from nine other countries for title of Best Band on the Planet The winning band in that competition gets professional production "I think we can take this," said JP Molfetta "Three other bands are gonna give us a good run when the bands play at the Taubertal Festival 2008 in Germany Susan Wagner QB Alyssa Badalamenti gets set to launch a Hail Mary at the end of the first-half that was hauled in for a touchdown (Photo courtesy of Matthew Colchamiro)photo credit .st1{fill-rule:evenodd;clip-rule:evenodd;fill:#2a2a2a}By James Speciale | youthsports@siadvance.comAs has been documented in this space numerous times the sport of girls’ flag football is on the rise on Staten Island The “forgotten borough” has dominated the scene in PSAL play and has had its share of success in the early stages of the CHSAA Joseph by-the-Sea (CHSAA) are reigning city champions in their respective divisions and quarterback play has always been crucial to success in this sport The Advance/SILive.com has put together a poll to hear from the readers who they feel will be the top signal caller on the Island in 2024 Voting starts now and will remain open until April 24 Congrats to all the girls who made the list Michelle Adamov (CSI/McCown): The play of this junior is a big reason for the turnaround at CSIM The Dragons are off to a solid 3-1 start and Adamov has been the sparkplug She has thrown for 670 yards and eight touchdowns one of the top cagers in the PSAL last year has switched from linebacker/wide receiver to QB for the Central Cougars She has tossed three touchdowns through ND’s two games thus far has looked anything but inexperienced since taking the helm of the Hilltoppers offense from day one She has tossed 10 touchdowns and ran in another score for coach George Clark’s club Alyssa Badalamenti (Susan Wagner): She led the Falcons to a city championship as a junior and has picked up right where she left off with 12 touchdowns and also ran for another pair Jillian Molfetta (Sea): The Vikings have a two-headed threat under center and Molfetta has dazzled in the pocket and in the open field with her legs She has thrown 14 touchdown against one interception while throwing for an Island-high 714 yards Kristina Williamson (Curtis): Williamson is a dual-threat for Charlie Massara’s Warriors the junior has thrown for 434 yards and five scores while on the ground she has added 146 yards Olivia Dubner (Moore Catholic): The strong-armed junior who guided the Mavs to the CHSAA title game a year ago is putting up big numbers again in 2024 She has been a tough matchup for opponents Use of and/or registration on any portion of this site constitutes acceptance of our User Agreement, (updated 8/1/2024) and acknowledgement of our Privacy Policy, and Your Privacy Choices and Rights (updated 1/1/2025) © 2025 Advance Local Media LLC. All rights reserved (About Us) The material on this site may not be reproduced except with the prior written permission of Advance Local Community Rules apply to all content you upload or otherwise submit to this site YouTube's privacy policy is available here and YouTube's terms of service is available here Ad Choices Today we give you a first look at "GUNDAMA" certainly one of the best ones from the series The artist fused Obama with a Gundam character More images of GUNDAMA follow after the jump Via The Daily Blurb. Please be aware that our efforts to maintain accessibility and usability are ongoing. While we strive to make the Website as accessible as possible some issues can be encountered by different assistive technology as the range of assistive technology is wide and varied. If, at any time, you have specific questions or concerns about the accessibility of any particular webpage on this Website, please contact us at accessibility@highsnobiety.com, +49 (0)30 235 908 500. If you do encounter an accessibility issue, please be sure to specify the web page and nature of the issue in your email and/or phone call, and we will make all reasonable efforts to make that page or the information contained therein accessible for you. Prep time: 20Cook time: 10Traditional Italian pasta soup dish Link copiedShareShare articlePrintJump to RecipeAs part of Adelaide's new migrant community food festival ABC presenter Sonya Feldhoff learns how to make traditional Molfetta pasta sheets for the Italian soup dish U'Tridd U'Tridd is a hearty and warming dish combining pasta and soup BoilingVegetablesWinter WarmersSoupItalianMolfetta Pasta SheetsPrep time: 20Cook time: 10abc.net.au/news/molfetta-pasta-sheets/9817304Link copiedShareShare articlePrintIngredientsFor the pasta sheets: 1-1/2 cups of water - added little by little Watch Sonya Feldhoff's video on Facebook 1. On a clear work surface, pour the flour and semolina and mix together 2. Make a well in the middle of the flour and sprinkle the parsley around the edges 3. Add the eggs into the middle of the well and begin to mix the flour and eggs together rigorously 4. Begin to knead the dough until it's smooth 5. Add water, a little at a time, if the dough is dry 6. Once the dough ball is smooth, roll it into a log and cut off 2-inch pieces 7. Flatten the piece out, and then using a pasta roller, feed it through gently until it is very thin 8. Lay the pieces of pasta down on a dry surface and allow to dry, once dry turn over onto the other side to dry 9. The pieces of pasta are now ready to be cut or broken by hand and used straight away in the soup dish or stored in the freezer The pasta sheets are then added to a broth of osso buco, carrots, celery, carrots, onions and sprinkled with pecorino cheese. YUM! Stay tuned - the broth recipe will be added to this page shortly. CNN and the BBC World Service which is copyright and cannot be reproduced AEST = Australian Eastern Standard Time which is 10 hours ahead of GMT (Greenwich Mean Time) .st1{fill-rule:evenodd;clip-rule:evenodd;fill:#2a2a2a} McMahon has announced several new promotions and hires to the Richmond County District Attorney's office Joining the office as chief of detective investigators is former NYPD Lt a veteran of the police department with 27 years of experience Also new to the office is Assistant District Attorney Jevet T a career prosecutor who has been named bureau chief of RCDA’s Special Victims Bureau Assistant District Attorney Michele Molfetta has been promoted to chief of the Narcotics-Investigations Bureau after previously serving as the bureau’s deputy chief Assistant District Attorney Wanda DeOliveira has been named chief trial counsel after previously serving as chief of the Special Victims Bureau “The passion and expertise these talented individuals bring to the table will go far in holding criminals accountable and combating the many issues we face on Staten Island every day,” McMahon said in a press release During her career at the Staten Island D.A.’s office Wanda DeOliveira worked as the deputy bureau chief in the Special Victims Bureau from 2005 to 2008 and then as the deputy bureau chief in the Trials Bureau until 2010 when she was named chief trial counsel to continue her love of trial advocacy in mentoring the junior assistants with their trials DeOliveira was asked to return to the Special Victims Bureau as the new bureau chief a position she held until July 2017 when she was promoted to the Executive Bureau as chief trial counsel in over 75 cases during the course of her career as a prosecutor has tried over 15 homicide cases in Richmond County alone and prosecuted hundreds of other murder cases She was assigned to lead a team of investigators and was the sole prosecutor in the county assigned to review over 150 cold-case homicides dating back to the 1980s for new DNA evidence DeOliveira has been a lead participant in the several of Staten Island’s most noteworthy cases and has personally taken several of them to trial Michele Molfetta  began her career as an assistant district attorney in the Richmond County D.A.’s Office in September 2005 Molfetta was transferred to the Office of the Special Narcotics Prosecutor in Manhattan where she prosecuted hundreds of felony narcotics and weapons cases and conducted numerous felony narcotics trials During her time with the Special Narcotics Prosecutor multi-jurisdictional -- including international -- narcotics investigations working in the Investigations Bureau where she conducted numerous long-term major narcotics and gang related investigations which resulted in the recovery of kilogram quantities of narcotics and the arrest and prosecution of over 100 defendants most of whom were violent felony offenders Molfetta has tried numerous felony cases ranging from complex wiretap investigations to homicides Molfetta worked as the deputy bureau chief in the Criminal Court Bureau  Molfetta was promoted to deputy bureau chief of RCDA’s Narcotics-Investigations Bureau and was responsible for managing its day-to-day operations which includes the supervision of all narcotics and gang-related prosecutions and investigations as well as overseeing all drug related diversion programs such as Staten Island Treatment Court and HOPE David Nilsen is a 27-year veteran of the NYPD He served as commanding officer of the Staten Island Homicide Squad from 2006-2014 supervising over 300 non-fatal shootings and over 100 homicide investigations  Nilsen served as commanding officer of the 120th Precinct Detective Squad Nilsen was responsible for leading investigations into some of the most notable cases on Staten Island He supervised the homicide investigation into the deaths of Det who were both tragically shot and killed March 10 2003 while involved in an undercover buy and bust operation on Staten Island Nilsen supervised all investigative operations into the crash involving a Staten Island Ferry boat which claimed the lives of 11 people and seriously injured dozens of others  Nilsen supervised several other high-profile homicides on Staten Island including the December 2007 investigation into the death of FDNY Fire Marshall Douglas Mercereau he served as lieutenant commander of the NYPD’s Detective Squad and commanding officer of the Cold Case Squad which is responsible for investigating open unsolved homicides throughout the city Jevet Johnson began her career as an assistant district attorney in the Bronx D.A.’s Office working in the Criminal Court and Grand Jury Bureau from 2001-2004 and then in the Narcotics Bureau from 2004-2012 where she prosecuted over 15 jury trials ranging from narcotics to homicides She was also weekend supervisor of the Complaint Room from 2008-2013 and worked in the office’s Child Abuse and Sex Crimes Bureau from 2012-2013 where she prosecuted violent sexual assault and child abuse cases Johnson worked as an agency attorney for the Department of Education in the Office of the General Counsel where she conducted hearings against teachers and other employees of the Department of Education accused of violating the chancellor’s regulations and/or New York State criminal statutes she worked as an assistant district attorney in the Westchester County D.A.’s Office worked as an agency attorney for the New York City Department of Correction Click here for a story on top NYPD officials on Staten Island.  Nilsen served as commanding officer of the 120th Precinct Detective Squad Nilsen was responsible for leading investigations into some of the most notable cases on Staten Island.  2003 while involved in an undercover buy and bust operation on Staten Island.   Nilsen supervised several other high-profile homicides on Staten Island which is responsible for investigating open unsolved homicides throughout the city.  The Molfetta twins from New Windsor were the talk — of the nation after they sparked a nasty spat among "American Idol" — judges Tuesday night — John Paul and Rich Molfetta's performance of "I'll — Make Love to You" by Boyz II Men split the show's four judges — Paula — Abdul — Jackson and Abdul voted for the duo to advance in — the competition while Cowell and Simmons voted against them The rift — apparently caused Jackson and Abdul to storm off stage — "We sure as hell have been able to create some drama," — JP said yesterday over the phone Rich Molfetta got through the next round — of "American Idol." 'I'm — gonna do my thing' and that's exactly what he did," JP said — The 27-year-old twins graduated from Newburgh Free — Academy in 1995 and went to Boston College They used to live in New — Windsor and now live in North Jersey — The Molfettas flirted with the music industry for — a few years One label went bankrupt — and the other dropped the pair after the Sept — "We were discouraged in the music industry because — being white guys singing R&B music you're met with a ton of resistance — and are likened a lot to boy bands," JP said "We started pursuing — a soulful rock vibe." — That's the vibe that got at least two "American — Idol" judges excited about them John Paul and Rich were shown — blasting the judges you've — got to be able to get a point across," JP said 'Thank you very much' you never would've seen me on 'American — Idol.' " — Not discouraged by Tuesday night's showing Rich — flew to Las Vegas for the next set of auditions — The Molfettas are returning to their home turf at — 6 p.m where they'll be the judges as well as performers at — the "One Soul Talent Show" at NFA — "They're supporting our idea," said Natalie Torres — a counselor for Liberty Partnerships Program and the sponsor of the — event "They're going back to where they started to support the kids." — "They're very dynamic and gracious and very focused — on the craft," she said.