Ready to start planning your care? Call us at 800-525-2225 to make an appointment Our scientists pursue every aspect of cancer research—from exploring the biology of genes and cells Our highly-specialized educational programs shape leaders to be at the forefront of cancer care and research Adults: 800-525-2225 Children & Teens: 833-MSK-KIDS our experts provide the care and support you need Refer a patient Memorial Sloan Kettering was founded in 1884 and today is a world leader in patient care Age is considered the most important risk factor for cancer That’s because genetic mutations build up in cells over years and decades and ultimately drive the development of cancer Now a study from researchers at Memorial Sloan Kettering Cancer Center (MSK) and their collaborators provides new evidence about how advanced age can also be protective against cancer. The study, conducted in a mouse model of lung cancer, was published in Nature on December 4 “We know that as people get older, they’re more likely to get cancer,” says study first author Xueqian Zhuang, PhD, a postdoctoral fellow in the lab of senior study author Tuomas Tammela, PhD, at MSK’s Sloan Kettering Institute “But there’s still a lot that’s unknown about how aging actually changes the biology of cancer.” lung cancer is diagnosed in most people around age 70 the incidence rate starts to come down again “Our research helps show why,” she adds “Aging cells lose their capacity for renewal and therefore for the runaway growth that happens in cancer.” To investigate why cancer incidence peaks in the early senior years and then starts to decline again the MSK research team studied a genetically modified mouse model of lung adenocarcinoma a common type of lung cancer that accounts for about 7% of all cancer deaths worldwide One of the things that makes it challenging to study aging in laboratory models is that mice take two years to develop to an age that’s equivalent to 65–70 years in people making experiments a lengthy and resource-intensive proposition The scientists found that as the mice get older More NUPR1 makes the cells in the lungs function as if they are iron deficient “The aging cells actually have more iron but for reasons we don’t yet fully understand they function like they don’t have enough,” Dr Since the cells in the older mice functioned as though they didn’t have enough iron they lost some of their ability to regenerate And because that regenerative capacity is directly linked to the rise of cancer the older mice developed far fewer tumors than their younger counterparts this effect could be reversed by giving the older mice additional iron or by reducing the amount of NUPR1 in their cells “We think this discovery may have some immediate potential to help people,” Dr especially following the COVID-19 pandemic live with insufficient lung function because their lungs didn’t fully heal from an infection Our experiments in mice showed that giving iron can help the lungs regenerate and we have really good ways of delivering drugs directly to the lungs — like asthma inhalers.” But this is also where the double-edged nature of the discovery comes into play By restoring the ability of the cells in the lungs to regenerate one is also increasing the tissue’s ability to develop cancer “So this type of approach might not be appropriate for people who are at a high risk of developing cancer,” he adds The team’s findings also have important implications for therapies based on a type of cell death called ferroptosis and there are a number of ferroptosis-inducing small molecule compounds as well as drugs previously approved by the FDA that are being investigated for their potential to kill cancer cells Older cells are far more resistant to ferroptosis than younger cells because they function as if they don’t have enough iron This means treatments that target ferroptosis may not be as effective in older patients as they are in younger ones “One of the things that we showed exploring all of this iron biology is that ferroptosis is tumor suppressive as everybody suspected — but much more profoundly in younger animals,” Dr this says that because the biology of cells changes with aging So doctors might need to really be careful in clinical trials to look at the effects in both older and younger patients.” the research ultimately has an even bigger takeaway “What our data suggests in terms of cancer prevention is that the events that occur when we’re young are probably much more dangerous than the events that occur later,” he says or from other obvious carcinogenic exposures are probably even more important than we thought.” and Yuna Landais of the Victor Chang Cardiac Research Institute Wong of the Victor Chang Cardiac Research Institute and University of New South Wales; Alexander Ferrena and Deyou Zheng of the Albert Einstein College of Medicine; Simon Joost Carrasco of MSK and Weill Cornell Medicine; Yang Zhao and Thomas Pisanic of Johns Hopkins University; Joo-Hyeon Lee of the University of Cambridge U.K.; Pekka Katajisto of the University of Helsinki Soto-Feliciano of the Massachusetts Institute of Technology; and Tiffany Thomas of Columbia University This work was supported by a Mark Foundation for Cancer Research Emerging Leader Award; the GO2 Foundation for Lung Cancer; and by MSK’s Cancer Center Support Grant from the National Cancer Institute (P30-CA008748) Additional support was provided by the New York Stem Cell Science NYSTEM (C32559GG) from the Center for Stem Cell Biology at MSK; the Druckenmiller Center for Lung Cancer Research at MSK; Hope Funds for Cancer Research; The Alan and Sandra Gerry Foundation; a National Health and Medical Research Council Investigator Grant (GNT2009309); an ARC Discovery Project (DP200100250); a Snow Medical Fellowship; Josie Robertson; the American Cancer Society; Rita Allen; and the V Foundation The work also relied on MSK’s Integrated Genomics Operation Core (funded by Cycle for Survival and the Marie-Josée and Henry R and Histology Core Facilities at the Sloan Kettering Institute as well as the Victor Chang Cardiac Research Institute Innovation Centre Tammela is a scientific advisor with equity interests in Lime Therapeutics His spouse is an employee of and has equity in Recursion Pharmaceuticals The Tammela Laboratory receives funding from Ono Pharma unrelated to this work where her spouse is a co-founder of and equity holder The other authors declare no competing interests Read the article: “Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis,” Nature JKMM Architects unveils Finland’s first hybrid football stadium a highly anticipated addition to Tampere’s Tammela district Designed in collaboration with the City of Tampere and Pohjola Rakennus the architectural team conceived the stadium as a miniature city combining sports facilities with residential The 13,500-square-meter venue seats 8,000 spectators and meets UEFA category 4 standards hosting elite matches such as the Europa League and national team games while accommodating 15,000 attendees for concerts and public events its suspended steel canopies blending with the residential rooftops images by Tuomas Uusheimo Tammela stadium replaces the original Tammela football pitch, a historic venue dating back to the 1930s. Instead of relocating, the new structure densifies the site while respecting its heritage. Helsinki-based JKMM Architects’ competition-winning design integrates the stadium with a hybrid block spanning nearly 50,000 square meters The development comprises five residential buildings weaving into the district’s urban fabric Apartments in the residential buildings offer diverse layouts with upper levels providing views of the field or surrounding cityscape while a light art installation by artists Tommi Grönlund and Petteri Nisunen animates the canopy undersides evoking the energy of football with dynamic JKMM Architects unveils Finland’s first hybrid football stadium Central to Tampere’s urban renewal goals JKMM Architects prioritizes sustainability Existing structures from the old stadium were repurposed for other city fields The central location encourages public transport use while the block is connected to district heating and cooling networks Light-colored roof materials reduce urban heat and air pollution while the compact hybrid design maximizes land use.  Tammela Stadium’s design is defined by its tectonic approach where architectural and structural elements coalesce and suspended canopy structures ensure robust yet refined forms supported by tension cables and steel pylons flexes to carry snow loads and seasonal shifts while the stadium’s green artificial turf takes center stage as a symbol of Finnish football culture and spectators are positioned for optimal flow while visiting team supporters have a dedicated northeast entrance Parking and service areas are tucked into the basement The stadium offers year-round functionality serving local clubs like Ilves Tampere and hosting diverse events Ground-level commercial spaces add vibrancy to the Tammela area further cementing its role as a community hub the 13,500-square-meter stadium seats 8,000 spectators and meets UEFA category 4 standards Tammela Stadium accommodates up to 15,000 attendees for concerts and public events | image by Hannu Rytky the stadium replaces the original Tammela football pitch | image by Hannu Rytky the new structure densifies the site while respecting its heritage | image by Hannu Rytky brick-clad residential buildings frame the stadium elevated courtyards are nestled between the structures the development comprises five residential buildings architect: JKMM Architects | @jkmmarchitects floor area: 11,631 square meters (3,435-square-meter heated space) seating capacity: 8,000 (15,000 for concerts) Juha Mäki-Jyllilä (founding partners) Alli Bur extensive team of architects and designers contributing to housing geotechnical engineering: A-Insinöörit electrical and audiovisual design: Ramboll Finland Oy landscape design: VSU maisema-arkkitehdit Oy photographers: Hannu Rytky | @hrytky, Tuomas Uusheimo | @onarchitecture AXOR presents three bathroom concepts that are not merely places of function but destinations in themselves — sanctuaries of style JKMM Architects' Tammela Stadium has been announced as the winner of this year’s Finlandia Prize for Architecture by the journalist Antti Kuronen and Association of Finnish Architects (SAFA) The multipurpose stadium was constructed in 2023 and covers 509,193 square feet with a capacity of 8,000 people for sporting events and 15,000 for concerts Samuli Miettinen led the firm’s design team which impressed the noted war correspondent for its response to challenging site parameters and ability to promote sustainability and a "peaceful coexistence for all." Kuronen commented: "In creating the stadium the designers at JKMM Arkkitehdit have made a bold and fresh contribution to Finnish urban design and urban culture Tammela Stadium is less a monument or a piece of architectural eye candy and more a secret destination whose existence only becomes apparent as you actually enter it A first-time visitor might well pass here without ever realising they are in the presence of a well-appointed sporting venue Tammela Stadium makes a bold and fresh contribution to Finnish urban design." The 2024 pre-selection jury included Professor Jenni Reuter (Chair) architects Harri Hautajärvi and Kirsi Korhonen 500,000€ Prize / Free registration / DUBAI URBAN ELEMENTS CHALLENGE UNESCO ANCIENT THEATRE: Valorising an Extraordinary Historical Heritage viewed from the research vessel Kronprins Haakon While antibiotics are the linchpin of modern medicine we continue to face a global “antimicrobial crisis,” the authors wrote as more and more resistant strains of bacteria are evolving while the rate of discovery of fundamentally new antibiotics has been much slower researchers have looked for antibacterial compounds in natural products “A considerable number of antibacterial agents are derived from bacterial metabolites numerous known compounds that impede bacterial virulence stem from bacterial metabolites soil actinobacteria have produced 80% of all currently licensed antibiotics on the seafloor or within the microbiome of marine organisms have received far less attention as possible sources of antibiotics even more so with respect to virulence-modifying compounds.” Focusing the search on actinobacteria in other habitats could thus represent a promising strategy especially if this search could yield novel molecules that neither kill bacteria outright nor stop them from growing but only reduce their “virulence” or capacity for causing disease This is because it is hard for targeted pathogenic strains to evolve resistance under these conditions “Inhibiting bacterial virulence is a well-studied alternate method to the more traditional killing of microorganisms or inhibiting their growth,” the scientists explained the idea is to inhibit the action of virulence-causing molecules using pharmaceutical interventions the treated pathogens would then remain incapable of causing symptoms and thus selection pressure for resistance would not form so easily.” And it’s likely that such drugs would have fewer adverse effects on normal flora which are affected adversely by drugs that inhibit bacterial growth or viability in general Tammela and colleagues developed a suite of methods that can test for the antivirulence and antibacterial effect of hundreds of unknown compounds simultaneously “Our aim was to design and validate an isolation and automated screening workflow for use with fractions from microbial cultures and explore the presence of virulence-inhibitory compounds within marine bacterial fractions and their potential application for drug development as the complex nature of extracts and extract fractions may interfere with screens that have been developed and validated using pure chemical compounds only.” Aug 2020 [Yannik Schneider]They targeted an EPEC strain that causes severe diarrhea in children under the age of five years EPEC isolates have also been shown to display many different forms of antimicrobial resistance EPEC causes disease by adhering to cells in the human gut EPEC injects so-called “virulence factors” into the host cell to hijack its molecular machinery “EPEC virulence is caused by it adhering to enterocytes and causing lesions in the intestinal epithelium characterized by the destruction of microvilli a phenomenon called attaching and effacing (A/E) lesions,” the team wrote “Among the secreted factors is the translocated intimin receptor (Tir) which is critical for A/E lesion formation,” they wrote The team tested compounds derived from four species of actinobacteria isolated from invertebrates sampled in the Arctic Sea off Svalbard during an expedition of the Norwegian research vessel Kronprins Haakon in August 2020 and their contents separated into fractions against EPEC adhering to cultured colorectal cancer cells and further tests were carried out on the bioactive fractions to identify the relevant compounds “Three bioactivity screening methodologies were used for each extract,” the team further explained “These included 1) testing for their capacity to inhibit the translocation of Tir 2) their capacity to prevent actin pedestals and 3) their capacity to inhibit the growth of EPEC in liquid culture … recognized active fractions were then studied further to narrow down their possible mechanism of action and to elucidate the chemical structure of the active compounds.” The researchers found two unknown compounds with strong antivirulence or antibacterial activity: one from an unknown strain (called T091-5) of the genus Rhodococcus and another from an unknown strain (T160-2) of Kocuria The compounds showed two complementary types of biological activity One by inhibiting the formation of “actin pedestals” by EPEC bacteria a key step by which the pathogen attaches to the host’s gut lining The other by inhibiting EPEC from binding to the Tir receptor on the host cell’s surface a step necessary to rewire its intracellular processes and cause disease Aug 2020 [Yannik Schneider]Unlike the compounds from T160-2 the compound from T091-5 didn’t slow down the growth of EPEC bacteria This means that T091-5 is the most promising strain of the two as EPEC is less likely to ultimately evolve resistance against its antivirulence effects “ … the specific inhibition of enteropathogenic Escherichia coli (EPEC) virulence could offer an alternative to conventional antibiotic-based approaches helping to mitigate the issue of antimicrobial resistance over the long term,” the investigators stated the authors determined that the active compound from T091-5 was most likely a phospholipid: a class of fatty phosphorus-containing molecules that play important roles in cell metabolism “Our findings include the bioassay-guided identification and isolation of a large phospholipid and a likely antimicrobial peptide demonstrating the usefulness of this approach in screening for compounds capable of inhibiting EPEC virulence,” the investigators wrote “We show that this workflow can indeed recognize bioactive compounds in these microbial fractions,” they stated “The next steps are the optimization of the culture conditions for compound production and the isolation of sufficient amounts of each compound to elucidate their respective structures and further investigate their respective bioactivities.” Copyright © 2025 Sage Publications or its affiliates including those for text and data mining and training of large language models Official magazine of the Royal Geographical Society (with IBG) By the Norwegian Parliament approved a government plan to open a large part of its seabed to mining exploration a team of scientists led by Päivi Tammela was analysing samples taken from microbes found in the Arctic sea contain previously undiscovered compounds that could one day become new drugs for dangerous bacteria ‘I would say the deep ocean is a highly promising source of new discoveries.’ From these samples, Tammela and her colleagues have identified two new compounds that could be used to target a type of E Coli that causes severe – and sometimes deadly – diarrhoea in children under five a professor of pharmaceutical biology at the university explains that as antibiotics aren’t selective about the bacteria they target they aren’t recommended for the treatment of intestinal infections caused by bacteria such as E ‘You’re potentially killing all the beneficial microbiota in your gut it’s generally better understood that taking multiple courses of antibiotics actually does a lot of harm and can have really long-lasting effects.’ The other problem Coli causing your infection could already be resistant to antibiotics Antimicrobial resistance is already a global crisis It is currently responsible for 1.27 million deaths every year and this number could reach 10 million by 2050 While the global overuse and misuse of antibiotics the crisis has been compounded by very few new antibiotic discoveries in recent decades In an attempt to tackle the rising problem of antibiotic resistance Tammela’s research has focused on compounds with antivirulence effects Unlike traditional antibiotics that kill or inhibit the growth of bacteria antivirulence drugs effectively disarm them ‘When you expose a bacterial population to an antibiotic that kills them there’s always a few with mutations that survive and start a new ‘Because antivirulence compounds are not intended to kill a bacterium we avoid this selective pressure that causes it to evolve in a certain direction We are just preventing it from causing disease.’  It will be a long time before we find out whether these two newly-discovered compounds can be used to develop new antivirulence drugs but Tammela’s research has made it easier for other scientists searching for solutions to the antimicrobial crisis in the deep ocean She and her colleagues are the first to trial a new time-saving process that analyses hundreds of unknown compounds simultaneously and in greater detail than commonly used methods ‘We are constantly looking for new chemical compounds that could be used as drugs or pharmaceuticals,’ says Tammela ‘Our key message from our paper is that it really pays off to use more advanced technology to look at these samples.’ 70 per cent of all licenced antibiotics have been derived from bacteria in the soil We’re only just starting to look for useful products that can be developed from microscopic life – an activity known as bioprospecting – in Earth’s other environments Yet scientists are already concerned that human activities such as the development of deep sea mining could disrupt ecosystems and organisms that are yet to be discovered Filed Under: Science & Environment Tagged With: , Click Here for SUBSCRIPTION details Want to access Geographical on your tablet or smartphone Android or PC/Mac image below to download the app for your device Copyright © 2025 · Site by Syon Media – The stadium entity has been successfully adapted to the existing urban structure Construction is based on extensive reconciliation of different materials and hybrid construction of demanding structures enabled by load-bearing concrete structures The stadium block has been founded on reinforced concrete piles and with support structures on challenging – The end result of the Tammela Stadium project is extremely unique and successful even though it was long-lasting and challenging in many respects We received a stadium that is successful in terms of the cityscape and functionality at a central location with good transport connections A special feature of the Tammela Stadium are the suspended canopies of more than 100 metres in length which serve as a shelter for the end stands The glass entrances at the ends of the stadium protect the field from wind and maintain a spatial connection to the environment while creating a microclimate inside the stadium The column-free construction ensures unobstructed views of the entire field from all seats The inclined columns built at each corner of the stadium are supported by load-bearing concrete structures or concrete anchors the competition jury wants to encourage investments in the quality of the environment and construction through both technical and architectural means and commercial services has required architectural and structural innovation – The implementation of open-minded ideas was successful thanks to good cooperation between the parties Awarded for the design and implementation were The City of Tampere/Tilapalvelut as the developer JKMM Architects Oy for architectural design Ramboll Finland Oy for structural planning and contractors Pohjola Rakennus Oy Finland The Finnish Concrete Structure of the Year competition is organised by Betoniteollisuus ry and has been organised since 1970 The award is given to a building project that best represents concrete construction in Finland The jury of the competition includes members from the Finnish Association of Architects the Finnish Association of Construction Engineers and Architects (RIA) the Finnish Organisation of Civil Engineers (RIL) Suomen Betoniyhdistys ry (“Finnish Concrete Association”) Betoniteollisuus ry (“Concrete Industries of Finland”) The football stadium has approximately 8,000 seats and offers space for up to 15,000 people for concerts The hybrid block consists of a football field and residential buildings and business premises built on the sides of the stadium as well as a parking facility and shopping centre located under the stadium You are on the official website of the City of Tampere.  E-mail[email protected] Metrics details Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand The Wnt responder cells showed increased tumour propagation ability suggesting that these cells have features of normal tissue stem cells Genetic perturbation of Wnt production or signalling suppressed tumour progression Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells leading to improved survival of tumour-bearing mice These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies Prices may be subject to local taxes which are calculated during checkout An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control Repair and regeneration of the respiratory system: complexity Lung development: orchestrating the generation and regeneration of a complex organ The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma Defining the mode of tumour growth by clonal analysis Tumour heterogeneity and cancer cell plasticity RSPO2 enhances canonical Wnt signaling to confer stemness-associated traits to susceptible pancreatic cancer cells A rare population of CD24+ITGB4+Notchhi cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells Recent clinical advances in lung cancer management Diminished WNT → β-catenin → c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium Wnt signaling pathway in non-small cell lung cancer WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974 Genome-scale transcriptional activation by an engineered CRISPR–Cas9 complex A transcriptional response to Wnt protein in human embryonic carcinoma cells The angiocrine factor Rspondin3 is a key determinant of liver zonation Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate: evidence for a network of interacting genes Wnt pathway inhibition via the targeting of frizzled receptors results in decreased growth and tumorigenicity of human tumors Therapeutic targeting of tumor-derived R-Spondin attenuates β-catenin signaling and tumorigenesis in multiple cancer types Stage-specific sensitivity to p53 restoration during lung cancer progression Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum Uncoupling cancer mutations reveals critical timing of p53 loss in sarcomagenesis Generation of primary tumors with Flp recombinase in FRT-flanked p53 mice A robust and high-throughput Cre reporting and characterization system for the whole mouse brain Adenomatous polyposis coli (APC) is required for normal development of skin and thymus Screening for tumor suppressors: loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma A global double-fluorescent Cre reporter mouse Identification of stem cells in small intestine and colon by marker gene Lgr5 Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase The differential effects of mutant p53 alleles on advanced murine lung cancer Toolkit for evaluating genes required for proliferation and survival using tetracycline-regulated RNAi Constitutive transcriptional activation by a β-catenin-Tcf complex in APC−/− colon carcinoma Development and applications of CRISPR–Cas9 for genome engineering Compact and highly active next-generation libraries for CRISPR-mediated gene repression and activation A modular assembly platform for rapid generation of DNA constructs Enzymatic assembly of DNA molecules up to several hundred kilobases Lentiviral vectors to probe and manipulate the Wnt signaling pathway DNA targeting specificity of RNA-guided Cas9 nucleases Genome engineering using the CRISPR–Cas9 system Rapid modelling of cooperating genetic events in cancer through somatic genome editing Rapid and efficient one-step generation of paired gRNA CRISPR–Cas9 libraries The molecular signatures database (MSigDB) hallmark gene set collection Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes EBSeq: an empirical Bayes hierarchical model for inference in RNA-seq experiments Replacing suffix trees with enhanced suffix arrays Identification of common molecular subsequences ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data SSW library: an SIMD Smith–Waterman C/C++ library for use in genomic applications Integrative genomics viewer (IGV): high-performance genomics data visualization and exploration Understanding the New Statistics: Effect sizes Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver Download references Sharp for critical reading of the manuscript and T Papagiannakopoulos for helpful discussions; H Clevers for Lgr5CreER/+ mice; Janssen Pharmaceuticals for human tissue; J Bronson for expertise in animal pathology; Y Levine for massively parallel sequencing expertise; L Weissman for Lgr5 CRISPR gene activation sgRNA sequences; A Li for help with generation of TCGA data catalogues; M Cormier and the Hope Babette Tang (1983) Histology Facility for histology support; S Yee for administrative support; and the Swanson Biotechnology Center for excellent core facilities This work was financially supported by the Transcend Program and Janssen Pharmaceuticals by the Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute is supported by the National Cancer Institute (K99 CA187317) the Hope Funds for Cancer Research and the Maud Kuistila Foundation is a Howard Hughes Medical Institute Investigator Koch Institute for Integrative Cancer Research University of Massachusetts Medical School performed all types of experiments reported in the study; F.J.S.-R performed CRISPR gene activation experiments and analysed CRISPR-mutated loci; N.M.C performed gene expression analysis and N.M.C performed cell culture experiments; M.C.-B developed and used microcomputed tomography analysis methodology; W.X conducted bioinformatic analyses; F.J.S.-R. wrote the manuscript with comments from all authors The authors declare no competing financial interests Clevers and the other anonymous reviewer(s) for their contribution to the peer review of this work Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations qRT–PCR analysis of the Wnt target genes Axin2 (m) and Lgr5 (n) in 3D cultures of sublines of a KP LUAD cell line (TT5764) expressing the CRISPR-activator system driving expression of Rspo2 (Rspo2-a) Data are mean ± s.d.; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; n.s. Lgr5 and Lgr6 transcripts in sublines of a KP LUAD cell line stably expressing shLgr4 Note minimal effects of the indicated shRNAs on other Lgr5 family members n = 3 technical replicates per condition; representative data from three experiments carried out in different cell lines Formation of 3D tumour spheroids of sublines of a KP LUAD cell line expressing the indicated shRNAs in response to 1 μg ml−1 Rspo1 (b representative data from three experiments carried out in different cell lines No difference in cell morphology (f) or growth rate (g) in sublines of a KP LUAD cell line expressing shLgr4 shLgr6 or control shLuciferase (shLuc) over six days in two-dimensional cell culture Data are mean + s.d.; *P < 0.05; **P < 0.01; ***P < 0.001; Student’s two-sided t-test (a) or two-way ANOVA (c All experiments were performed three times each time with a different KP LUAD cell line a, Schematic representation of the lentiviral vector46 used to transduce a KPT LUAD cell line tdTomato and 7TCF::Luciferase signals at baseline (0 h) and 48 h after treatment with 10 mg per kg per day LGK974 or vehicle Red arrows indicate two subcutaneous tumours with reduced 7TCF-dependent bioluminescence in response to 48 h of LGK974 treatment Suppression of 7TCF-driven bioluminescence by LGK974 relative to the tdTomato signal in mice with subcutaneous transplants of the KPT LUAD cell line stably expressing the 7TCF::Luciferase-PGK-Puro lentivirus three mice per group; representative data from two independent experiments Data are mean ± s.d.; Student’s two-sided t-test Haematoxylin and eosin (HE) or β-catenin staining in KP adenomas or in adenocarcinomas Immunofluorescence for β-catenin (red) and porcupine (green) in a KP LUAD arrowheads) in KP lung adenomas or adenocarcinomas Immunofluorescence for porcupine (green) in an autochthonous grade 3 KPT adenocarcinoma Arrowheads indicate peritumoural porcupine+ cells CD11b (green) and porcupine (red) immunofluorescence in a peritumoural region Immunohistochemistry for β-catenin or porcupine in human LUAD Arrowheads indicate cells with nuclear β-catenin 65 human LUAD tumours in two tissue microarrays were analysed Comparison of PORCN gene expression in tumours versus normal tissue in the TCGA lung adenocarcinoma cohort: Empirical cumulative density function (CDF) plots of standardized gene expression values are shown A right-shift indicates relatively higher expression with P values indicated to assess statistical significance (Kolmogorov–Smirnov test) Qualitative analysis of mutations introduced by sgPorcn.2 in vivo base pair (indicates the size of the insertion or deletion); INS Ratio indicates frequency of event across the 15 samples analysed not significant; Student’s two-sided t-test (a Immunofluorescence for GFP (green) and EpCAM (red) in a subcutaneous transplant established from a single-cell clone of a KPT;Lgr5CreER/+ cell line Immunofluorescence for GFP (green) and porcupine (red) in a subcutaneous transplant established from a single-cell clone of a KPT;Lgr5CreER/+ cell line Data are representative of four replicate experiments each with a different KP;Lgr5CreER/+ cell line ISH for Lgr5 mRNA (purple) in KP;Pdx1::Cre PDAC Representative of three PDAC tumours analysed Immunofluorescence staining for GFP (green) in a tdTomato+ (red) autochthonous KP;Lgr5GFP-CreER/+;Rosa26tdTomato/+;Pdx1::Cre PDAC Quantification of primary spheroids containing EdU+ cells per 100 Lgr5+tdTomato+ or Lgr5−tdTomato+ primary mouse PDAC cells plated Data are mean ± s.d.; *P < 0.05; Student’s two-sided t-test Immunofluorescence staining for GFP (green) and porcupine (red) in autochthonous KP;Lgr5GFP-CreER/+;Pdx1::Cre PDAC Note juxtaposition of Lgr5+ and porcupine+ cells in the tumours Representative data from six KP;Lgr5GFP-CreER/+;Pdx1::Cre PDAC tumours analysed Immunofluorescence staining for GFP (green) and porcupine in an autochthonous ApcΔ/Δ;Lgr5GFP-CreER/+intestinal adenoma note juxtaposition of Lgr5+ and porcupine+ cells in the tumours Immunohistochemistry for porcupine (brown) in human colorectal adenocarcinoma Five human colorectal adenocarcinoma samples were analysed Qualitative analysis of mutations introduced by sgLgr4 or sgLgr5 in vivo base pair (indicates size of insertion/deletion); INS Ratio indicates frequency of event across all samples analysed qPCR analysis of Rspo gene expression in 16 KP LUAD tumours Tumours were collected at 16 weeks after initiation with adenoviral Cre Note the Rspo1 transcripts in endothelial cells qPCR for Rspo1 and Rspo3 in tdTomato+ tumour cells (tumour) CD31+ endothelial cells and the rest of the cells (stroma) in microdissected KPT LUAD tumours following sorting The expression of Pecam1 (which encodes CD31) was found to be >400-fold enriched in the CD31+ fraction compared to the stroma (not shown) representative of two replicate experiments Heatmap showing relative expression levels of Porcn and the 19 mouse Wnt genes on the basis of the qPCR analysis in sorted tdTomato+ KP LUAD cells (T) versus tdTomato− stromal cells (S) in microdissected tumours collected at 20 weeks after tumour initiation (a time point when most tumours are adenocarcinomas) Volcano plot of qPCR array gene expression analysis showing statistically significant differentially expressed genes (in red x axis is the log2 fold change (tumour/stroma) and y axis is the –log10P value of the differential enrichment (two-sided t-test) Wnt7a and Wnt7b gene expression in KP tumours microdissected at 9 weeks (adenomas) or 20 weeks (adenocarcinomas) after initiation with adenoviral Cre Comparison of WNT gene expression in tumours versus normal tissue in the TCGA lung adenocarcinoma cohort: Empirical CDF plots of standardized gene expression values for WNT5A and WNT7B are shown Heatmap showing relative expression levels of Lrp5 Lrp6 and nine mouse Fzd genes on the basis of the qPCR analysis in sorted tdTomato+ KP LUAD cells (T) versus tdTomato− stromal cells (S) in microdissected tumours collected at 20 weeks after tumour initiation (a time point when most tumours are adenocarcinomas) qPCR analysis of eight Fzd receptors in KP tumours microdissected at 9 weeks (adenomas) or 20 weeks (adenocarcinomas) after initiation with adenoviral Cre Data are mean ± s.d.; *P < 0.05; Student’s two-sided t-test (b qPCR analysis of Axin2 and Lgr5 transcripts in KP LUAD tumours two weeks after treatment with 10 mg per kg per day LGK974 or vehicle Treatment was started at 11 weeks after tumour initiation Quantification of μCT data showing change in tumour volume compared to baseline (obtained at 76 days after tumour initiation dashed line) after four weeks of 10 mg per kg per day LGK974 or vehicle control Recipient mouse lungs four weeks after orthotopic GEMM-DA of 50,000 primary tdTomato+ (red) mouse LUAD cells Donor mice bearing autochthonous KPT LUAD tumours were treated for two weeks with LGK974 or vehicle (starting at 84 days after tumour induction) The recipient mice were treated with LGK974 or vehicle for four weeks tdTomato+ tumours in sections from lungs in c containing EdU+ cells (white arrowheads) or not containing EdU+ cells (yellow arrowheads) Quantification of EdU+ (black) or EdU− (grey) tumours per section through the lungs depicted in c representative data from three replicate experiments Data are mean ± s.d.; *P < 0.05; Student’s two-sided t-test (a This file contains additional discussion on the differences between R-spondin and Wnt ligand stimulation This file contains Supplementary Tables 1-4 Download citation Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Lung adenocarcinomas are aggressive tumours which are associated with poor treatment outcome Tyler Jacks and colleagues now show that lung adenocarcinomas display two distinct subpopulations of tumour cells One of these shows high levels of Wnt signalling and gives rise to the second one that produces Wnt ligands The latter population fuels tumour growth of the former showing that lung cancer cells can produce their own niche These findings shed new light on the mechanisms underlying intratumoural heterogeneity which may have therapeutic implications Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research About us | Advertise with us | Contact us Posted: 20 November 2023 | | No comments yet Eliminating AT1-like cells in experimental models has shown potential to improve KRAS inhibitor treatment for lung adenocarcinoma Memorial Sloan Kettering Cancer Center (MSK) scientists have gained a new understanding of lung cancer cells’ ‘memories’ which suggests a new strategy for improving treatment Research from the lab of cancer biologist Dr Tuomas Tammela demonstrates that some lung cancer cells keep a ‘memory’ of the healthy cell where they originated from This could be exploited to make KRAS inhibition more effective The study focused on lung adenocarcinoma a type of non-small cell lung cancer that is the most frequent type of lung cancer in the US and responsible for seven percent of all cancer deaths This cancer is often driven by mutations in the KRAS gene The study’s co-first author Zhuxuan “Zoe” Li a doctoral student in the Tammela lab at MSK’s Sloan Kettering Institute cancer driving KRAS proteins were considered ‘undruggable.’” She continued: “Within the last few years Food and Drug Administration approved the first KRAS inhibitors and most patients’ cancers eventually acquire resistance to the drugs and come back.” discovered valuable information about lung cancer cells that remain after treatment with a KRAS inhibitor They suggest that separately targeting these cells alongside treatment with a KRAS inhibitor could help prevent recurrence Oxygen is absorbed into the lungs and carbon dioxide released via air sacs called alveoli The lining of the alveoli is made from two different types of cells:  alveolar type 1 (AT1) and alveolar type 2 (AT2) with a large surface to facilitate gas exchange between the lungs and the bloodstream secrete compounds that are crucial for the health and function of the lungs They also aid in maintaining and repairing the lungs by dividing to create replacement AT1 cells Dr Tammela described them as “stem cells with a day job.” Lung cancer cells usually develop from AT2 cells These cancer cells adopt some ‘remembered’ properties of the AT1 cells that AT2 cells differentiate into when they are playing their stem cell role KRAS has an essential role in regulating cell growth and division in healthy cells. However, when the gene becomes mutated, it can lead to excessive cell proliferation KRAS inhibitors can switch off this explosive growth but they still leave behind cancer cells that are not sensitive to the drug This gives the cancer the opportunity to develop new mutations to resist the drugs’ effects The scientists used genetically engineered mouse models, mice implanted with patient-derived tumours and tumour samples from patients to study determine the mechanisms of this resistance They found that the cancer cells that remained after treatment were AT1-like cells and they have the capacity to reignite the cancer’s runaway growth we found that if you get rid of these AT1-like cells it greatly improves the treatment response to KRAS inhibitors,” Dr Tammela said Eliminating those cells in experimental models is fairly easy but doing so in the clinic will require further research Dr Tammela explained: “Now that we’ve done these proof-of-concept experiments the next step would be to find surface proteins that are unique to these AT1-like cells and then develop a therapeutic that can bind to them and kill them.” The study was published in Cancer Discovery Related topics, , Related conditions Related organisations, Related people, , By No comments yet , , , , , All subscriptions include online membership giving you access to the journal and exclusive content By By , , , Comment * document.getElementById("comment").setAttribute( "id" "ad98543042ef8a419d4cc4031332f1d8" );document.getElementById("a3f6228d48").setAttribute( "id" Write for us | Advertise with us Drug Target Review is published by: Russell Publishing Ltd.Court LodgeHogtrough HillBrasted © Russell Publishing Limited, 2010-2025. 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functionalities of the website CookieTypeDurationDescriptioncf_ob_infopersistent1 minuteThis cookie is set by Cloudflare content delivery network and in conjunction with the cookie 'cf_use_ob' Published in 4/2024 - Colour Article Four new-builds and one refurbishment project are in the running for this year’s Finlandia Prize for Architecture The latest Finlandia Prize for Architecture shortlist an opportunity to speculate about what the choice of candidates might reveal about the current state and future of Finnish architecture the winner will be chosen by a non-architect selector their own personal likes and private preferences The jury charged with selecting the shortlist consists exclusively of professional architects ideally placed to accurately sniff out the choicest architectural gems each year a total of 47 buildings have been shortlisted among them Helsinki University Main Library (Anttinen Oiva 2012) the Löyly building housing a public sauna and restaurant (Avanto 2016) Helsinki’s Central Library Oodi (ALA 2018) That none of the above projects went on to win speaks volumes about just how unpredictable the selection process can be is made up of five candidates: four new-builds and one refurbishment project What immediately jumps out upon surveying the shortlist is how extremely well the Tampere region has fared this year having bagged as many as three spots on the list the first ever candidate from within the city itself a joint venture between Tampere and its neighbouring Kangasala and the Hyytiälä Forestry Field Station in Juupajoki has this year had to settle for just one candidate in the form of the Tapiola Church refurbishment project is a new building for the Step Education in Järvenpää Although much of the development that has taken place in Finland in recent years has been heavily concentrated in the country’s growth centres only Tammela Stadium is located in a densely-built urban setting Representing the opposite end of the spectrum is Hyytiälä Forestry Field Station with its idyllic rural setting exerts a new and serenely white influence over a somewhat higgledy-piggledy campus while the new Lamminrahka neighbourhood has gained its first ever landmark in the form of the newly built school the most visible sign that the garden city’s iconic church has undergone a refurbishment is its new entrance Although much of the development in recent years has been heavily concentrated in the growth centres a handful of architectural practices have managed to bag multiple shortlist spots year after year Overwhelmingly topping the nominations leaderboard is JKMM who bagged yet another nomination this year The shortlist also features two other past winners: last year’s number one who won in 2016 with their Puukuokka Housing Block who have received the nod on more than one occasion too we do have a first-time nominee in Raudanko + Kankkunen in light of the other names on the shortlist particularly prevalent in Finnish school and nursery buildings is again a visible presence on the shortlist thanks to Lastu and the Hyytiälä Forestry Field Station Both feature visually striking CLT interiors But given that the main prize last year went to the Martta Wendelin Daycare Centre surely we’re due something new and exciting on the timber construction front a secondary school and cultural centre in Tuusula designed by AOR Architects which uses laminated logs on a scale that has never really been seen before And what about the aesthetic side of things Does the shortlist tell us something about the kind of architecture we can expect to see in the next few years all the shortlisted works represent confident skillful design that draws on the modernist tradition rely on the “authentic” natural colour of the materials used.  Tammela Stadium and Hyytiälä Forestry Field Station both have the sort of tectonic quality that is rarely seen in Finnish architecture With its 100-metre long suspended roof structures and sculptural concrete pillars while the forest station’s archetypal form recalls Gottfried Semper’s theories on the fundamental elements of architecture those elements consist of an elevated platform both rely on symmetry while deliberately disrupting it: the stadium’s convex roof is compromised by the high-rise residential buildings towering above it complete with irregular window placement while at the forest station a series of symmetrical blocks wrap around the outdoor space Tammela Stadium and Hyytiälä Forestry Field Station both have the sort of tectonic quality that is rarely seen in Finnish architecture Lastu and Lamminrahka School Centre represent an entirely different approach They consist of seemingly randomly interlinking volumes between which a series of open public spaces are created the whiteness of the roof and external walls both highlight its geometric form and set it apart from its neighbours a series of materials choices have been employed to break up the vast mass By far the most modernist of the shortlisted candidates is Tapiola Church an outstanding example of modern sacral architecture in Finland that dates back to 1965 A number of Finlandia Prizes have already been awarded to refurbishments of our modern architectural classics will Aarno Ruusuvuori’s ascetic concrete design wow Antti Kuronen like his predecessors were bowled over by the rhythmical majesty of Käärmetalo the heroic flair of the Olympic Stadium and the light-filled interiors of Jyväskylä University Library The answer will be revealed in early October when the winner of this year’s Finlandia Prize for Architecture is announced Kristo Vesikansa is the Editor-in-Chief of the Finnish Architectural Review Interview built next to the Finlandia Hall during its renovation has been designed in accordance with the principles of circular economy construction and reverse building design It is also the first big completed project for three architecture students Rainer Mahlamäki sees at least three factors that explain the modest international visibility of contemporary Finnish architecture The photos in the article show the 11 Finnish buildings that have been shortlisted for the Mies van der Rohe Award The decade-long engagement and consultation process that preceded the launch of Helsinki’s new central library Oodi meant that building came heavily laden with expectations Subscribe Read on to discover our latest interviewee’s answers for The Luxury Lifestyle List We caught up with Enly Tammela, the leading fashion model and visionary founder behind the premium ENLY candle brand Enly’s dedication to her craft keeps her name on everyone’s lips and campaigns for distinguished multi-million dollar clients such as Ralph Lauren Enly has called New York City her home for the last decade I drive quite a bit in the city and having a big car just makes me feel safe My choice of car is a Mercedes Benz G-Class I do have a little crush on the convertible right now It is also perfect for a little getaway and it is always fun to drive My favourite destination for some time has been St Barths recently I traveled to Turks and Caicos and fell in love with the Amanyara hotel It was unbelievably beautiful with white sand I like to think that I can live without any gadget but if I had to pick one it would be my phone just because having a new business requires me to use my phone more than before But I am definitely not a tech/gadget person I love interacting with people in real life I love their quality and comfort that comes with a little kick of colour texture and effortless look but still makes me feel sexy My go to brand for essentials such as tank tops perfect little black dresses and custom pieces is Travis Taddeo I love supporting brands that have soul and authenticity I don’t like flying even though it has been a very big part of my whole life My favourite flying experience is definitely a Blade seaplane to the Hamptons just because it’s short and sweet I never thought that I would be into watches but I treated myself to a Rolex a few years ago and I have been wearing it ever since and I love it Something more feminine like gold Panthere de Cartier I have been going there for so many years and have become very friendly with the team They always take good care of me and seat me and my pup Strawberry at my favourite table A perfect glass of Beaujolais while watching Sex and the City I love supporting local small businesses because they are the heart of what New York City is about Through my business I plan on giving back to charities that are supporting children’s education and artistry Open image viewerIlves were not expected to beat Austria Vienna Image: IMAGO/Branislav Racko/ All Over PressYle News1.8.2024 11:04Ilves Tampere pulled off a shock win over Austria Vienna to go through to the third qualifying round of the Uefa Conference League in the best result a Finnish club has achieved in European football so far this season They had won the first leg 2-1 last week at Tammela The second leg on Wednesday evening was a real thriller with Ilves levelling the tie on aggregate three times before winning a penalty shootout 5-4 scoring all five of their kicks and substituting their goalkeeper specifically for penalties right at the end of extra time Otso Virtanen had been injured in the first leg and replaced by Ville Seppä but was brought on for penalties and saved the final kick from Dominik Fitz Ilves are now set to play Swedish team Djurgården in the third qualifying round who are 3-0 up after their first leg against Progrés from Luxembourg Users with an Yle ID can leave comments on our news stories. You can create your Yle ID via this link. Our guidelines on commenting and moderation are explained here Scientists at the Sloan Kettering Institute, the Koch Institute at MIT, and the Klarman Cell Observatory at the Broad Institute have identified an unusual cell state that emerges early in tumor evolution and supports a cancer’s ability to outwit chemotherapy Cancer’s knack for developing resistance to chemotherapy has long been a major obstacle to achieving lasting remissions or cures While tumors may shrink soon after chemotherapy Scientists once thought that unique genetic mutations in tumors underlay this drug resistance nongenetic changes in cancer cells to explain their adaptability For example, one way that cancer cells can develop resistance is by changing their identity. A prostate cancer cell that is sensitive to hormone-blocking therapy might morph into a cell type that does not require the hormone for its growth Rather than specific mutations driving them identity changes like these come about through changes in gene expression — cells turning specific genes on or off a single tumor can become very different in its cellular makeup This heterogeneity creates challenges for treatment since a single drug is unlikely to work against so many different cell types A new study from a team of researchers at the Sloan Kettering Institute the Koch Institute for Integrative Cancer Research at MIT and the Klarman Cell Observatory at the Broad Institute finds that this tumor heterogeneity can be traced to a common source: a particularly flexible cell state that is characteristic of a subset of cells in a tumor and can generate many other diverse cell types “The high-plasticity cell state is the starting point for much of the heterogeneity we see in tumors,” says Tuomas Tammela, an Assistant Member in the Cancer Biology and Genetics Program at SKI and the corresponding author on the new paper, published July 23 in the journal Cancer Cell “It’s kind of like a busy intersection of many roads: Wherever a cell wants to end up identity-wise it has to go through this cell state.” Because this cell state produces nearly all the cellular heterogeneity that emerges in tumors it is an attractive target for potential therapies The particular tumors the researchers examined were lung cancer tumors growing in mice. Jason Chan a physician-scientist doing a fellowship in the Tammela lab and one of the paper’s lead authors says finding this unusual cell state was a surprise “This highly plastic cell state is something completely new,” he says we didn’t know what it was because it was so different It didn’t look like normal lung cells where the cancer came from and it didn’t really look like lung cancer either It had features of embryonic germ layer stem cells he and his colleagues found these cells in every tumor they examined which suggested that the cells were doing something biologically very important The researchers identified these highly plastic cells by employing a relatively new laboratory technique called single cell RNA sequencing (scRNA-Seq) This technique allows researchers to take “snap shots” of individual cells’ gene expression profiles — revealing which genes are on or off By performing scRNA-Seq on tumors as they grew over time they were able to watch when and how different cell types emerged over the course of a tumor’s evolution the researchers were able to create a kind of map of which cells came from which other cells “The map contains major highways and little dirt roads,” Dr “The high-plasticity cell state that we identified sits right in the middle of the map and it has even more paths coming out.” This high-plasticity cell state emerged consistently in a tumor’s evolution and persisted throughout its growth “it was the only cell state that we found to be present in every single tumor.” Plasticity — the ability of a cell to give rise to other cells that take on different identities — is a well-known feature of stem cells Stem cells play important roles in embryonic development and in tissue repair Many scientists think that cancers arise from specific cancer stem cells Tammela and colleagues do not think these high-plasticity cells are stem cells “When we compare the gene expression signature of these highly plastic cells to normal stems cells or known cancer stem cells They look completely different,” he says they’re not there at the very beginning of a tumor’s growth Many prior studies have looked for possible “resistance mutations” — genetic changes that account for a tumor’s ability to resist the effects of cancer drugs more often the basis of resistance remains a mysterious The new findings offer a potential solution to the mystery “Our model could explain why certain cancer cells are resistant to therapy and don’t have a genetic basis for that resistance that we can identify,” Dr it’s not all the cells in the tumor that are adapting It’s a subset of the cancer cells that are just more plastic By combining chemotherapy drugs with new medications that target these highly plastic cells the researchers think it might be possible to avert the emergence of resistance and provide longer lasting remissions save lives during surgeries and shield us from fatal infections That’s why scientists are exploring new sources Our regular soil might just be the knight in shining armor Soil is the birthplace of about 70% of all currently licensed antibiotics specifically a group of organisms known as actinobacteria the charming little blue-green planet we call home Many of her nooks and crannies are still unexplored including a plethora of untapped habitats for actinobacteria And who knows, these little microbes could hold the key to the next generation of antibiotics Here’s the best part: these fresh antibiotics might not annihilate bacteria but they could reduce their ‘virulence’ or disease-causing capability That’s like turning a fearsome dragon into a harmless lizard it’s harder for bacteria to fight back Now, let’s meet the brain behind this revolutionary idea. Dr Päivi Tammela of the University of Helsinki and her team have developed advanced screening assays to spot these antivirulence and antibacterial metabolites in actinobacteria extracts They discovered a compound from the Arctic Ocean that can inhibit the virulence of E coli that wreaks havoc on children under five This nasty bacterium sticks to cells in the gut and injects destructive ‘virulence factors’ into the host cell The team then sailed off to the Arctic Sea to an island called ‘Svalbard,’ aboard the Norwegian research vessel ‘Kronprins Haakon.’ and extracted and separated their cells into fractions Researchers found two unknown compounds from the strains Rhodococcus and Kocuria which showed strong antivirulence or antibacterial activity “Here we show how advanced screening assays can identify antivirulence and antibacterial metabolites from actinobacteria extracts,” said Dr Tammela “We discovered a compound that inhibits enteropathogenic E coli (EPEC) virulence without affecting its growth both in actinobacteria from the Arctic Ocean.” That makes it a promising candidate since E. coli is less likely to evolve resistance against this strain Tammela and her team found that the active compound was most likely a phospholipid a fatty molecule crucial for cell metabolism The discovery of these novel compounds presents a paradigm shift in the pursuit of new antibiotics. By focusing on antivirulence strategies rather than outright bacterial elimination, researchers can potentially reduce the evolutionary pressure that drives antibiotic resistance This means that we might not only preserve existing antibiotics for longer but also ensure that treatments can evolve alongside ever-adapting bacteria As the tide of resistance continues to rise such innovative approaches could safeguard our arsenal of medications granting us additional time to explore further solutions for the looming antibiotic crisis As we stand on the brink of this exciting new frontier the journey ahead demands collaboration across various scientific disciplines and clinicians must join forces to rigorously test and refine these promising compounds funding institutions and policy-makers should prioritize research initiatives that explore microbial biodiversity and its potential applications By promoting an environment of interdisciplinary research and innovation we can encourage the discovery of even more exciting treatments that could stem the tide of bacterial resistance keeping our communities safe and healthy for generations to come The team is now focused on optimizing culture conditions for antibiotic compound production isolating enough of each compound for further study and understanding their respective bioactivities That’s the great thing about science The study is published in the journal Frontiers in Microbiology Like what you read? Subscribe to our newsletter for engaging articles Check us out on EarthSnap, a free app brought to you by Eric Ralls and Earth.com Metrics details involves specification of endothelial cells to tip cells and stalk cells whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting we found that endothelial deletion of Vegfr3 postnatally led to excessive angiogenic sprouting and branching and decreased the level of Notch signalling indicating that VEGFR-3 possesses passive and active signalling modalities macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching FoxC2 is a known regulator of Notch ligand and target gene expression and Foxc2+/−;Vegfr3+/− compound heterozygosity recapitulated homozygous loss of Vegfr3 These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele Failure of blood island formation and vasculogenesis in Flk-1-deficient mice Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2) A reassessment using novel receptor-specific vascular endothelial growth factor mutants Lymphangiogenesis: molecular mechanisms and future promise Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts Cardiovascular failure in mouse embryos deficient in VEGF receptor-3 Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish Expression of the fms-like tyrosine kinase FLT4 gene becomes restricted to lymphatic endothelium during development Transgenic induction of vascular endothelial growth factor-C is strongly angiogenic in mouse embryos but leads to persistent lymphatic hyperplasia in adult tissues Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins Vascular endothelial growth factor D is dispensable for development of the lymphatic system Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching Regulation of vascular morphogenesis by Notch signaling Endothelial tubes assemble from intracellular vacuoles in vivo The molecular basis of vascular lumen formation in the developing mouse aorta Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis Macrophage diversity enhances tumor progression and metastasis Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis inducible Cre-recombinase activation in vascular endothelium VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain and macrophage recruitment by vascular endothelial growth factor-C in melanoma A model for gene therapy of human hereditary lymphedema Endothelial cell adhesion to the extracellular matrix induces c-Src-dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic kinase activity Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting Hematological characterization of congenital osteopetrosis in op/op mouse Possible mechanism for abnormal macrophage differentiation Critical role of endothelial Notch1 signaling in postnatal angiogenesis Convergence of Notch and β-catenin signaling induces arterial fate in vascular progenitors Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1 Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth Endothelial extracellular matrix: biosynthesis and functions during vascular morphogenesis and neovessel stabilization VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development Vascular endothelial growth factor receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF(165) and VEGF(121) Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression Vegfc is required for vascular development and endoderm morphogenesis in zebrafish Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells Isolated lymphatic endothelial cells transduce growth survival and migratory signals via the VEGF-C receptor VEGFR-3 Generalized lacZ expression with the ROSA26 Cre reporter strain Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors The Notch ligand Jagged-1 is able to induce maturation of monocyte-derived human dendritic cells Angiopoietin-1 promotes lymphatic sprouting and hyperplasia Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization Lymphatic endothelium and Kaposi’s sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3 Recessive primary congenital lymphoedema caused by a VEGFR3 mutation Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal antibody that antagonizes receptor activation by VEGF-C Functional interaction of VEGF-C and VEGF-D with neuropilin receptors Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting Download references Pytowski at Eli Lilly for VEGFR-2- and VEGFR-3-blocking antibodies Jeltsch (Molecular/Cancer Biology Laboratory Kaijalainen (Molecular/Cancer Biology Laboratory Finland) for generating mDll4-Fc and mDll4–ECTM–eGFP expression vectors Alitalo (Institute of Pharmaceutical Sciences Switzerland) for valuable help with experiments and K Helenius for critical comments on the manuscript The Biomedicum Molecular Imaging Unit is acknowledged for microscopy services Tainola for excellent technical assistance as well as personnel of the Meilahti Experimental Animal Center (University of Helsinki) for expert animal husbandry This work was supported by grants from the Academy of Finland the Association for International Cancer Research the Louis-Jeantet Foundation and the European Research Council (ERC-2010-AdG-268804-TX-FACTORS) was supported by personal grants from the Emil Aaltonen Foundation the Orion-Farmos Research Foundation and the Paulo Foundation was supported by personal grants from the K the Ida Montin Foundation and the Orion-Farmos Research Foundation the Lister Institute of Preventive Medicine the European Molecular Biology Organization (EMBO) Young Investigator Programme and the Leducq Transatlantic Network ARTEMIS was supported by an EMBO long-term postdoctoral fellowship was supported by a Marie Curie FP7 postdoctoral fellowship Present address: Present addresses: Vascular Biology Department of Medical Biochemistry and Biophysics Sweden (L.K.); Lymphatic Development Laboratory Cancer Research UK London Research Institute Tuomas Tammela and Georgia Zarkada: These authors contributed equally to this work Research Programs Unit and Department of Pathology London Research Institute—Cancer Research UK Department of Developmental and Molecular Biology Virtanen Institute and Department of Medicine Institut National de la Santé et de la Recherche Médicale U833 directed and carried out experiments and data analysis designed and carried out cell culture and biochemistry experiments carried out three-dimensional embryoid body sprouting experiments and analysed data; K.H morphometry of retinal vessels and qRT-PCR carried out biochemistry experiments and analysed data; W.Z produced and validated Notch ligand and inhibitor proteins; C.A.F carried out three-dimensional embryoid body sprouting experiments and analysed data; A.M carried out retina experiments and analysed data; E.A provided op/op retinas and carried out genotyping; N.M analysed retinas of Vegfr3+/LacZ mice; J.W.P interpreted results and helped write the paper; K.A is the chairman of the Scientific Advisory Board of Circadian Download citation Journal of Experimental & Clinical Cancer Research (2023) Neuroscience and Behavioral Physiology (2022) Sign up for the Nature Briefing newsletter — what matters in science Suggestions or feedback? an aggressive form of cancer that accounts for about 40 percent of U.S is believed to arise from benign tumors known as adenomas MIT biologists have now identified a major switch that occurs as adenomas transition to adenocarcinomas in a mouse model of lung cancer They’ve also discovered that blocking this switch prevents the tumors from becoming more aggressive Drugs that interfere with this switch may thus be useful in treating early-stage lung cancers “Understanding the molecular pathways that get activated as a tumor transitions from a benign state to a malignant one has important implications for treatment These findings also suggests methods to prevent or interfere with the onset of advanced disease,” says Tyler Jacks director of MIT’s Koch Institute for Integrative Cancer Research and the study’s senior author The switch occurs when a small percentage of cells in the tumor begin acting like stem cells allowing them to give rise to unlimited populations of new cancer cells “It seems that the stem cells are the engine of tumor growth They’re endowed with very robust proliferative potential and they give rise to other cancer cells and also to more stem-like cells,” says Tuomas Tammela a postdoc at the Koch Institute and lead author of the paper which appears in the May 10 online edition of Nature the researchers focused on the role of a cell signaling pathway known as Wnt This pathway is usually turned on only during embryonic development but it is also active in small populations of adult stem cells that can regenerate specific tissues such as the lining of the intestine One of the Wnt pathway’s major roles is maintaining cells in a stem-cell-like state so the MIT team suspected that Wnt might be involved in the rapid proliferation that occurs when early-stage tumors become adenocarcinomas The researchers explored this question in mice that are genetically programmed to develop lung adenomas that usually progress to adenocarcinoma they found that Wnt signaling is not active in adenomas about 5 to 10 percent of the tumor cells turn on the Wnt pathway These cells then act as an endless pool of new cancer cells about 30 to 40 percent of the tumor cells begin to produce chemical signals that create a “niche,” a local environment that is necessary to maintain cells in a stem-cell-like state “If you take a stem cell out of that microenvironment it rapidly loses its properties of stem-ness,” Tammela says “You have one cell type that forms the niche and then you have another cell type that’s receiving the niche cues and behaves like a stem cell.” While Wnt has been found to drive tumor formation in some other cancers this study points to a new kind of role for it in lung cancer and possibly other cancers such as pancreatic cancer “What’s new about this finding is that the pathway is not a driver but it modifies the characteristics of the cancer cells It qualitatively changes the way cancer cells behave,” Tammela says “It’s a very nice paper that points to the influence of the microenvironment in tumor growth and shows that the microenvironment includes factors secreted by a subset of tumor cells,” says Frederic de Sauvage vice president for molecular oncology research at Genentech When the researchers gave the mice a drug that interferes with Wnt proteins they found that the tumors stopped growing when these treated tumor cells were implanted into another animal The researchers also analyzed human lung adenocarcinoma samples and found that 70 percent of the tumors showed Wnt activation and 80 percent had niche cells that stimulate Wnt activity These findings suggest it could be worthwhile to test Wnt inhibitors in early-stage lung cancer patients They are also working on ways to deliver Wnt inhibitors in a more targeted fashion to avoid some of the side effects caused by the drugs Another possible way to avoid side effects may be to develop more specific inhibitors that target only the Wnt proteins that are active in lung adenocarcinomas The Wnt inhibitor that the researchers used in this study which is now in clinical trials to treat other types of cancer The research was funded by the Janssen Pharmaceuticals-Koch Institute Transcend Program and the Cancer Center Support grant from the National Cancer Institute This website is managed by the MIT News Office, part of the Institute Office of Communications Massachusetts Institute of Technology77 Massachusetts Avenue Metrics details Traditional cloning methods have limitations on the number of DNA fragments that can be simultaneously manipulated which dramatically slows the pace of molecular assembly a Gibson assembly-based modular assembly platform consisting of a collection of promoters and genes which allows for one-step production of DNA constructs GMAP facilitates rapid assembly of expression and viral constructs using modular genetic components as well as increasingly complicated genetic tools using contextually relevant genomic elements Our data demonstrate the applicability of GMAP toward the validation of synthetic promoters establishment of inducible lentiviral systems tumor initiation in genetically engineered mouse models and gene-targeting for the generation of knock-in mice GMAP represents a recombinant DNA technology designed for widespread circulation and easy adaptation for other uses These traditional cloning methods rely on the presence of restriction sites in both vector and insert and their prevalence – or lack thereof – can constrain possible assemblies in particular those involving multiple inserts overcome these sequence requirements and allow for assembly of multiple inserts in a given reaction particularly toward the engineering and study of synthetic biology pathways With these previous advances in synthetic biology circuit design in mind we sought to develop a modular assembly platform using libraries of promoters genes and destination vectors applicable towards a broader range of techniques common to biomedical research such as viral production and gene targeting we establish a common platform for assembly of genetic tools ranging from expression and viral constructs to homologous recombination targeting constructs in order to address questions of increasing biologic complexity Gibson assembly-based modular assembly platform (GMAP) genes and backbones from established GMAP-compatible collections are used in a one step isothermal assembly reaction to produce DNA constructs on demand (B) Schematic of possible orderings of genes and promoters Promoter A (pA) is flanked by sites 1 and 2 promoter B (pB) is flanked by sites 3 and 4 promoter C (pC) is flanked by sites 1 and 3 gene B (gB) is flanked by sites 4 and 5 and gene C (gC) is flanked by sites 2 and 5 (C) Schematic diagram of experiment using GMAP retroviral backbone Retroviruses expressing GFP driven by different promoters were assembled using GMAP and used to transduce murine 3T6 fibroblasts or murine lung cancer (KP) cells human phosphoglycerate kinase 1 promoter; CMV cytomegalovirus immediate-early promoter; EFS clara cell secretory protein promoter; UBC (D) Bar graph shows flow cytometry measurements of median fluorescence intensity (MFI) of GFP from 3T6 and KP cells transduced with GMAP-generated retrovirus Data are representative of at least three independent experiments (E) GMAP-generated lentiviruses expressing mTagBFP2-AUTR (i) or mKO2-CUTR(iii) sensor cassettes were assembled and used to transduce a Cre reporter cell line (3TB) 3TB cells were selected with hygromycin and visualized by confocal microscopy (F-H) Histograms from 3TB cells expressing mTagBFP2-AUTR (F) or mKO2-CUTR (H) transfected with three inducible hairpin constructs targeting the A After transfection 3TB cells were selected with blasticidin treated with doxycycline and knockdown was assessed by flow cytometry analysis on GFP+ cells Grey histograms represent cells lines transfected with an inducible shRNA targeting luciferase one must screen at least three bacterial colonies for two-fragment (not including backbone) reactions and five for four-fragment reactions to have a greater than 99% probability of obtaining at least one correctly assembled colony These results demonstrate the ability of GMAP to rapidly assemble and functionally test in vitro retroviral and lentiviral constructs using standard genetic components such as synthetic promoters In vivo applications of GMAP using lentiviral and Rosa26 targeting constructs (A) K-rasLSL−G12D/+;p53fl/fl mice were infected with GMAP-generated hypoxia response element (HRE):GFP-pGK:Cre or pGK:Cre lentivirus After 30 weeks tumors were assessed for GFP expression hypoxia as determined by pimonidazole staining and hematoxylin and eosin (H&E) (B) Column scatter plot shows quantification of immunohistochemistry shown in (A) Data are presented as fraction of tumor area that expressed GFP or pimonidazole staining (C) FACS histogram of KP cells engineered to express CloverCP in the presence of doxycycline and rtTA (VerdeGo) that were transduced with a GMAP-generated pGK:tTR-KRAB-rtTA3-Luc (TRL)-EFS:iRFP670 lentivirus and treated with media (grey histogram) or doxycycline (green line) Data are representative of at least three independent replicates (D) Bar graph shows quantification of flow cytometry shown in (C) p > 0.05; **p = 7.68 × 10−4; ***p = 2.46 × 10−4 (E) Map of a GMAP-generated Rosa26 targeting vector (R26TV) and scheme for knock-in of a Cre-dependent tTR-KRAB-rtTA3-Luc construct into the Rosa26 locus bovine growth hormone polyadenylation signal; DTA Relevant primer binding sites (black half arrow) for PCR screening and restriction sites and probe (grey line) for Southern analysis are shown C57BL/6J-Tyrc-2J ES cells were electroporated with AsiSI-linearized R26TV and subclone genomic DNA was digested with BamHI and probed yielding a 5.8 kb product for the wild type Rosa26 locus and a 4.8 kb product for the targeted Rosa26 allele (G) Bioluminescence imaging of C57BL/6J-Tyrc-2J or R26LSL-TRL (clone D1) ES cells transduced with increasing multiplicity of infection (MOI) CMV-Cre adenovirus (Ad-Cre) (H) Plot shows flow cytometry measurement of iRFP670 expression in C57BL/6J-Tyrc-2J or R26LSL-TRL ES cells transduced with a GMAP-generated tetracycline response element promoter (pTRE):iRFP670-EFS:Cre-2A-GFP lentivirus and treated with doxycycline **p = 3.71 × 10−3; ***p = 6.51 × 10−4; ****p = 3.60 × 10−5 These results demonstrate the versatility of GMAP to create genetic tools of increasing complexity in particular toward the rapid validation and generation of knock-in mice rely on the ease of construction of increasingly more complicated DNA constructs As genomics and systems biology lead to the identification of novel genes and pathways of interest efficient assembly of DNA constructs to interrogate these genes and pathways will become increasingly important Together with its adaptability for various applications and for use by other investigators GMAP provides a modular assembly platform that simplifies and accelerates this discovery process All TOPO constructs containing the promoters and genes described herein have been deposited in Addgene Compatible backbones were created by designing gene blocks (gBlocks) from IDT (Supplementary Table S2) to clone into viral or R26TV constructs such that digestion and gel purification would yield linearized backbones with sites #1 and 5 or sites #2 and 5 terminal The retroviral backbone (RV 2-5) was created by cloning “RV 2–5 gBlock” into MSCV linearized with BglII and ClaI using Gibson Assembly such that digestion with PmeI followed by PCR purification yields a GMAP compatible backbone The lentiviral backbone (LV 1–5) was created by cloning “LV 1–5 gBlock” into pLL3 linearized with XmaI and AscI using Gibson Assembly such that digestion with PmeI and BsrGI eliminates the 469 bp spacer sequence between sites #1 and 5 The CAG-driven R26TV LSL backbone (R26TV CAG LSL 2−5) was created by cloning “Rosa26 LSL 2–5 gBlock” into a R26TV LSL-GFP plasmid (Addgene plasmid 16103) linearized with Asc and XmaI such that digestion with PmeI eliminates a 389 bp spacer sequence between sites #2 and 5 This targeting construct has 5′ and 3′ homologous arms of 1.1 and 4.3 kb TOPO backbones were created by linearizing PCR-BluntII TOPO with BamHI and cloning in “TOPO 1-4 gBlock” or “TOPO 2-5 gBlock” using Gibson Assembly such that digestion with PmeI and NheI eliminates a 361 bp spacer sequence between sites #1 and 4 or digestion with PmeI eliminates a 389 bp spacer sequence between sites #2 and 5 linearized backbones were adjusted to 57nM with Tris-EDTA buffer (pH = 8.0) All GMAP backbones described herein have been deposited in Addgene This reaction mix was then transformed into competent bacteria and screened using XmaI The sequence for blasticidin resistance was PCR amplified and cloned using Gibson Assembly into a pcDNA5 donor vector such that it is inverted and flanked by two sets of incompatible loxP sequences The inverted and floxed blasticidin resistance sequence was then PCR amplified and cloned using Gibson Assembly into a MSCV pGK-PuromycinR vector such that inverted blasticidin resistance expression is driven by the retroviral LTR (FFiBlast MSCV Puro) Murine 3T6 fibroblasts were transduced using FFiBlast MSCV Puro selected in 5 μg/mL puromycin (Life Technologies) single cell cloned and screened using CMV-Cre adenovirus (Ad-Cre) A Cre-responsive clone was expanded for in vitro use (3TB) 3TB cells and KP cells were cultured in DMEM (Corning) supplemented with L-glutamine (2 mM) streptomyocin (100 μg/mL) and 10% fetal calf serum (FCS; Gibco) at 37 °C in a 5% CO2 humidified atmosphere Embryonic stem (ES) cells were cultured on primary irradiated mouse embryonic fibroblasts in Knockout DMEM (Life Technologies) supplemented with β-mercaptoethanol (100 μM) leukemia inhibitory factor (200 pg/mL; Amsbio) CHIR99021 (3 μM; P212121) and PD0325901 (1 μM; Selleck Chemicals) and 15% FCS at 37° in a 5% CO2 humidified atmosphere Following transduction of 3TB or KP cells with lentivirus or retrovirus or 20 μg/mL blasticidin (Invitrogen) selection was applied transfected 3TB cells were treated with 5 μg/mL doxycycline (Sigma) for 48 hr VerdeGo cells were treated with 1 μg/mL doxycycline for 7 days ES cells were treated with varying doxycycline for 3 days 40 μg of R26TV was linearized with AsiSI (NEB) and electroporated into 1 × 106 C57BL/6J-Tyr c−2J ES cells with a single pulse of 600V After 24 hr cells were selected with 300 μg/mL G418 (Life Technologies) for 7 days Cells were plated on Cover Glass Circles (Fisher) at 250 cells/mm2 After 24 h cells were washed with PBS and nuclear staining was accomplished using DAPI (5 μg/mL) or TO-PRO-1 (Invitrogen) prior to fixation with 1% paraformaldehyde (PFA Electron Microscopy Sciences) and mounting with Vectashield Mounting Medium (Vector Laboratories) Images were acquired on an Olympus FV1200 Laser Scanning Confocal Microscope and analyzed with ImageJ (NIH Flow cytometry data were collected after 3–7 days of selection Cells were trypsinized and fixed with Cytofix/Cytoperm (BD) and read on a BD LSR II HTS-2 Data was analyzed using Flowjo software (Tree Star) To visualize hypoxic areas by immunohistochemistry a commercially available hypoxyprobe kit (Hypoxyprobe™-1 Omni) was utilized Pimonidazole hydrochloride was injected intraperitoneally into tumor-bearing mice at a dose of 60 mg/kg body weight 1 h before euthanasia Lungs were perfused through the trachea with 4% PFA transferred to 70% ethanol and subsequently embedded in paraffin Sections were cut at a thickness of 4 μm and stained with hematoxylin and eosin for pathological examination Slides were antigen retrieved using Thermo citrate buffer pH 6.0 and treated with Peroxidase and Alkaline Phosphatase Block (Dako) primary antibody and anti-rabbit (Vector Labs) HRP-polymer The slides were developed with ImmPACT DAB Peroxidase (Vector Labs) counterstained with haematoxylin in a Thermo Gemini stainer and coverslips added using the Thermo Consul cover slipper The following antibodies were used for IHC: anti-TTF1 / Nkx2.1 (Epitomics All images were obtained using a Nikon 80i microscope with a DS-U3 camera and NIS-elements software Primers to detect the R26LSL-TRL allele (R26For, GAAGAGGCTGTGCTTTGGG; R26Rev, ACCACTGGAAAGACCGCGAAGAG) were designed by the Primer3 program (www.http://biotools.umassmed.edu/bioapps/primer3_www.cgi) PCR amplifications were performed on 50 ng of genomic DNA using Green Taq DNA Polymerase (GeneScript) Targeted Rosa26 allele yields a 1302 bp product and wild type Rosa26 yields no product ES cells (1 × 104) were seed in each well of a 48-well and transduced with varying Ad-Cre 150 μg/mL D-Luciferin (Perkin Elmer) was applied and cells were imaged using the IVIS Spectrum Imaging System (Perkin Elmer) lysed with 30 μL Cell Culture Lysis Reagent (Promega) and supernatant was incubated with Luciferase Assay Reagent (Promega) Luminescence was measured using a Tecan Infinite M200 PRO Plate Reader Transduced 3T6 fibroblast subclones (2 × 104) were seed in a 24-well and transduced with Ad-Cre (MOI=100) 20 μg/mL blasticidin was applied and after 4 days cells were washed with PBS and fixed with 1% PFA stained with 0.5% crystal violet in 2.5% methanol for 30 min and rinsed in dH2O Statistical analysis was performed using unpaired two-tailed Student t tests in Prism 5 (Graphpad Software) Data are presented as mean ± standard error of the mean Accession Codes: The following plasmids were deposited into Addgene: TOPO 2-5 3TB cells and VerdeGo cells are available upon request A Modular Assembly Platform for Rapid Generation of DNA Constructs Harnessing homologous recombination in vitro to generate recombinant DNA via SLIC Ligation-independent cloning of PCR products (LIC-PCR) Directed PCR-free engineering of highly repetitive DNA sequences Fast track assembly of multigene constructs using Golden Gate cloning and the MoClo system A Modular Cloning System for Standardized Assembly of Multigene Constructs Chemical synthesis of the mouse mitochondrial genome modular and reliable construction of complex mammalian gene circuits Rapid construction of insulated genetic circuits via synthetic sequence-guided isothermal assembly One-pot DNA construction for synthetic biology: the Modular Overlap-Directed Assembly with Linkers (MODAL) strategy A Modular Plasmid Assembly Kit for Multigene Expression Gene Silencing and Silencing Rescue in Plants GoldenBraid 2.0: A Comprehensive DNA Assembly Framework for Plant Synthetic Biology Functional Identification of Optimized RNAi Triggers Using a Massively Parallel Sensor Assay Hypoxia Response Elements in the Aldolase A Enolase 1 and Lactate Dehydrogenase A Gene Promoters Contain Essential Binding Sites for Hypoxia-inducible Factor 1 Real-time Imaging of Hypoxia-inducible Factor-1 Activity in Tumor Xenografts In vivo characterization of a reporter gene system for imaging hypoxia-induced gene expression Hypoxia-Inducible Factor-1α Promotes Nonhypoxia-Mediated Proliferation in Colon Cancer Cells and Xenografts Genetic Screens in Human Cells Using the CRISPR-Cas9 System Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb Development and Applications of CRISPR-Cas9 for Genome Engineering The Differential Effects of Mutant p53 Alleles on Advanced Murine Lung Cancer Simplified mammalian DNA isolation procedure Download references Dimitrova for critical reading of the manuscript Taipale for cloning the HRE:GFP-pGK:Cre lentiviral construct Bauer for technical assistance using the IVIS Spectrum Imaging System Cabeceiras for single cell cloning of the VerdeGo cell line and L This work was supported by the Howard Hughes Medical Institute MIT Amgen-UROP Program (E.A.G.) and the MIT Peter J Thales Papagiannakopoulos & Tyler Jacks RNA Therapeutics Institute and Program in Molecular Medicine All authors read and approved the manuscript for submission Download citation Sorry, a shareable link is not currently available for this article. Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma. The Respect Cup is a soccer tournament designed for children to enjoy sports and to respect other players. PUMA was honored to be a partner of this wonderful event for the fifth time. PUMA’s local brand ambassador Ilaripro was involved and also provided sports equipment for the children. PUMA is honoured to be a partner of the Respect Cup for the fifth time. Ilaripro brings a lot of joy to the participants with his skillful football tricks and energetic personality. It is heartwarming to see the joy the balls and personalised jerseys bring to the participants. For us, the Respect Cup is an annual sports day of dreams! We come together to enjoy football, togetherness and a great atmosphere. Every participant gives their best for their team and the best part is that it encourages everyone. In addition to the Respect Cup, the Saliband Championship of Tammela Elementary Schools for grades 5-6 was held on the Day of Dreams in Eerikkilä. All age groups came together to celebrate the event, either playing field hockey or cheering. A course was also set up along the nature trail where students could test their skills in history, sports or biology. With this event, we want to encourage children and young people to get active. It is great that we can also enable schools in our region to participate in the Day of Dreams. Sieh dir diesen Beitrag auf Instagram an Ein Beitrag geteilt von Ilaripro (@ilaripro) PUMA's Heiko Desens explains the story behind the PUMA Mostro Greatness starts with the courage to be yourself Love to run but can’t resist the snooze button? Here's our advice. SIGN UP FOR OUR NEWSLETTER AND NEVER MISS A STORY I agree that the PUMA group may use my personal data (including my e-mail address) for promotional and marketing purposes in accordance with the PUMA privacy policy and send information about products of the PUMA group to my e-mail address. I can withdraw my consent at any time in the future by sending an e-mail to catchup@puma.com or via the link in each e-mail. 08 Apr 2025 15:30:00 GMT?.css-1txiau5-AnswerContainer{color:var(--GlobalColorScheme-Text-secondaryText2);}Finland won 3–0 over Hungary on Tue This is 4 of the UEFA Women's Nations League B Grp Predicted lineups are available for the match a few days in advance while the actual lineup will be available about an hour ahead of the match The current head to head record for the teams are Finland 1 win(s) 08 Apr 2025 15:30:00 GMT?Finland won 3–0 over Hungary on Tue 08 Apr 2025 15:30:00 GMT.InsightsHaven't scored in their last 2 matches Finland is playing home against Hungary at Tammela Stadion on Tue 05 Apr 2025 12:00:00 GMT?.css-1txiau5-AnswerContainer{color:var(--GlobalColorScheme-Text-secondaryText2);}Ilves won 3–2 over HJK on Sat The current head to head record for the teams are Ilves 5 win(s) Have scored 13 goals in their last 5 matches 05 Apr 2025 12:00:00 GMT?Ilves won 3–2 over HJK on Sat 05 Apr 2025 12:00:00 GMT.InsightsHave scored 8 goals in their last 5 matches Ilves is playing home against HJK at Tammela Stadion on Sat I guess first off it’s good to go back to the basics – you joined HIFK in the summer of 2010 and stayed at HIFK for one and a half season After my playing career in Germany ended in 2008 I moved back to California to pursue coaching at the University I attended (St During that time I met my future wife Maija Lähde as she was playing her final season for the women’s basketball team at St She was given the opportunity to play on the Finnish national team and also was offered a professional contract to play for Espoo Team (Now Honka) We realized that we were probably going to spend the rest of our lives together and decided to move to Finland so she could continue to play basketball and also so I could hopefully gain the trust of her family and learn a bit more about her Finnish culture and after a few tryouts with a couple of clubs in Finland I ended up signing with HIFK It was the best decision I could have ever made Do you remember your first impressions of the team I definitely remember my first training session for HIFK but I was also very excited because I knew about the traditions and ambitions of the club but as I walked into the locker room for the first time I really don’t think they expected me to make the team I was the only foreign player at the time and I hadn’t played soccer at a high level for about 2 years I guess that I made a good enough impression because they offered me a spot on the team a day later after training and I soon found out that a few of them (Sami and Innu) played college soccer in the US almost every time I visit in the summer we try to arrange a night for a lot of players from that 2010 team to get together but usually try to do a night out in the bars in Helsinki The players from that team really hold a special place in my heart I think we all bonded so well off the field and that’s why we had so much success on the field I’m still in touch with a lot of them to this day one of the other goalkeepers from that team Jens Forsman I consider to be one of my best friends in the world and he’s also the Godfather to my son Kayden It’s now 10 years since the 10th of October 2010 A date that will long be remembered by HIFK fans What are your memories from the match against Ilves on that day it’s crazy to think it’s already been 10 years because in my mind it truly still feels like it happened yesterday The Ilves game was especially fun because the stadium was full of fans and of course it was the most meaningful game for HIFK in many years I remember feeling like there was no doubt in my mind we were the best team in the Kakkonen We were on a streak of I think about 9-10 matches where we didn’t drop any points and the entire team was filled with confidence We loved playing soccer with each other and you could feel within the team that we were going to do something special in the promotion games it was one of those situations where Ilves kept putting pressure and pressure but didn’t score – and then HIFK scored an unforgettable goal when Petri Heinänen headed the ball into Ilves’ net What was it like in the last minutes of that match and how was it to see the last goal from the other side of the pitch I felt like we were controlling most of the match and of course scored a great goal to go ahead early in the game late in the 2ndhalf Ilves scored a goal to tie the game and the feeling of calm and control became a feeling anxiety I remember the goal Ilves scored very well because as a goalkeeper those types of moments are unfortunately the ones you remember the most They continued to pressure our defensive line without success in the final 10 minutes and after feeling like we were going to draw the match late into injury time Heinänen scored one of the most memorable and special goals of my playing career The view I had of this moment from the back of the field was incredible because it happened directly in front of Stadin Kingit The fan section exploded in joy and I even remember some of the players from our bench running onto the field to celebrate the goal Shortly after that goal the referee ended the match and we all ran to the far side of the field to celebrate with the fans It was a magical moment in all of our lives but we also realized that we were only half way finished with our ultimate goal of promotion Then after a few weeks it was time for the match against FC Santa Claus and how did it feel when Markus Tanner scored the winner in the 86th minute of the match After we beat Ilves in the first match away we knew that it would all come down to the home game against Santa Claus I won’t tell you that we didn’t have any nerves going into the match but I will tell you that we were very confident that we could win that game on our home field Markus Tanner (The Fireman) was definitely a fan favorite and after he scored the goal that eventually sent us to the Ykkonen we knew that promotion was possible I very much remember the final chance Santa Claus had to attack our goal It was a free kick deep into our half of the field They sent everyone on their team into our penalty box and I remember thinking if we defend this moment properly we will be champions I came off my line and punched the ball out of the box and about 20 seconds later we were promoted It was truly one of the best and most memorable moments of my life what was your favourite moment at the club Well obviously my most memorable moment at the club was our promotion to the Ykkonen there was one other moment that stands out in my mind With about 3-4 fixtures left in the regular season in 2010 we played an away game against SC Riverball in Joensuu We were both at the top of the table maybe separated by 1 point at the time It was a LONG bus drive out to Joensuu and this was the game that would probably decide 1stplace in our division The team was very motivated and if I remember correctly we won the game 4-0 It was a massive step towards what we wanted to accomplish and that game in my opinion was the game that gave us the confidence to win it all but the bus ride home was even more memorable for me I truly feel like we became a much closer team after that bus ride and in the end of it became a single unit rather than a collection of individual players and truly enjoyed every single minute of that ride home after our dominating performance It was a moment that definitely stands out in my memory and a bus ride that I will never forget A bit of an oddball question but; do you still get chills when you think of the “USA USA” chant going off from the fans after a big save I was the number 3 goalkeeper when I first joined the team but I believe after 2-3 games of sitting on the bench I was given the opportunity to be the number 1 and start my first match for HIFK I will never forget the first time I heard the greatest fans in Finnish soccer chant “USA It was quite unexpected because I didn’t think any of the fans knew who I was or specifically where I came from I was truly humbled by their support and it made me want to save 100 shots per game so I could hear them shout it more What have you been up to since leaving HIFK I really wanted to somehow stay in the sport of soccer the next logical step for me was to try and find a place I could coach the game I love Although I never imagined that I would coach on the women’s side of soccer I was given the opportunity to coach Division 1 Women’s soccer at the University level It was one of the best decisions I have ever made and now I am entering my 9thyear of coaching at California State University Fullerton We have won 5 conference championships in the past 8 years and I absolutely love my career in coaching Do you manage to follow HIFK from California so we visit Finland every summer and every other Christmas I try to make it to at least 1 HIFK game every summer with my kids Madeleine (7) and Kayden (4) It truly brings me great joy to follow HIFK’s success in making it back to the Veikkausliiga and of course I wake up every match day to check their results I wish there was some way I could live stream their games from California but I have not been able to figure out a reliable way to do that the club and of course the fans have turned me into a HIFK fan for life but completely valid in your case: Is there anything you would like to say to the HIFK fans thank you for your constant support through both the good and of course some of the bad times during my days in Finland I will never forget the journey we went through in 2010 I think I speak for all of the players that have ever played for HIFK when I say YOU are the lifeline and heartbeat of the club The energy you bring to EVERY SINGLE MATCH is out of this world and always helps us to give our best effort on the field you are the ones who make it fun to come to the stadium every single day I hope to see you all very soon at a HIFK match next summer They are now prospecting for the precious metal in southern Finland as well as Lapland Finland is gradually emerging as a significant producer of gold Europe’s largest gold mine is located at Kittilä in the fells of Finnish Lapland and now a potential new mine in Häme is stirring interest among mineral companies A quantity of the coveted soft metal has recently been confirmed at the Satulinmäki claim in Tammela The Geological Survey of Finland initially detected it and now Australian mining company Avalon Minerals and Canada’s Nortec Minerals have carried out drilling tests this autumn and are comparing the data with that from the state agency we’re encouraged,” Avalon CEO Malcolm Norris told Yle Avalon isn’t the only foreign firm interested in Finland’s gold: other companies from Sweden Canada and Australia are also hot on the trail president of the mining industry association says that Finland is the EU’s largest gold producer Some 5,500 kilos of that comes from the EU’s largest goldmine in Kittilä Four mines in Finland now primarily produce gold are owned by the Australian firm Dragon Mining Meanwhile other mining companies also produce gold alongside their regular operations And gold deposits have been found well over 100 other locations around the country Geologist Markku Tiainen from the Geological Survey says that the Finnish mining industry has only woken up to the idea of mines focusing solely on gold since the turn of the millennium He says that there are half a dozen promising deposits in Southern Finland alone – but points out that the Tammela seam may take another decade of drilling before it might begin commercial operations The precious metal has been found in two spots there with an estimated concentration of up to 10-15 grams per thousand kilos of rock The Geological Survey says that five grams per thousand kilos is usually considered to be a minimum viable level for a mine The main deciding factor in the financial feasibility of a potential mine which now hovers around 1,200 dollars an ounce (or just under 40 euros per gram) This story is posted on Independent Barents Observer as part of Eye on the Arctic, a collaborative partnership between public and private circumpolar media organizations Published by: The Independent Barents Observer AS About us The Barents Observer follows the Code of Ethics of the Norwegian Press and the document Right and Duties of the Editor We report under full editorial independence and have no external interference Donate to our independent journalism Støtt oss via Vipps: 105 792 - Det betyr mye newstips@thebarentsobserver.com atle@thebarentsobserver.com thomas@thebarentsobserver.com☏ +47-905 73 143 denis@thebarentsobserver.com georgii@thebarentsobserver.com liza.vereykina@thebarentsobserver.com olesia@thebarentsobserver.com Privacy policy services and collaboration opportunities for researchers My research is aimed at finding new microbial drugs especially from natural substances or derivatives based on natural substances My colleagues and I are particularly focused on developing new increasingly efficient tools and techniques in addition to which we are investigating potential new sites of action in bacteria The capacity of bacteria to resist the currently available antibiotics is increasing at an accelerating rate Infections caused by multiresistant bacteria or bacteria that are able to resist a range of therapies are already routine in our healthcare system When resistance spreads among infectious bacteria treatment becomes more difficult and prolonged predictions show that the infectious disease situation will become catastrophic 10 million people will die of infections every year by 2050 Glimmers of hope for the future can be generated through the increasingly calculated consumption of antibiotics and investment in the development of novel antibiotics The astounding qualities of bacteria – in spite of being single-celled and essentially simple organisms they are peerless in terms of their adaptive ability Päivi Tammela is a professor of pharmaceutical biology at the Faculty of Pharmacy Get to know the other new professors. Predicted lineups are available for the match a few days in advance while the actual lineup will be available about an hour ahead of the match. The current head to head record for the teams are Ilves 12 win(s), AC Oulu 6 win(s), and 3 draw(s). Tammela StadionNewsAbout the matchIlves is playing home against AC Oulu at Tammela Stadion on Sat The current head to head record for the teams are Ilves 12 win(s) Open image viewerYellow paint was splattered on the columns walls and stairs of Ateneum's entrance 16:13The entrance to the Ateneum Art Museum in Helsinki was splattered with yellow paint on Saturday believed to be made with paint or a similar substance were discovered on the museum's doors The museum staff notified authorities about the damage around two o'clock on Saturday afternoon The police are investigating the incident as a case of property damage The exact sequence of events remains unclear and it is not yet certain whether there was a single perpetrator or multiple individuals involved Open image viewerPaint on Ateneum's front door Image: Linda Tammela / Yle{"@id":"74-20143949","@context":"https://schema.org","image":{"@type":"ImageObject","description":"The paint had spread across a wide area.","copyrightHolder":"Linda Tammela / Yle","url":"https://images.cdn.yle.fi/image/upload/ar_1.0,c_fill,g_faces,h_767,w_767/dpr_2.0/q_auto:eco/f_auto/fl_lossy/39-142254367b082f7d26aa","keywords":""}}Open image viewerThe paint had spread across a wide area Image: Linda Tammela / YleLocated in central Helsinki Ateneum is a nationally protected landmark and Finland's oldest art museum The neo-Renaissance building was designed by architect Theodor Höijer and completed in 1887 Ateneum is part of the Finnish National Gallery Last autumn environmental activists sprayed the Finnish Parliament with a red dye in protest of Finland's involvement in the peat industry in Sweden. Open image viewerElias the language robot speaks Finnish Elias will enrich the teaching of 1st and 2nd grade preschoolers in Tampere Image: Santeri Holappa / Tampereen kaupunki13.3.2018 16:04Talking robots have become the newest addition to classrooms in Tampere preschools for English The robots will also be tested with first- and second-year pupils in a few select schools four robots are to be tested out in classrooms Three will be small owl-like robots to assist in maths lessons while the fourth will be a small humanoid robot for language practice The first mathematics robot arrived in the south-central on Friday and will be tested at the Sorila preschool The other math robots will be placed at Vahmainen preschool and the Pohjois-Hervanta school A language robot known as "Elias" will become a feature of Tammela school classrooms Open image viewerThe mathematics robots bear a resemblance to small owls Image: Santeri Holappa / Tampereen kaupunkiThe mathematical robot is the first of its kind in Finland These owl-like robots are produced by the Finnish company AI Robots They are now being put to the test for the first time in Tampere The body design of the humanoid robot is French but the software is designed by a Finnish company The City of Tampere has acquired the robots to support everyday teaching The machines will not tire from repetition and they can conform to the skill level of each pupil The test run in Tampere is aimed at examining children’s experiences and interactions with robots also interested in how these robots could improve the quality of teaching,” says project manager Marika Korpinurmi The testing of the robots is part of the Smart Tampere digital programme an initiative to improve everyday life in Tampere through digital services Feel like exploring the pub and gastropub scene in Tampere Here are some of the best places to pop in for a drink or more Established in the year 1969 and still working under its original name Salhojankadun pub is Finland’s oldest British-style pub Their drink selection consists mainly from beers exported from Europe traditional Pub Pikilinna has been serving great beer for over 20 years The place is known for their relaxed atmosphere and love for sports Paapan Kapakka is a legendary jazzpub in the corner of Hämeenkatu and Hatanpään valtatie the front of pub is full of life with an open area terrace that offers views for the busy street and rapids the warm milieu invites you to escape from the frost Olutravintola Konttori is known for its’ vast fashionable beer selection and continuously changing beers on tap Friends of sports find themselves there too O’Connell’s hosts a bunch of live gigs and a unique If you are looking for that international atmosphere and possibly an extensive selection of beer Huurupiilo is a pub in Kaleva with a long-lived reputation as a gig and comedy venue Current owner Patrick and his wife Ansku make sure all their customers feel welcome and at home and pub quizzes and gigs are still a part of the weekly program Gastropub Soho offers a traditional pub menu and atmosphere with a mixture of good music and sports Soho is a homely place to spend an evening out with your friends Plevna Brewery Pub & Restaurant is creating beer culture in Finland producing a vast selection of beers made on the premises Siperia Stout – Finland’s best beer of 2015 A very dark and bitter stout also made it to the Adrian Tierney-Jones book: 1001 beers You Must Try Before you Die Chosen many times as the best beer restaurant in Finland Gastropub Tuulensuu is a cozy Belgian-style gastropub with an impressive selection of beer Start your tasting course with Lindemans Lambik by a small family brewery in Belgium Tuulensuu is the only place outside the brewery you can enjoy this lambic raw Thanks to warm friendship between the brewery and the gastropub’s owner Teerenpeli Beer Restaurant & Brewery’s products won gold medals as the best microbrewery beers in Finland You beer journey here will be crowned by a smoked lager Suomi 100 Juhlaolut will give a wake-up call for your taste buds This beer was produced to mark the 100th anniversary of Finland’s independence and immediately found itself in Alko’s centenary selection With Gastropub Nordic’s origins in the local Gastropub empire Nordic Brewery produces no-nonsense beers for the slightly more conservative palate Havu Nordic Ale offered here was one of the two beers in the whole Finland to be honored with the official Finland 100 jubilee mark you are going to taste one of a hundred of products Finland is proud On Kauppakatu street you can find a cosy pub called Kievari Kahdet Kasvot They are specialized in Finnish craft beers and whiskeys and they serve good pub food to go with your excellent beer Paja Bar pays a tribute to the rock culture of Tampere some of them uniquely produced for the bar This is the place to open the world’s Best Mild Dark Ale (2016) The amber color and berrylike flavor owe to natural rowan berries (picked in the Tampere surroundings!) Pyynikki Brewhouse is brewery restaurant owned by Pyynikin käsityöläispanimo and Chef Hans Välimäki  The selection is vast in quality and quantity since all the products of this craft brewery are available in the restaurant Public House Huurre is working in the same building with Kaleva Brewing Company which ensures that there is always at least three different “house” beers available from the tap Sailor’s Bar & Grill serves traditional night grub and beer from near and far Δdocument.getElementById( "ak_js_1" ).setAttribute( "value"