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Volume 2 - 2022 | https://doi.org/10.3389/fnume.2022.870910 This article is part of the Research TopicProf. Frank Rösch’s legacy in the Radiopharmaceutical Chemistry fieldView all 7 articles Bisphosponates are an interesting molecular class and in recent years their application has found its way into radiopharmaceutical research and thus into molecular imaging In addition to great imaging of bone metastases bisphospnate-based tracers for imaging also have some significant drawbacks this can lead to complex and almost impossible purification and quality control This has limited the production and labeling of suitable molecular and their widespread use to a few facilities Our squaric acid-based approach provides a way to overcome these problems and makes the synthesis as well as the purification of the compounds much easier we were able to demonstrate that labeling with 68Ga is possible under the typical conditions Since bone metastases show increased activity of bone remodeling and bisphosphonates otherwise show little uptake into soft tissue and healthy bone they are an excellent lead structure for the development of radiopharmaceuticals for the diagnosis and therapy of bone metastases In bisphosphonate-chelator conjugates the bisphosphonate serves as targeting vector and complexes different nuclides by means of a chelator and can thus be used for the diagnosis or therapy of bone metastases (13) The solution would be synthesis of a protected BP which would require an increased synthetic effort (A) Important structures of bisphosphonates for therapy and diagnosis of bone metastases: 1: DOTA-zoledronate 2: zoledronic acid 3: squaric acid pamidronate 4: DOTAGA.SA.PAM 5: NODAGA.SA.PAM; (B) left: binding hypothesis for zoledronic acid to hydroxyapatite; right: possible binding of the SA.PAM fragment A comparable effect as for zoledronic acid is assumed For the detection of bone metastases in clinics The radionuclide Tc-99m used for this purpose is bound to BPs such as hydroxymethylene bisphosphonate (HMDP) methylene diphosphonate (MDP) or diphosphono-1,2-propanedicarboxylic acid (DPD) and the patient is examined using a gamma camera General advantages of this method are good availability there are a variety of advantages using PET/CT scans over bone scans to image bone metastases Especially the increased accuracy in detecting bone metastases better differentiation between benign and malignant tumors and higher resolution makes the more expensive PET/CT-scan a better tool for some investigations the time spent by the patient is significantly reduced on the one hand due to the reduced general examination time and on the other hand due to the potential need for further scans patient management can be significantly improved All chemicals were commercially available at Acros Organics (Nidderau Germany) and were used without further purification Deuterated solvents for NMR spectroscopy were purchased from Deutero (Kastellaun Silica gel (particle size: 0.040–0.063 mm) for column chromatography was purchased from VWR (Darmstadt The measurements of 1H- and 13C-NMR spectra were performed on a Bruker Avance II 400 (400 MHz) Mass spectra were recorded on an Agilent Technologies 6130B Single Quadrupole LC/MS system Semipreparative HPLC was performed on a Merck Hitachi LaChrom L-7100 Following column was used: Phenomenex Luna C18 (250 × 10 mm) 10 μm Radioactivity was measured with a dose calibrator (ISOMED 2010; MED Nuklear-Medizintechnik Dresden GmbH Radio thin-layer chromatography (radio-TLC) was analyzed with a RITA* TLC imager (Elysia-Raytest Germany) and an evaluation software (GinaStar TLC; Elysia-Raytest The analytical method for determining the radiochemical purity of the labeled chelator-bisphosphonate compounds was investigated by radio-TLC in a solution of acetone while unbound Ga-68 is detected as an acetylacetonate complex with a Rf = 1.0 Even if some methods for the determination of radiochemical purity by HPLC have been published none of these methods could be used efficiently for the determination of radiochemical purity Stability studies were performed in HS and PBS solution (pH adjusted to 7 by PBS buffer) in triplicate USA origin) were bought from Sigma Aldrich phosphate buffered saline (PBS) pH = 7.4 was purchased from Sigma Aldrich as well The final procedure used 50–70 μl of the labeling solution (5–10 MBq) added to 1 ml of either HS or PBS The pH was controlled to ensure no influence of the labeling buffer on the solution hydrochloric acid (10:10:1) was used to determine the stability The Wistar rats were housed in the animal facility of the Helmholtz-Zentrum Dresden-Rossendorf and experiments were performed according to the guidelines of the European and German Regulations for Animal Welfare approved by the local Ethics Committee for Animal Experiments (Landesdirektion Dresden; file numbers 24-9165.40-4/2013 were kept in a pathogen-free facility with ad libitum access to water and food Biodistribution studies were performed with [68Ga]Ga-NODAGA.SA.PAM (n = 4 5.8 MBq/animal) and [68Ga]Ga-DOTA-ZOL (n = 4 Animals were sacrificed at 5 min and 60 min post-injection (p.i.) and counted in a cross-calibrated γ-counter (Isomed 1000 Isomed GmbH) and Wallac WIZARD Automatic Gamma Counter (PerkinElmer) The activity of the tissue samples was decay-corrected and calibrated by comparing the counts in tissue with the counts in aliquots of the injected radiotracer that had been measured in the γ-counter at the same time was expressed as percent-injected activity per organ (%ID) and the activity concentration in tissues and organs as standardized uptake value (SUV in [MBq activity/g tissue] / [MBq injected activity/g body weight]) Values are quoted as mean ± standard deviation for each group of animals PET scans were performed using dedicated rodent PET/CT scanner (NanoPET/CT The PET experiments were carried out with rats under general anesthesia that was induced and maintained by inhalation of 12% and 9% (v/v) desflurane in 30/10% (v/v) oxygen/air Anesthetized rats were positioned on a warmed bed along the scanner axis The 68Ga-labeled radiotracers in 300 μL isotonic NaCl were infused over 1 min into a tail vein PET images were acquired beginning with the injection over 2 h and were reconstructed in dynamic mode with 36 frames and 0.5 mm3 voxel size Region-of-interest (ROI) quantification was performed with ROVER (ABX GmbH The ROI values were corrected for recovery and partial volume effects NH2-DOTAGA (30 mg; 58 μmol; 1 eq.) and squaric acid diethyl ester (26 μL; 30 mg 176 μmol; 3 eq.) were dissolved in phosphate buffer (0.5 M; pH 7; 0.5 mL) and stirred for 2 h at RT The pH value of the reaction was controlled and adjusted to pH 7–7.5 with sodium hydroxide solution (1 M) The product DOTAGA.SA (28 mg; 43.5 μmol; 75 %) was isolated by semi-preparative HPLC (column: Phenomenex Luna C18 (250 x 10 mm) 10 μm; flow rate: 5 mL/min; solvent: H2O/MeCN +0.1 % TFA; gradient: 0–18 % MeCN in 15 min; Rt = 13 min) and obtained as a colorless solid after lyophilisation J3HH = 7.1 Hz; J = 12 Hz; CH3); 1.81 (br: 2H; CH2); 2.37 (br: 2H; CH2); 2.77–3.99 (m: 27H); 4.58 (dq: 2H; J3HH = 7.1 Hz; J = 21 Hz; CH2-CH3) D2O): δ (ppm) = 15.01 (CH3); 33.04 (CH2-CH2); 39.45 (CH2-CH2); 39.45 (CH2-CH2); 39.75 (CH2-CH2); 43.62 (CH2-CH2); 43.80 (CH2-CH2); 55.05 (CH2); (70.64 (CH2-CH3); 113.32 (COOH); 115.26 (COOH); 117.19 (COOH); 119.12 (COOH); 162.54 (CH2); 162.78 (CH2); 163.25 (CH2); 173.74 (CO-NH); 176.75 (C.SA); 177.22 (C.SA); 183.34 (C.SA); 188.72 (C.SA) MS (ESI positive): m/z (%): 322.2 [M+2H]2+; 643.3 [M+H]+; [M] calculated: 642.29; UPLC (Gradient: 0-100 % B in 15 min): [M] Rt = 3.01 min NH2-NODAGA (5 mg; 12 μmol; 1 eq.) and squaric acid diethyl ester (9 μL; 10 mg 60 μmol; 5 eq.) were dissolved in phosphate buffer (0.5 M; pH 7; 0.5 mL) and stirred for 2 h at RT The product NODAGA.SA (6 mg; 11 μmol; 93 %) was isolated by semi-preparative HPLC (column: Phenomenex Luna C18 (250 × 10 mm) 10 μm; flow rate: 5 mL/min; solvent: H2O/MeCN + 0.1 % TFA; gradient: 0–30 % MeCN in 20 min; Rt = 13.1 min) and obtained as a colorless solid after lyophilisation.1H-NMR (300 MHz 1.77–2.02 (m: 2H; CH2); 2.29 (dt; 2H; J3HH = 7.5 Hz; J3HH = 6.6 Hz; CH-CH2-CH2); 2.85-3.01 (m: 4H; cyclic-CH2); 3.02–3.22 (m: 8H; cyclic-CH2); 3.25–3.35 (m: 2H; CH2); 3.40–3.53 (m: 2H; CH2); 3.57–3.63 (m: 1H; CH); 3.78 (br: 4H; CH2-COOH); 4.61 (dq: 2H; J3HH = 7.1 Hz; J = 13 Hz; CH2-CH3) MS (ESI positive): m/z (%): 542.2 [M+H]+; 1084.3 [2M+H]+; [M] calculated: 541,24; UPLC (Gradient: 0–100 % B in 15 min): [M] Rt = 3.38 min 1 eq.) and phosphonic acid (4.1 g; 50 mmol; 2 eq.) were dissolved in sulfolane and then phosphorus trichloride (4.4 mL; 6.9 g; 50 mmol; 2 eq.) was added dropwise within 15 min The reaction mixture was then stirred for 3 h at 75°C The mixture was cooled to 0°C and diluted with water (25 mL) The mixture was then stirred for another 12 h at 105°C Via crystallization by addition of ethanol (20 mL) and cooling of the reaction mixture to 0°C pamidronate (2.1 g; 8.9 mmol; 36%) was obtained.1H NMR (300 MHz D2O): δ (ppm) = 2.20 (tt: J3HH = 6.2 Hz; J3PH = 13 Hz; 2H; NH2-CH2-CH2); 3.27 (t: J3HH = 6.2 Hz; 2H; NH2-CH2) MS (ESI positive): m/z (%): 236.0 (100) [M+H]+; 471.0 (25) [2M+H]+; (ESI negative): 233.9 (100) [M-H]−; 469.0 (90) [2M-H]−; 703.9 (80) [3M-H]−; 939.0 (70) [4M-H]−; 1174.0 (30) [5M-H]−; 1409.0 (5) [6M-H]−; [M] calculated: 235.0 UPLC (gradient: 0-30% B in 4 min): [M] Rt = 0.32 min NODAGA.SA (19.6 mg; 36.2 μmol; 1 eq.) was dissolved with pamidronate (10 mg; 42.55 μmol; 1.2 eq.) in phosphate buffer (0.5 M; pH 9; 1 mL) and stirred for 24 h at RT The pH of the reaction was monitored and adjusted to pH 9–10 with sodium hydroxide solution (1 M) if necessary By semipreparative HPLC (column: Phenomenex Luna C18 (250 × 10 mm) 10 μm; flow rate: 5 mL/min; running medium: H2O/MeCN + 0.1% TFA; gradient: 5–6.5% MeCN in 9 min; Rt = 7.5 min) the product NODAGA.SA.PAM (8 mg; 10.96 μmol; 30%) was isolated and obtained as a colorless solid after lyophilization.1H NMR (300 MHz D2O): δ (ppm) = 1.87–2.03 (m: 2H; CH2); 2.09-2.38 (m: 2H; CH2); 2.85-3.04 (m: 4H; ring-CH2); 3.05–3.25 (m: 8H; ring-CH2); 3.27-3.39 (m: 2H; CH2); 3.49 (t: 1H; J3HH = 7 Hz; CH); 3.57–3.70 (br: 2H; CH2); 3.78 (br: 4H; CH2-COOH); 4.61 (dq: 2H; J3HH = 7.1 Hz; J = 13 Hz; CH2-CH3) MS (ESI positive): m/z (%): 366.2 (35) [M+2H]2+; 731.1 (100) [M+H]+; [M] calculated: 730.2; [M(natGa)]: 399.2 (80)/400.1 (75) [M(Ga)+2H]2+; 797.0 (100)/799.0 (60) [M(Ga)+H]+; calculated: 796.2 (100)/798.2 (65) UPLC (gradient: 0–100% B in 15 min): [M] Rt = 0.81 min; [M(Ga)] Rt = 0.89 min DOTAGA.SA (27 mg; 42 μmol; 1 eq.) was dissolved with pamidronate (24.7 mg; 105 μmol; 2.5 eq.) in phosphate buffer (0.5 M; pH 9; 1 mL) and stirred for 24 h at RT The pH of the reaction was monitored and adjusted to pH 9 to 10 with sodium hydroxide solution (1 M) if necessary By semipreparative HPLC (column: Phenomenex Luna C18 (250 × 10 mm) 10 μm; flow rate: 5 mL/min; running medium: H2O/MeCN + 0.2% TFA; gradient: 0–8% MeCN in 12 min; Rt = 11 min) the product DOTAGA.SA.PAM (17 mg; 20.5 μmol; 49%) was isolated and obtained as a colorless solid after lyophilization D2O): δ (ppm) = 1.88 (br: 2H; CH2); 2.12–2.36 (m: 2H; CH2); 2.47 (br: 2H; CH2); 2.90–4.00 (m: 29H) MS (ESI positive): m/z (%): 416.7 (50) [M+2H]2+; 832.2 (100) [M+H]+; [M] calculated: 831.25; [M(natGa)]: 449.7 (100)/ 450.5 (65) [M(Ga)+2H]2+; 898.2/899.2 (5) [M(Ga)+H]+; calculated: 897.25 (100)/899.25 (65); [M(natLu)]: 335.5 (20)/ 450.5 (65) [M(Lu)+3H]3+; 502.6 (100) [M(Lu)+2H]2+; calculated: 1003.25; UPLC (gradient: 0-10% B in 4 min): [M] Rt = 0.48 min; [M(Ga)] Rt = 0.55 min; [M(Lu)] Rt = 0.56 min quantitative radiochemical yields can be achieved in a short time even with small amounts of substance With DOTAGA.SA.PAM radiochemical yields of up to 90% can be obtained Both compounds were investigated in vitro in human serum and PBS buffer and provided excellent stabilities with values >95% over 2 h it is noteworthy that this stability only gives insights into desorption of 68Ga and does not evaluate the metabolism of the probe (A) Synthesis scheme for the reaction between DOTAGA.SA/NODAGA.SA with pamidronate Both reactions take place under the same conditions (phosphate buffer (0.5 M (B) left: labeling kinetics of DOTAGA.SA.PAM with 68Ga with different amounts of precursor right: labeling kinetics of NODAGA.SA.PAM with 68Ga (C) in vitro stability of [68Ga]Ga-NODAGA.SA.PAM in human serum and PBS buffer For NODAGA.SA.PAM, further in vivo studies were performed in young, healthy wistar rats. For comparisons to an established bisphosphonate compound, DOTA-ZOL was investigated under the same conditions. For both compounds, biodistributions were established after 5 and 60 min p.i. (see Figure 3). In addition, a dynamic PET scan was recorded for each compound over 120 min (see Figure 4) Biodistribution shows that both derivatives have a high uptake and retention in bone with a slightly higher uptake of [68Ga]Ga-NODAGA.SA.PAM (2.97 ± 0.10 %ID/g) in comparison to [68Ga]Ga-DOTA-ZOL (2.33 ± 0.21 %ID/g) both compounds show renal excretion and only little retention in the remaining tissue it is noteworthy that after 5 min there is significant higher uptake for NODAGA.SA.PAM into pancreas and spleen compared DOTA-ZOL This uptake decreases after 60 min which suggests that it is not a specific accumulation Particularly important besides the general uptake into the bone is the specific uptake into a bone area with increased bone remodeling rate This area is represented by the epiphyses in young Ex vivo biodistribution of the [68Ga]Ga-NODAGA.SA.PAM and [68Ga]Ga-DOTA-ZOL expressed as activity concentration (%ID/g tissue n = 4) at 5 and 60 min after single intravenous injections in Wistar rats H) of registered PET/CT studies (midframe time 90 min p.i.) of [68Ga]Ga-NODAGA.SA.PAM (A–D) and [68Ga]Ga-DOTA-ZOL (E–H) in addition to its facilitated synthesis compared to the established DOTA-ZOL In biodistribution studies as well as in the in vivo PET images an increased uptake into bone and especially into the epiphyses was demonstrated the higher epiphyses -to-blood ratio resulted in better imaging quality a promising molecule with a simple synthetic strategy that can be used for labeling with both 68Ga and 177Lu we hope to take a further step toward a simple diagnosis and therapy of bone metastases in the future labeling and in vivo potential remains to be demonstrated The raw data supporting the conclusions of this article will be made available by the authors The animal study was reviewed and approved by Landesdirektion Dresden; file numbers 24-9165.40-4/2013 LG and TG: writing—original draft preparation FR and RB: writing—review and editing All authors contributed to the article and approved the submitted version The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher We would like to thank the International Center of Precision Oncology (ICPO) for finical support for open access publication We also thank the Max Planck Graduate Center Mainz (MPGC) for supporting Lukas Greifenstein and Tilmann Grus Metastatic bone disease: clinical features PubMed Abstract | CrossRef Full Text | Google Scholar Metastasis and bone loss: advancing treatment and prevention Bone metastases: pathophysiology and management policy PubMed Abstract | CrossRef Full Text | Google Scholar Biological and medical significance of calcium phosphates doi: 10.1002/1521-3773(20020902)41:17<3130::AID-ANIE3130>3.0.CO;2-1 Bisphosphonates as radionuclide carriers for imaging or systemic therapy Dissociation of binding and antiresorptive properties of hydroxybisphosphonates by substitution of the hydroxyl with an amino group Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy Cation exchange-based post-processing of (68)Ga-eluate: a comparison of three solvent systems for labelling of DOTATOC PubMed Abstract | CrossRef Full Text | Google Scholar Alendronate localization in rat bone and effects on osteoclast ultrastructure Bisphosphonates: a review of their pharmacokinetic properties PubMed Abstract | CrossRef Full Text | Google Scholar Well-designed bone-seeking radiolabeled compounds for diagnosis and therapy of bone metastases PubMed Abstract | CrossRef Full Text | Google Scholar and DOTA-peptides: practical consequences for the future of gallium-68-PET Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid 68Ga- und 177Lu-markierte Bisphosphonate als Knochenmetastasen-Theranostika A promising tool in diagnosis and palliative therapy of bone metastasis-challenges and critical points in implementation into clinical routine 177LuLu-DOTA-zoledronate therapy - first application in a patient with primary osseous metastatic bronchial carcinoma Squaric acid-based radiopharmaceuticals for tumor imaging and therapy labeling and preclinical evaluation of a squaric acid containing PSMA inhibitor labeled with 68 Ga: a comparison with PSMA-11 and PSMA-617 Synthesis and labeling of a squaric acid containing PSMA-inhibitor coupled to AAZTA5 for versatile labeling with 44 Sc Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA 5m chelators AAZTA 5-squaramide ester competing with DOTA- DTPA- and CHX-A″-DTPA-analogues: promising tool for 177 Lu-labeling of monoclonal antibodies under mild conditions Processing of generator-produced 68Ga for medical application Matching chelators to radiometals for radiopharmaceuticals PubMed Abstract | CrossRef Full Text | Google Scholar Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling DOTAZOL and NODAGAZOL for theranostics of bone metastases Google Scholar Novel radiolabeled bisphosphonates for PET diagnosis and endoradiotherapy of bone metastases Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent Evaluation of Ga-DOTA-(D-Asp) n as bone imaging agents: D-aspartic acid peptides as carriers to bone Rösch F and Bergmann R (2022) Squaric Acid Bisphposphonates for Theranostics of Bone Metastasis – the Easy DOTA-Zoledronate Received: 07 February 2022; Accepted: 01 April 2022; Published: 10 May 2022 Copyright © 2022 Greifenstein, Engelbogen, Máthé, Grus, Rösch and Bergmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Lukas Greifenstein, Z3JlaWZlbnN0ZWluQGN1cmFub3N0aWN1bS5kZQ== Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Introduction: Recent advancements in radiomolecular medicine have centered around fibroblast activation protein inhibitors (FAPi's) which target cancer-associated fibroblasts (CAFs) or disease-associated fibroblasts (DAFs) serving both diagnostic and therapeutic roles while improving diagnostic sensitivity compared to FDG suffer from limited therapeutic effectiveness due to their low uptake and short tumor retention specifically designed for prolonged tumor retention and minimal uptake in healthy tissues The research encompasses the automated manufacturing of gallium-68 (Ga-68) and lutetium-177 (Lu-177) labeled 3BP-3940 and the development of an analytical HPLC method for quality control this study offers an initial glimpse into the clinical potential of these compounds Methods: The study utilized GMP-grade 3BP-3940 precursor and [natGa]Ga-3BP-3940 reference standard from 3B Pharmaceuticals GmbH (Germany) Ga-68 was eluted from a 68Ge/68Ga-generator (GalliaPharm and radiolabeling was performed at 85°C with an All-In-One mini synthesis module (Trasis Lu-177 was obtained from ITM Isotope Technologies Munich (Germany) and radiolabeling was carried out at 85°C with the same module Analytical HPLC was used for quality control and validation of the used method LLOQ were measured for UV and radioactivity detector respectively Stability studies were conducted in triplicate in human serum (HS) PET/CT and SPECT/CT imaging were performed after injection of [68Ga]Ga-3BP-3940 and [177Lu]Lu-3BP-3940 Results: The study focused on the optimization and quality control of the labeling process for 3BP-3940 with Ga-68 and Lu-177 An automated process using a mini-All-in-One cassette-based module was employed Process optimization revealed an ideal temperature of 85°C providing decay-corrected radiochemical yields (RCY) of ≥90% within 20 minutes using 50 μg of 3BP-3940 The automated synthesis demonstrated robust production with an average RCY of 94.8 ± 4.5% and radiochemical purity (RCP) ≥ 97.0% a similar set-up and environment were used Radiolabeling was performed at 85°C for 30 minutes with 37–50 μg of precursor per GBq providing the highest RCY results Process validation showed an average RCY of 91.5 ± 9.1% and RCP ≥ 96.0% The automated synthesis yielded activities between 5.7 and 35 GBq Both [68Ga]Ga-3BP-3940 and [177Lu]Lu-3BP-3940 met specifications ensuring drug products of adequate quality In vitro stability studies in human serum and saline indicated complex stability of >90% under both conditions for two half-lives of the isotopes HPLC method validation for [68Ga]Ga-3BP-3940 involved linearity Similar validations were conducted for the radioactivity detector In a 53-year-old patient with moderately differentiated ductal pancreatic adenocarcinoma and hepatic metastasis the PET/CT study showed successful imaging of very small tumor lesions [177Lu]Lu-3BP-3940 exhibited significant uptake and retention in the primary tumor and metastases upon delayed imaging with no adverse effects Conclusions: The study optimized and validated the quality control of labeling processes for 3BP-3940 with Ga-68 and Lu-177 Automated synthesis showed robust production for both compounds meeting radiochemical purity and yield criteria A validated HPLC method and stability measurements were presented including PET/CT for diagnosis and SPECT/CT after therapeutic use highlighting the compounds' clinical potential Thank you for your interest in spreading the word on Journal of Nuclear Medicine NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it Get the best experience and stay connected to your community with our Spectrum News app. Learn More A+ Teacher Dale Greifenstein highlights how instructors administrators and staff working together with students’ best interests at heart can make the difference when challenges arise Greifenstein is a physical education teacher at Riverdale Elementary School in Orlando Before Hurricane Ian barreled through Central Florida on Sept his students went out in the great outdoors — running "There's a good group of us that have been there over 20 years at that school it was just a punch to the gut,” Greifenstein said The water intrusion was so bad that the school was forced to close "We had students that lost everything — their homes and that's a whole other side of it — they lost their homes and now their school has been moved," Greifenstein said Riverdale Elementary's kindergarten through fifth-graders are now attending East River High School Their teachers and administrators are right there with them "There's just thousands of high schoolers and then we have our 600 kids,” Greifenstein said It's almost like they’re on a month’s- long field trip see that we're going to be there every day for them Things work out the way they're supposed to and I can't imagine my life being any other way." A Thompson Township woman was charged with voluntary manslaughter of her husband following an apparent domestic dispute in the Rustic Pines mobile home park late Friday night told the Geauga County Sheriff’s Office dispatcher around 10:42 p.m. audibly shaken up after telling the dispatcher her husband Rita told the dispatcher she had some lumps on her head because he hit her in the head numerous times with a pan and that her husband had a history of getting physical with her had reportedly been arguing for some time throughout the evening Geauga County Sheriff Dan McClelland said during a Tuesday afternoon press conference .380 semi-automatic handgun was produced by Rita Greifenstein striking the victim in the chest and he expired from those wounds there.” She had told the dispatcher she might have left the gun in the kitchen Geauga County Prosecutor Jim Flaiz arrived on scene shortly after a search warrant was obtained and the Ohio Bureau of Criminal Investigation was brought in to help process evidence “as we work to piece together what transpired up to the shooting,” the sheriff said Given the evidence at hand and Greifenstein’s statements Flaiz said he found the voluntary manslaughter charge Clearly there’s been an issue raised here of self defense “After responding to the scene that evening I was able to observe a portion of her interrogation and after responding to the scene there was some evidence at the scene that corroborated her story which is why I asked the sheriff’s department to file charges for the voluntary manslaughter because there does appear to be some issue of provocation,” Flaiz said be presented to the Geauga County Grand Jury and they will determine whether probable cause exists for a felony indictment to be filed,” he said “And that presentation will not be made until we have a thorough investigation of all facts and circumstances in this case.” Rita made her initial appearance in Chardon Municipal Court Tuesday morning to have her bond set She was represented by Geauga County Public Defender Robert Umholtz Judge Terri Stupica gave Rita a 10 percent of $15,000 bond there has been “some encounters with these folks in the past,” regarding Rita and her husband “All of that will be part of the investigation as we work to establish if a pattern and specifically leading up to the event,” he said McClelland said the gun is believed to belong to Rita but officials are still investigating all the facts “This is a tragic event and it will impact a lot of people the families and members of the community as well,” the sheriff said “We want to provide the media with the information we know at this point To access our complete online news coverage Copyright Geauga County Maple Leaf. All rights reserved. | Privacy Policy | Terms of Use Website Designed & Developed by Company 119 Enrollment at the Academy of Greifenstein will begin shortly Spells & Secrets is an eye-catching, dungeon-crawling, magic-slinging action-rougelite with a lot of potential — and it's set in an academy for wizards, so basically catnip to me as a fan of a good high school story. I first became aware of this upcoming game while covering last summer's Future Of Play Direct and I've been itching to write something about it ever since I've had the opportunity to speak with Florian Mann CEO and co-founder of Spells & Secrets development team Alchemist Interactive visually resembles a mash-up of a venerable posh private school (see the wall sconces!) and a modern campus (see the football pitch!) but it's an odder choice for a rougelike-inspired action-adventure piece Mann's explanation for this is rather straightforward: most people who play video games have had personal experience of being at school so having your game take place in a school is a good way to ensure that your players intuitively click with the basics of the setting the addition of magic transforms those familiar surroundings into something that will feel fresh and new for everyone "The mix of the well-known and the unpredictable makes a great experience!" Mann enthuses "You can throw your wildest ideas into it and with a little bit of tweaking nothing will feel odd or stand out in a negative way." come from the fact that the whole team are long-time fans of the genre and have wanted to produce something along these lines for a while consistently referred to as "roguelike-inspired" in official materials which he attributes to Alchemist Interactive wanting to "give it our own flavour" "We generate from a set of carefully designed components like rooms then arrange and combine them procedurally," Mann tells me "Because we know that each of these components works well on its own we then get interesting gameplay situations from the countless combinations that are created." the solutions to puzzles to change between runs meaning that players can't get complacent even if they encounter the same basic puzzle on numerous occasions Even though I'm sometimes sceptical of games which seem to be rougelite for roguelite's sake I have to admit that Mann makes a good case for procedural generation here where it clearly extends the scope of what an indie studio can hope to accomplish an impenetrable school with a constantly shifting layout sounds appropriately magical to me if a bit impractical from a student onboarding perspective This would perhaps be of particular concern to the player character who's a first-time student at Greifenstein there's not a lot that's set in stone for your character "We chose to implement a character creator that makes it possible to create your very own character that you can identify yourself with," Mann tells me adding that you'll have the option to change up your avatar's physical appearance at any time if you fancy something different You'll also have an extensive series of wardrobe options from the start and will unlock more by progressing through the game It's no secret that many games taking place in academic settings do have a tendency to sideline the actual day-to-day business of school life When was the last time a video game made you sit through six lessons for every lunch break in which you continued your heartfelt teen romance/investigation of a murder/desperate fight against a horde of zombies I was a little surprised to learn that Spells & Secrets won't actually feature the option to attend classes at all and Mann assures me that Greifenstein's teachers will still be on-hand to impart knowledge of new spells and help you level up your existing ones He also drops an intriguing reference to "student factions" opening up unique spells and progression routes depending on which you choose to join When asked to describe his personal favourite spell Mann initially tells me that he likes all of them but later relents and gives me a little glimpse of one in particular "I personally like the spell Switch," he says "It allows you to switch places with your target It always feels good to switch in the right moment with an enemy and to let them get hit by their own shot or to escape a tricky situation." Switch can also be used to enable quicker movement allowing you to hop across a large room by changing places with the objects within it This neatly demonstrates the really interesting and quite unique thing about magic in Spells & Secrets Every spell in the game can be used against any target "A few spells will straight up deal damage to an opponent but a wider selection of spells will not," Mann says "Those spells have the potential to weaken enemies or to set up powerful synergies with other spells A keen eye will also discover opportunities to use the environment or to manipulate objects and enemy behaviour to their advantage." is what makes Spells & Secrets stand out from other wizarding games Combat and puzzle-solving alike will go much more smoothly once the player learns how to wield their magic in a way that makes intelligent use of their environment you'll spend at least as much time improvising with nearby props as you do directly blasting your opponents with magic beams any dungeon-crawler worth its salt has to have enemies your primary antagonists will be a variety of oddball magical creatures who — in typical fantasy fashion — overrun the school on your hapless protagonist's very first day Hence the fact that no-one's too concerned with keeping track of attendance "Every [creature] has very unique characteristics," Mann tells me explaining that players must "learn how to defend themselves against their enemies' strengths and exploit their weaknesses." There's a sort of bad-Pokémon vibe to the creatures showcased so far although it's hard right now to judge whether they'll be evil or simply mischievous Or maybe I'm only thinking that way because they're rather cute I could have easily kept asking questions about Spells & Secrets all day but Mann very kindly agreed to this interview at quite short notice and I know I've taken up enough of his time for now and I'm still as intrigued as I first was back on that feverish summer night last June when it first caught my eye since this interview Spells & Secrets has been given a release window of Q2 2023 meaning that with luck we won't need to wait too much longer to crawl those scholastic dungeons No part of this website or its content may be reproduced without the copyright owner's permission Rock Paper Shotgun is a registered trademark of Gamer Network Limited You've been selected to join the prestigious wizarding school Greifenstein fighting against an almighty evil organisation that has terrorised the castle and overtaken it Spells & Secrets is a wizarding roguelike where you'll jump into the castle to fight back to retake it as the castle's defences have also activated and it has turned into an endless maze — to save Greifenstein The story isn't the most innovative you'll come across and sometimes the writing can feel a bit off I did appreciate the unique reasoning as to why you are the only person who can enter Greifenstein and fight the boss back as the teachers standing in the courtyard waiting for you to complete everything would have felt uncomfortable otherwise you'll be jumping into the castle to complete runs time and again and what ensues is spell-hurtling gameplay where you can choose three different incantations to have equipped at any given point As you progress through the game and complete each floor of the castle you start unlocking new professors who teach you new These tend to correlate with abilities you'll see scattered throughout the floor and some even work as your new "basic attack" The gameplay loop then revolves around going into the castle and spending those on various spells that you can buy and upgrade with me reaching the final boss on my first attempt (though I promptly panicked and failed to defeat them that same run) the difficulty isn't really a bad thing — I liked feeling powerful and using combinations of spells to defeat enemies or exploiting their weaknesses you will be traversing the castle past your first defeat of the final boss and the game gets slightly harder with each successful run And there's a lot of variety in terms of battle — you can equip three different spells (with your third one working as a Flex Spell and unlock various artefacts throughout your run that affect your spells The offensive abilities all feel great within their own builds and have different purposes so it isn't rare to change mid-run to another one if you feel it'll work better against any given foe Combat is also where one of my only complaints of the game is however — you have too few choices to have slotted at any given moment With so many great abilities that work offensively having three that you can use quickly feels like too little This stopped me from using the tactical spells too much I opted for anything that would ensure I could deal sufficient damage or mandatory attacks that make the game much more manageable (like Levitate) Since I thoroughly loved the spell-hurtling gameplay that encourages you to try different combinations I did try the split-screen co-op with my wife which led to a lot of laughter as we moved each other around with telekinesis or made the other levitate constantly While she and I are always looking for an enjoyable title to play together Spells & Secrets was a breath of fresh air as an enjoyable title the game is borderline unplayable on the joypad in contrast to the mouse and keyboard as aiming with the right joystick and casting spells with buttons meant that you were forced to use the lock-in mechanic Player one also can't play with the mouse and keyboard as both players are obliged to play on the controller regardless — if you don't have two lying around you are gated from playing split-screen co-op altogether this would be one of my favourite cooperative titles to play both players being forced to use the controllers and its integration being bad makes it difficult to love Aside from jumping into Greifenstein time and again to fight back the forces you have a couple of other things you can do this consists of challenges that you can complete for cosmetic rewards joining one of the four houses and getting their house-specific spell and maxing their reputations to get their cosmetics Ending a run always felt very gratifying because there are a slew of challenges to complete and spending your Experience in the Courtyard to master your spells felt like genuinely enjoyable progression Spells & Secrets is an absolute joy of a roguelike that I had fun with Completing puzzles scattered across Greifenstein and going through the floors is some of the best spell-based gameplay you can get in gaming right now and with a severe lack of magic-focused titles My only gripes are predominantly mechanical and slightly limiting options Spells & Secrets is an easy no-brainer for magic lovers and enthusiasts looking for a wizarding home This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page Introduction: Fibroblast activating protein (FAP) is a transmembrane serine protease rarely expressed in normal adult connective tissue but abundant on cancer associated fibroblasts (CAFs) and expressed in 90% of epithelial cancers The purpose of this study was to determine the feasibility of using a novel FAP-targeted cyclic peptide 3BP-3940 for peptide targeted radionuclide therapy (PTRT) and present first-in-humans results using 177Lu 90Y and 225Ac labeled 3BP-3940 in end-stage cancer patients Methods: 28 patients (16 men and 12 women; mean age 59.4 ± 10.5 years) with advanced metastatic cancers of the pancreas (PDAC) and bowel sarcoma presented with disease progression after previous treatments and were treated with PTRT between March 2021 and December 2022 Pre-treatment PET/CT imaging was done with Ga-68 3BP-3940 to determine tumor uptake Treatment response was evaluated according to RECIST and EORTC Kaplan–Meier survival analysis was performed to calculate overall survival (OS) Results: Cumulative activity was for 177Lu 12.6 ± 11.5 GBq (n=21; up to 43.1 GBq) and 225Ac 15.2 ± 8.5 MBq (n=23; up to 33 MBq) Visual analysis of posttherapy whole-body scans and SPET/CT scans demonstrated significant uptake and retention of 3BP-3940 in tumor lesions on delayed imaging in all patients 12/28 patients passed away due to disease progression One patient died due to sepsis following check-point inhibitor therapy One patient died post bowel bypass surgery Two patients withdrew from the study before their 2nd cycle due to disease progress For the entire cohort from the start of PTRT (n = 28) In the subgroup of patients with advanced pancreatic adenocarcinoma (n = 8) Conclusions: 3BP-3940 PTRT is feasible with 177Lu/90Y/225Ac either alone or as TANDEM treatment of end-stage cancer patients Treatments were well-tolerated without significant adverse effects 3BP-3940 PTRT demonstrated a favorable biodistribution significant uptake and retention in tumor lesions with very high tumor-to-background ratio and should objective responses in advanced metastatic adenocarcinomas and sarcomas The survival benefit for PDAC patients seems to be very promising The magical action-adventure game only has a few hours left on Kickstarter Hogwarts Legacy indie-alternative Spells & Secrets has received a new co-op trailer that shows what kind of antics you and another player can get up to in the Academy of Greifenstein.  where we can see the perks of playing in local co-op mode Don’t worry if you don’t have any local co-op friends to play with though as Spells & Secrets will also support online co-op via Steam Remote Play.  it seems like having a secondary player to help face up against enemies and solve puzzles in the Academy of Greifenstein really comes in handy having someone to play alongside you will also give you the added bonus of playing a quick game of football - with the help of a little magic of course If this is the first time you’ve heard about Spells & Secrets Closely resembling the likes of Hogwarts Legacy and other elements of the Harry Potter franchise Spells & Secrets is a 3D action-adventure game with puzzle mechanics and procedural elements within it Players will be able to customize their own character as they make their way through Greifenstein improving their magical abilities as they go along.  Spells & Secrets isn’t expected to release until Q2 (April - June) 2023 on PC/Steam and Q3 (July - September) on Nintendo Switch but the developer has said it plans to release an Early Access PC version sometime this year the Spells & Secrets Kickstarter campaign has less than five hours to go - so we suggest checking it out quickly if this sounds like your kind of game.  Wondering what other games you should keep an eye out for in the near future? Take a look at our new indie games list.  Hope BellinghamSocial Links NavigationNews WriterAfter studying Film Studies and Creative Writing at university I was lucky enough to land a job as an intern at Player Two PR where I helped to release a number of indie titles I then got even luckier when I became a Trainee News Writer at GamesRadar+ before being promoted to a fully-fledged News Writer after a year and a half of training  My expertise lies in Animal Crossing: New Horizons but especially in the Kingdom Hearts series I'm also known to write about the odd Korean drama for the Entertainment team every now and then deer: Florida teacher rescues young buck from fenceStudents gathered to watch featAdrienne Cutway ORANGE COUNTY – A group of students at an Orlando elementary school got a wild hands-on lesson Monday as their physical education teacher bolted into action to save a deer that got its antlers caught in a fence An Orange County Public Schools spokesman said a fourth grade teacher at Riverdale Elementary School told coach Dale Greifenstein around 11 a.m that a young buck had gotten its antlers caught in the fence and needed some help [TRENDING: 2020 Voter Guide | What to expect if Trump wins | What to expect if Biden wins] Greifenstein was able to maneuver the chain link in order to set the animal free all while about 30 fourth grade students who were at recess watched The deer was able to regain its balance within a few seconds and frolic back into the forest An OCPS spokesman joked about calling the young buck Rudolph Greifenstein has worked at the school for more than two decades and isn’t a stranger to deer sightings but Monday marked the first time he had the chance to rescue one so we had to make sure to save Christmas,” Greifenstein said Copyright 2020 by WKMG ClickOrlando - All rights reserved TV Listings Email Newsletters RSS Feeds Contests and Rules Contact Us / Follow on Social Media Careers at WKMG Closed Captioning / Audio Description Public File Current EEO Report Terms of Use Privacy Policy Do Not Sell My Info FCC Applications EEO Report Disability Assistance Copyright © 2025 ClickOrlando.com is managed by Graham Digital and published by Graham Media Group Posted in: Games, Indie Games, Video Games | Tagged: , , Enjoyed this? 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It’s time to scratch your head solving more nonograms with Piczle Cross: The 2025 Atari Studios Publisher Sale has now started on the Nintendo eShop Gameloft has announced that new Premium Shop content has been released for Rokaplay and Alchemist Interactive have shared a new gameplay trailer for Spells & Secrets, which will release on Nintendo Switch next year you play as a first-year student who has started studying the magical arts at the Academy of Greifenstein After a strange incident on your first day sees the modern-day wizarding school descend into turmoil it is up to your to explore the procedurally-generated castle grounds and save it After crafting your own wizard using the game’s in-depth character creation system you will have the chance to team up with a friend in local co-op unleash an arsenal of physics-based magic and use different spell combinations to overcome puzzles and defeat enemies The publisher has outlined the game’s key features as below: Spells & Secrets will release digitally on the Nintendo eShop for Nintendo Switch worldwide in 2023 Δdocument.getElementById( "ak_js_1" ).setAttribute( "value" Not again,” I weakly gasp as I stagger from my ten-dollar-a-night bed towards the bathroom One step inside the blue tile shower/toilet combo and I projectile vomit everywhere I drop to my knees before the porcelain throne as painful convulsions leave me gasping for air After a half-minute of hope-you're-not-eating-lunch-while-reading-this My formerly swollen, I'm-gonna-stuff-my-face-because-it’s-impossible-to-get-fat-on-this-SUP-trip torso feels like an empty tube of toothpaste I haven’t managed to keep any food or water down for the last 36 hours I'd grin at the naïveté of my original expectations of this expedition versus the pitiful reality I find myself in but any part of me capable of producing anything remotely akin to a smile is splattered on the floor around me The downside of hammock camping is the necessity to find adequate trees to hang the hammock After two weeks of logistical planning and zero physical preparation I launched my green 404 Monster into the murky brown waters of the Danube River in Ingolstadt I’d spent plenty of time paddling the temperamental Atlantic on Boston's north shore and SUP surfing world class breaks all around New Zealand Within minutes of standup paddling on the swift river trying to dodge barely submerged rocks at the last second with 60 pounds strapped to your board isn't the simplest task but nothing compared to the nightmarish vortex I'd imagined The tension and stress of planning a multi-week expedition evaporated into incessant grinning and semi-maniacal laughter in the glorious July sun Progress was swift…for the first ten miles The once 50-yard-wide river quadrupled in width and slowed to a painful crawl I’d hit the first of the Danube’s 62 dams a middle-aged bearded guy with a kayak—loaded with what must have been 250 pounds of superfluous gear—greeted me Flo, a Romanian martial arts expert beamed with excitement as we Hoorah’d his gear a half-mile to the other side of the dam I hardly got in two words as he educated me on meditation poses that guarantee immortality and the importance of drinking your own bodily fluids As we paddled passed Deggendorf and Regensburg over the next couple of days it became clear that my 12’6 race SUP was an incompatible travel companion to his bow-heavy sit-on-top kayak Seeing as we’d been doing just over 25 miles per day well shy of the 45-mile daily average I had planned I breathed a sigh of relief as I shifted my paddling into high gear I blasted 90's rock and the occasional Katy Perry song as I glided past pea stone beaches and the ancient Bavarian forests that hugged the winding shoreline but screaming along to “Wide Awake” without the judgment of others is so much sweeter You'd think paddling alone 8 hours a day would quickly lose its thrill, but the meditative qualities of repetitious motion with bright sunlight glistening off the sluggishly churning water put me in a trance that had time flying by. The pattern of paddle, stop for coffee, find someone to put sunscreen on my back explain that it's not a kayak and no I shouldn't be sitting provided variation and filled my daily schedule to the brim I'd lay in my jungle hammock at the end of the day write in my journal and wake up to the agro beeping of my alarm with a pen jabbing my side and a half written entry Another day paddling solo on the mighty Danube Being the first person to SUP the entire Danube River was a sweet bucket list item it was an ambition I didn't give much credence to I only planned to paddle 300 miles from Ingolstadt Germany to my old stomping grounds of Vienna As I greeted my friends at our designated pickup spot Few people were privy to my ambition of completing Europe's most famous and second longest river so when I announced my plans on the Facebook site I got more likes and messages than a kitten saving an orphaned mouse With the enthusiastic outpouring of support a few friends and I whipped together a website Despite best efforts to get back on the river before the summer weather sputtered it took more than four weeks to resume my expedition The cloudless July skies I had grown accustomed to morphed into a monotonous gray September haze as I set off from Dürnstein Austria for the remaining 1,265 miles to the Black Sea vicious mosquitos and run-ins with the occasional belligerently drunk fisherman Within five days I passed through the ship traffic and gothic architecture of Budapest as crowds of people stopped and waved at what must have looked like a crazy American the Hungarian water police slapped me with fines for “not having correct maritime lighting systems,” and “traveling outside of the designated ship channel,” in addition to various other infractions pertaining to ships and paddling enthusiastically towards the Serbian border the skies cleared and I managed to break 100 kilometers in a single day Having battled through rain and wind into the summery embrace of the mountainous Serbian/Romanian landscape Floating through the scenic Wachau Stay tuned for Part 2 of Paddling the Danube River More Field Notes here. a monument was erected to a famous citizen of Ulm the bronze head of the Erwin Piscator monument looks over the village and the landscape of his childhood Erwin Piscator was born in Ulm on 17 December 1893 German language and literature and philosophy and completed his traineeship at the Court and National Theatre in Munich he became a convinced pacifist and participated in a Belgian front theatre he first founded the theatre "Das Tribunal" in Königsberg then in 1920 the "Proletarian Theatre" in Berlin Piscator then took over the Central Theatre in Berlin-Kreuzberg and expanded its repertoire to include 19th century authors From 1924 to 1927 he directed political theatre at the Berlin Volksbühne in his own style using new methods he projects films or uses motorised bridges and develops a revolving stage for his performances His political playbill eventually leads to a rupture three Piscator stages were built in succession In 1931 Piscator takes on a film assignment in the Soviet Union and cannot return to Germany after the National Socialists seize power in 1933 as he is on the Gestapo wanted list as a communist It was not until 1936 that he left the Soviet Union and travelled to Paris on behalf of the International Revolutionary Theatre Association from where he left for the USA via London in 1938 In 1939 Piscator founded the Dramatic Workshop at the New School for Social Research in New York Its most famous graduates include Harry Belafonte Piscator left the USA and worked as a director in various German cities In 1962 he became artistic director of the Freie Volksbühne in West Berlin Erwin Piscator dies in Starnberg on 30 March 1966 He is buried at the Waldfriedhof in Berlin-Zehlendorf The erection of the memorial in the 50th year of Piscator's death was initiated by the Heimatverein Ulm The bronze head was created by the sculptress Gela Dömland and the pedestal by the versatile local artist Siegfried Fietz Translated with DeepL (www.deepl.com) Eighteen sixth- through eighth-grade students representing 10 area junior high and middle schools competed in the 32nd annual Knights of Columbus Spelling Bee held Saturday at the Knights of Columbus Hall in Arlington Heights The first-place finisher was Clarissa Gomez of St The second-place finisher was Sydney Sadler of Thomas Middle School in Arlington Heights; and the third place finisher was Daisy Alvarado of Carl Sandberg Junior High in Rolling Meadows The bee used 198 words and lasted for an exciting 18 rounds Spellers battled through words such as shiatsu before Clarissa Gomez spelled both bonsai and focaccia correctly to claim first place All three finalists have qualified to compete in the Regional Spelling Bee in March where the top three finishers of the Regional Bee will qualify for the state tournament in April Schools and students participating in the Spelling Bee were: Arlington Heights: Our Lady of the Wayside: Sarah Conneely and Emily Styzinski; St James Junior High School: Clarissa Gomez and Tony Toczycki; St Peter School: Alexi Armoush; South Middle School: Abby Citterman and Lilly Greifenstein; and Thomas Middle School: Sydney Sadler and Martina Macaggi Mount Prospect: Holmes Junior High School: Madhuvani Gowrabathuni and Stephanie Montesinos; and St Rolling Meadows: Carl Sandburg: Daisy Alvarado and Alex Hong; St Colette School: Daniel Fecko and Samantha Shirmer The bee was hosted by Holy Rosary Council #4483 of Arlington Heights and co-sponsored with Mount Prospect Council #6481 and Our Lady of the Grove Council #13448 from Buffalo Grove All public and private junior high schools and middle schools serving Arlington Heights and Wheeling were invited to send two representatives to participate • Send Your news to nbrcalendar@dailyherald.com Summer is nearly upon us again in Rhineland-Palatinate and the gardens paths and forests are slowly coming to life again as the mercury rises Children’s laughter can be heard in many places into the evening as the little ones use their lively imaginations to join in the adventure and attempt to be like the grown-ups now is the best time to make wonderful memories stories you will still be telling in 20 years’ time There will be fascinating excursions into unspoilt countryside the feeling of living close to the beating heart of the earth or even that special feeling of exclusiveness against a historic setting In order to make it easier for you to find these memorable experiences and sweeten the anticipation of Rhineland-Palatinate for your nearest and dearest we have put together six extraordinary accommodation options for families in our unique state Our first tip takes you to the ancient volcanic Eifel: With traditional camping, you often have to pitch your tent on a small parcel of land, while the Naturerlebnishof Vulkaneifel in Ulmen offers a whole 10,000 square metres of adventure playground for all the family you can spend the night in a luxurious glamping tent with its own terrace or even brave one of the suspended tree tents with wonderful views of the wide-open starlit sky watch the geese on the pond or interact with pigs you can tell stories about your daytime adventures over the crackling flames from the ancient fire pit before laying your heads down on the straw to rest Accommodation offers and experiences for families: Animals at Naturerlebnishof Vulkaneifel Outdoor Centre Lahntal in Greifenstein-Allendorf The magical forests above the Lahn are even closer to nature and also a little bit more mysterious for you and your loved ones. Among the trees to the south of the village of Allendorf, you will find the amazing wooden structures of the Outdoor-Zentrum-Lahntal to transport your family away to a different world you could believe you have been transported to the Mongolian steppes and the ground-level Hobbit house will have you dreaming of adventures in Middle Earth For big families or excursions with friends one of the real treats takes you back to the days of bison The huge tents in the tepee village promise the feeling of being at one with nature in the middle of the forest You sleep on wooden beds and grill your own food over the open fire pit in the tent before enjoying it together on the large group tables in front of the tepees Tipi as overnight accommodation at the Outdoor Centre Lahntal in Greifenstein-Allendorf Ehrenburg Hotel in Brodenbach on the Moselle You can either head for one of the stylish chambers inside the castle walls and feel like nobles from the Middle Ages or sleep in the shadows of the powerful defensive complex in one of the carriages or knights’ tents as if you were going to take part in a tournament the next day What with the range of medieval events around the Ehrenburg and the wonderful contemporary foods served up by the court kitchen any stay becomes an exciting adventure blurring fantasy and reality Castle room in the Ehrenburg Hotel in Brodenbach While the Ehrenburg is hidden in a side valley of the Moselle, the magnificent Diez Castle towers above the village of the same name on the Lahn The building originally dates back to an 11th-century castle but is now home to a modern youth hostel with stylish eating The complex is even certified based on the ‘Reisen für Alle’ (travel for all) accessibility scheme so you can genuinely bring the whole family with its historic half-timbered buildings and winding streets The castle’s location at the intersection of the Westerwald the Taunus and the Lahn valley makes it the perfect starting point for your adventures There are countless hiking trails criss-crossing the Geopark or you can simply glide down the cool waters of the river in a canoe Ferienbahnhof Reichenbach in Dahn in the Palatinate The Ferienbahnhof Reichenbach near Pirmasens in the Dahner Felsenland offers a similar level of variety in one of two original carriages from the Swiss national railway or a former sleeper and workshop carriage from the German state railway The trains originally date back to the 50s and 60s but have been converted into stylish apartments with real flair and great attention to detail You can also stay in the former engine shed while the old station building has been converted into a restaurant one of the loveliest regions of the Palatinate is on your doorstep with impressive natural scenery featuring bizarre red sandstone formations for you and your loved ones to explore Walking along the railway wagons of the Ferienbahnhof Reichenbach in Dahn Cosy sleeping cars for hire at Camping Nahemühle, Nahe Bad Neuenahr-Ahrweiler A modern and fascinating youth hostel like from a picture book. All rooms in the Bad Neuenahr-Ahrweiler youth hostel will be equipped with new, modern… To make sure you never miss out on your favourite NEW stories, we're happy to send you some reminders Click 'OK' then 'Allow' to enable notifications I’m a major fan of the ‘cosy’ game - and I know I’m not alone As many of us are entering the colder months of the year it is oh so very lovely to snuggle up under a blanket with a warm drink and a game that just oozes comfort and relaxation If that scene sounds appealing to you, and you just so happen to be a fan of Hogwarts Legacy, you’re going to want to check out this new wizarding roguelite. Alchemist Interactive are gearing up to release Spells & Secrets - and it looks truly delightful Spells & Secrets will allow you to play as a student wizard who’s tasked with defending the school from an array of magical creatures (the evil kind whilst solving a variety of mysteries and sourcing powerful artefacts Take a look at Spells & Secrets in action below Devs described the game as a “deep and motivating rogue-lite experience that invites newcomers to this rewarding genre with its adventure story” Hogwarts Legacy was a single-player wizarding experience but Spells & Secrets will allow you to play co-op with your family and friends You’ll additionally also have the chance to totally customise the appearance of your student wizard Devs are keen to highlight that you’ll have great freedom in the character creator with no clothing or appearance options locked to any particular gender you’ll also have ample opportunity to level up and it’s teased that the Academy of Greifenstein is “ever-changing” Spells & Secrets is set to launch on 6 November. In the meantime though, you can check out a free demo which is playable now on Steam. The game will also launch on Nintendo Switch Topics: Hogwarts Legacy, Indie Games, Harry Potter