Search

Secretion of beta human chorionic gonadotropin (β-hCG) is a rare, recently recognised paraneoplastic syndrome. Herein, we present a case of a woman in her 30s with right femur conventional high-grade osteosarcoma and a positive screening urine pregnancy test. Subsequent workup failed to reveal an intrauterine or extrauterine pregnancy. Rather, pathology and gene expression studies confirmed serum β-hCG production by osteosarcoma cells. Though the prognostic implications of β-hCG expression are unclear, β-hCG may be a useful surveillance marker to monitor disease progression or recurrence., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Approximately half of patients with localised, high-risk soft tissue sarcoma of the extremity develop metastases. We aimed to assess whether the addition of pembrolizumab to preoperative radiotherapy and surgery would improve disease-free survival., Methods: We completed an open-label, randomised clinical trial in patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or dedifferentiated or pleomorphic liposarcoma of the extremity and limb girdle. Patients were enrolled at 20 academic institutions in Australia, Canada, Italy, and the USA. Patients were randomly assigned to preoperative radiotherapy then surgery (control group) or preoperative pembrolizumab with radiotherapy (initiated 1-14 days after the first dose of pembrolizumab) then surgery and postoperative pembrolizumab (experimental group). Pembrolizumab (200 mg intravenously every 3 weeks) was administered as three neoadjuvant cycles (before, during, and after radiotherapy) and 14 or less adjuvant cycles. Primary endpoint was disease-free survival. This study is registered with ClincialTrials.gov (NCT03092323)., Findings: Between Nov 18, 2017, and Nov 14, 2023, 143 participants were randomly assigned to treatment. A modified intention-to-treat analysis of 127 patients with median follow-up of 43 months showed that the experimental group (n=64) had significantly longer disease-free survival than the control group (n=63; log-rank one-sided p=0·035; hazard ratio [HR] 0·61; 90% CI 0·39-0·96). The 2-year disease-free survival increased by 15% with addition of pembrolizumab: 52% (90% CI 42-64) and 67% (90% CI 58-78) for the control and experimental groups, respectively. Disease-free survival was similarly improved with pembrolizumab for the intention-to-treat patient population (HR 0·61 [90% CI 0·39-0·95]). Grade 3 or higher adverse events occurred more frequently in the experimental group (56%) than the control group (31%)., Interpretation: Addition of pembrolizumab to preoperative radiotherapy and surgery improves disease-free survival for patients with stage III undifferentiated pleomorphic sarcoma and pleomorphic or dedifferentiated liposarcoma of the extremity, which establishes a promising new treatment option for these patients., Funding: Stand Up to Cancer and Merck Sharp & Dohme., Competing Interests: Declaration of interests YMM reports leadership roles in ASTRO and NRG Oncology and an honorarium from the University of Wisconsin–Madison. YMM, KVB, KJW, and DGK report grant funding from Stand Up to Cancer (Merck Catalyst Program) to the institution to support this study. KVB reports funding from SARC and the National Cancer Institute. AMH reports grant funding paid to Australia and New Zealand Sarcoma Association from the GPA Andrew Ursini Charitable Fund to support sample shipment to the USA and grant funding paid from Cancer Australia to Australia and New Zealand Sarcoma Association for clinical research team support for this study in Australia. YMM, AMH, SMS, and CFM report royalties from UpToDate for authorship contributions. AMH reports payment for participating on an advisory board for Teli. SMS reports grant funding from TRACON, Adaptimmune, and GlaxoSmithKline (GSK) to the institution; travel support from the National Comprehensive Cancer Network; and payment for participation in an advisory board for BioAtla. AJW reports a leadership role on the Board of Directors for SARC. VM reports grant funding from Rising Tide Foundation for Cancer Research; honoraria for presentations from Association of Northern California Oncologists and Gundersen Health System; participation in an advisory board for Forma Therapeutics; and funding to the institution from Amgen, Prelude Therapeutics, Jazz Pharmaceuticals, Astex Pharma, Oblato Therapeutics, Orbus Therapeutics, and Novartis. SA reports grant funding to the institution from SARC, Merck, TRACON, Bayer, Novartis, Lilly, Karyopharm, Epizyme, Blueprint, Genmab, CBA Pharma, Philogen, Gradilis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen, Bavarian Nordic, BTG Pharmaceuticals, PTC Therapeutics, GSK, Forma Therapeutics, Ayala Pharma, Trillium, Boehringer Ingelheim, Salarius, Theseus, Monopar, C4 Therapeutics, Inhibrx, Noxopharm, Rain Therapeutics, Shanghai Pharma, PharmaMar, Cogen, and Jazz Therapeutics. SA reports grant funding to himself from Guardant. EC reports consulting fees from Sonata Therapeutics, Adaptimmune, Epizyme, and Bayer; and participation in advisory boards for Adaptimmune and Pfizer. DIP reports honoraria for presentations to Bayer. BAVT reports grant funding from Polaris; a patent on ALEXT3102; a patent on the use of ME1 as a biomarker; licences from Accuronix Therapeutics; consulting fees from Cytokinetics, Bayer, Deciphera Pharmaceuticals, Daiichi Sankyo, EcoR1, Advenchen, Putnam, Salarius Pharmaceuticals, Boxer Capital, Acuta Capital Partners, Aadi Bioscience, Race Oncology, Kronos Bio, Sonata Therapeutics, and Hinge Bio; honoraria for presentations from Iterion Therapeutics, and Total Health Conference; travel support from Adaptimmune, Advenchen Laboratories, Polaris, and Kronos Bio; participation in advisory boards for Apexigen, Daiichi Sankyo, Epizyme, Bayer US Medical Affairs Oncology, PTC Therapeutics, Asdi Biosciences, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals, Curis; and an unpaid role on the safety monitoring board for Polaris. GT reports receiving payment for participating on an advisory board for Servier and consulting fees from Daiichi Sankyo. BC reports funding paid to the institution by SARC for support of this study; grant funding for clinical trial support paid to the institution by Bristol Myers Squibb, Macrogenics, Karyopharm Therapeutics, Infinity Pharmaceuticals, Advenchen Laboratories, Xencor, Compugen, Iovance, RAPT Therapeutics, IDEAYA Biosciences, Ascentage, Atreca, Replimune, Instil Bio, Adagene, TriSalus Life Sciences, Kinnate, PTC Therapeutics, Xilio Therapeutics, Kezar Life Sciences, and Immunocore; payment for participation on advisory boards at Novartis, Delcath, Instil Bio, Replimune, Atreca, Regeneron, and Treeline Biosciences; and payment for participation on the data monitoring committee for SpringWorks Therapeutics. AG reports funding to the institution from PharmaMar and Nanobiotix; consulting fees from Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks, and Boehringer Ingelheim; honoraria for presentations from PharmaMar and Deciphera; travel support from PharmaMar; and leadership roles as the International Representative on the Executive Council of the Society of Surgical Oncology, a member of the Board of Directors of the European Society of Surgical Oncology, and a member of the Board of Directors of the Italian Sarcoma Group. CFM reports consulting fees for participating on advisory boards for Deciphera, Daiichi Sankyo, and Aadi Bioscience. MAD reports funding to the institution from Eli Lilly, Sumitomo Pharma, and Aadi Bioscience. LED reports funding from SARC to the institution to support this study; funding to the institution for clinical trial activities from Salarius, Inhibrx, BioAtla, Adaptimmune, GSK, SpringWorks, Epizyme, BTG Pharmaceuticals, Eisai, and Novartis; consulting fees from GLG Expert Network and Guidepoint Expert Network; educational payment from SpringWorks; payment for participating on advisory boards for Daiichi Sankyo, Inhibrx, Regeneron, and SpringWorks; leadership role on the scientific steering committee for SARC; leadership role on the scientific advisory board for the Osteosarcoma Institute; and a former leadership role on the Northwest Sarcoma Foundation Board of Directors. BEB reports consulting fees from Daiichi Sankyo, Deciphera, and Musculoskeletal Transplant Foundation; participation on a data safety monitoring board for PARITY Trial and SAFETY trial; and serving as a member of the Executive Board for the Musculoskeletal Tumor Society. RFR reports funding to the institution for clinical trial support from Aadi Bioscience, Adaptimmune, AROG, Ayala, BioAtla, Blueprint, Cogent, Daiichi-Sankyo, Deciphera, GlaxoSmithKline, InhibRx, NanoCarrier, Oncternal, PTC Therapeutics, SARC, SpringWorks, TRACON, and Trillium; consulting fees from Aadi Bioscience, Adaptimmune, Bayer, Blueprint, Boehringer Ingelheim, Daiichi-Sankyo, Deciphera, GSK, NanoCarrier, and SpringWorks; honoraria for lectures from SpringWorks; travel support for advisory board participation for Deciphera; leadership role as co-chair of the ECOG-ACRIN Sarcoma Working Group; medical writing assistance from Prescott Medical Communications Group with financial support from SpringWorks Therapeutics; and spouse ownership in Limbguard. DGK reports funding from MSD through the Merck Investigator Studies Program to the institution to support this study; and grant funding to the institution from Bristol Myers Squibb, Varian Medical Systems, the National Institutes of Health, and the Department of Defense. DGK has a licence for an imaging device through Lumicell; patents through Lumicell and XRad Therapeutics; membership on the scientific advisory board of Lumicell; membership on the independent data monitoring committee for the clinical trial SARCO; previous leadership role as the Councillor in Medicine on the Board of Directors of the International Association for Radiation Research; and holding stock in XRad Therapeutics and Lumicell. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

In the realm of enzymology, Carbonic anhydrase (CA) emerges as a pivotal protagonist orchestrating the rapid conversion of carbon dioxide and water into bicarbonate ions and hydrogen ions, respectively. Carbonic anhydrase inhibitors (CAIs) are the class of drugs that target various isoforms of the enzyme, and these inhibitors play a crucial role in the treatment and management of multiple diseases such as cancer, glaucoma, high altitude sickness, rheumatoid arthritis, obesity, epilepsy, and sleep apnea. Several structural classes of CAIs developed till date possess unique architects of the pharmacophoric requirements around the central core moiety for the selective targeting of various isoforms of the CA. Recent advancements in drug design and development, along with technologies that aid in structure determination, have led to the development of several isoform-selective inhibitors of CA enzymes. However, their clinical development was hampered by the lack of desired therapeutic efficacy, isoform selectivity and safety profile. This review covers the most recent approaches used by different researchers concerned with the development of isoform-selective carbonic anhydrase inhibitors belonging to distinct structural classes like sulphonamides, carbazoles, selenols, coumarin, organotelluride, topiramate, thiophene, triazole, uracil-modified benzylic amines, and thiourea etc. In addition, their structure-activity relationships, biological evaluation, and in silico studies inlcuding the forthcoming avenues of advancements have been discussed. This review serves as a valuable resource for developing potent and efficacious CAIs with remarkable therapeutic implications; offering insights into their potency, specificity, and potential clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A multitude of plant-derived bioactive compounds have shown significant promise in preventing chronic illnesses, with flavonoids constituting a substantial class of naturally occurring polyphenolic compounds. Apigenin, a flavone identified as 4',5,7-trihydroxyflavone, holds immense promise as a preventative agent against chronic illnesses. Despite its extensive research and recognized nutraceutical value, its therapeutic application remains underexplored, necessitating further clinical investigations. This review delves into the biological sources, nutraceutical prospects, chemistry, pharmacological insights, and health benefits of apigenin. Through multifaceted analytical studies, we explore its diverse pharmacological profile and potential therapeutic applications across various health domains. The manuscript comprehensively examines apigenin's role as a neuroprotective , anti-inflammatory compound, and a potent antioxidant agent. Additionally, its efficacy in combating cardiovascular diseases, anti-diabetic properties, and anticancer potential has been discussed. Furthermore, the antimicrobial attributes and the challenges surrounding its bioavailability, particularly from herbal supplements have been addressed. Available in diverse forms including tablets, capsules, solid dispersions, co-crystals, inclusion complexes and nano formulations. Additionally, it is prevalent as a nutraceutical supplement in herbal formulations. While strides have been made in overcoming pharmacokinetic hurdles, further research into apigenin's clinical effectiveness and bioavailability from herbal supplements remains imperative for its widespread utilization in preventive medicine.

Twelve 3,5-disubstituted-thiazolidine-2,4-dione (TZD) hybrids were synthesized using solution phase chemistry. Continuing our previous work, nine O -modified ethyl vanillin (8a-i) derivatives were synthesized and reacted with the TZD core via Knoevenagel condensation under primary reaction conditions to obtain final derivatives 9a-i. Additionally, three isatin-TZD hybrids (11a-c) were synthesized. The intermediates and final derivatives were characterized using 1 H and 13 C NMR spectroscopy, and the observed chemical shifts agreed with the proposed structures. The in vitro alpha-amylase and alpha-glucosidase inhibitory evaluation of newly synthesized derivatives revealed compounds 9F and 9G as the best dual inhibitors, with IC 50 values of 9.8 ± 0.047 μM for alpha-glucosidase (9F) and 5.15 ± 0.0017 μM for alpha-glucosidase (9G), 17.10 ± 0.015 μM for alpha-amylase (9F), and 9.2 ± 0.092 μM for alpha-amylase (9G). The docking analysis of synthesized compounds indicated that compounds have a higher binding affinity for alpha-glucosidase as compared to alpha-amylase, as seen from docking scores ranging from -1.202 to -5.467 (for alpha-amylase) and -4.373 to -7.300 (for alpha-glucosidase). Further, the molecules possess a high LD 50 value, typically ranging from 1000 to 1600 mg kg -1 of body weight, and exhibit non-toxic properties. The in vitro cytotoxicity assay results on PANC-1 and INS-1 cells demonstrated that the compounds were devoid of significant toxicity against the tested cells. Compounds 9F and 9G showed high oral absorption, i.e. , oral absorption >96%, and their molecular dynamics simulation yielded results closely aligned with the observed docking outcomes. Finally, compounds 9F and 9G were evaluated for in vivo antidiabetic assessment by the induction of diabetes in Wistar rats using streptozotocin. Molecule 9G has been identified as the most effective anti-diabetic molecule due to its ability to modulate several biochemical markers in blood plasma and tissue homogenates. The results were further confirmed by histology investigations conducted on isolated pancreas, liver, and kidney., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Purpose: Sarcomas are a complex group of highly aggressive and metastatic tumors with over 100 distinct subtypes. Because of their diversity and rarity, it is challenging to generate multisarcoma signatures that are predictive of patient outcomes., Materials and Methods: Here, we identify a DNA methylation signature for progression and metastasis of numerous sarcoma subtypes using multiple epigenetic and genomic patient data sets. Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly metastatic sarcomas with frequent loss of the histone methyltransferase, PRC2. Loss of PRC2 is associated with MPNST metastasis and plays a critical noncanonical role in DNA methylation., Results: We found that over 900 5'-C-phosphate-G-3' (CpGs) were hypermethylated in MPNSTs with PRC2 loss. Furthermore, we identified eight differentially methylated CpGs in the IL17D / RD family that correlate with the progression and metastasis of MPNSTs in two independent patient data sets. Similar trends were identified in other sarcoma subtypes, including osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. Analysis of scRNAseq data sets determined that IL17D / RD expression occurs in both the tumor cells and the surrounding stromal populations., Conclusion: These results might have broad implications for the clinical management and surveillance of sarcoma.

Introduction: Pleomorphic rhabdomyosarcoma is a rare subtype of rhabdomyosarcoma, a soft tissue sarcoma with skeletal muscle differentiation. Although rhabdomyosarcoma is typically seen in the pediatric population, the pleomorphic variant most frequently presents in adulthood and is characteristically aggressive with no currently established treatment regimen in the setting of metastatic disease. There has been growing interest in the application of immune checkpoint inhibitors alongside conventional chemotherapeutic agents in the treatment of pleomorphic rhabdomyosarcoma., Case Presentation: In the present case series, we report 2 patients with metastatic pleomorphic rhabdomyosarcoma treated with combination doxorubicin and pembrolizumab who had confirmed objective responses. Of note, these 2 patients had variable PD-L1 status - negative and low positive. Duration of treatment response was notable at 14 months and 9 months, respectively, with the first patient remaining on maintenance pembrolizumab therapy and the second patient subsequently achieving complete response with third-line trabectedin. Both patients are currently undergoing routine interval imaging with no evidence of disease at this time., Conclusion: This report highlights and discusses the potential role of PD-1 blockade in the treatment of pleomorphic rhabdomyosarcoma and also discusses burgeoning immunological data that may explain the clinical responses seen in these 2 cases., Competing Interests: The authors have no conflicts of interest to declare. All the co-authors have seen and agree with the contents of the manuscript, and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Diabetes is one of the fastest-growing metabolic disorders, nearly doubling the number of patients each year. There are different treatment approaches available for the management of diabetes, which lacks due to their side effects. The inhibition of enzymes involved in the metabolism of complex polysaccharides to monosaccharides has proven beneficial in patients with type 2 diabetes mellitus. Two enzymes, α-amylase and α-glucosidase, have emerged as potential drug targets and are widely explored for drug development against type 2 diabetes mellitus. In this context, thiazolidine-2,4-diones (TZDs) have emerged as potential drug candidates for developing newer molecules against α-amylase and α-glucosidase. Nineteen TZD-hybrids were synthesized and evaluated in vitro α-amylase and α-glucosidase inhibitory activity. The compounds 7i, 7k, and 7p have emerged as the best dual inhibitors with IC 50 of 10.33 ± 0.11-20.94 ± 0.76 μM and 10.19 ± 0.25-24.07 ± 1.56 μM against α-glucosidase and α-amylase, respectively. The derivatives had good anti-oxidant activity, displaying IC 50  = 14.95 ± 0.65-23.27 ± 0.99 μM. The compounds 7k and 7p showed the best inhibition of reactive oxygen species in the PNAC-1 cells. The molecules exhibit good binding within the active site of α-amylase (PDB id: 1B2Y) and α-glucosidase (PDB id: 3W37), displaying binding energies of -7.5 to -10.7 kcal/mol and -7.4 to -10.3 kcal/mol, respectively. Further, the compounds were nontoxic (LD 50  = 500-1311 mg/kg) and possessed good GI absorption. The compounds 7i, 7k, and 7p were evaluated in vivo antidiabetic activity in an STZ-induced diabetic model in Wistar rats. The compound 7p emerged as the best compound in the in vivo studies; however, the activity was lesser than that of the standard drug pioglitazone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione ( 16a-e, 17a-d, 18a-c ) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC 50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC 50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a , which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a , wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents.Communicated by Ramaswamy H. Sarma.

Objectives: Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC., Materials and Methods: This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy., Results: Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease., Conclusion: In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Renata Ferrarotto: Advisory board/consulting: Ayala Pharmaceuticals, Bicara Therapeutics, Elevar Therapeutics, ExpertConnect, G1 Therapeutics, Guidepoint, Merck, Prelude Therapeutics, Regeneron, Sanofi, Remix. Royalties: Ayala Pharmaceuticals, EMD Serono, Genentech, ISA Therapeutics, Merck, Nanobiotix, Pfizer, Prelude Therapeutics, Rakuten. Paul L. Swiecicki: Grant or institutional research support: ACCRF, Ascentage Pharma; Consulting/honoraria: Elevar, Prelude Therapeutics, Remix. Dan P. Zandberg: Advisory board/consulting: Blueprint Medicines, Macrogenics, Prelude Therapeutics, Merck. Grant or institutional research support: Aduro, Astellas, AstraZeneca, Bicara, Bristol Myers Squibb, Checkmate Pharma, GlaxoSmithKline, Macrogenics, Merck, Lilly, Novasenta. Robert A. Baiocchi: Advisory board/consulting: Atara Biotherapeutics, Agenus, Viracta Therapeutics. Grant or institutional research support: Prelude Therapeutics, CODIAK Biosciences. Robert Wesolowski: Advisory board: Celcuity, Seagen. Cristina P. Rodriguez: Grant or institutional research support: AstraZeneca, Bristol Myers Squibb, Cue Biopharma, Kura, Prelude Therapeutics, Merck. Advisory board: Cue Biopharma, Coherus Biosciences. Data and safety monitoring committee: Pionyr. Meredith McKean: Grant or institutional research support: Aadi Biosciences, Accutar Biotechnology, Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, Astellas, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, G1 Therapeutics, Genentech, Gilead Sciences, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Moderna, NBE Therapeutics, Nektar, Novartis, OncoC4, Oncorus, PACT Pharma, Pfizer, Plexxikon, Poseida, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seattle Genetics, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences, Xilio. Consulting: Astellas Pharma, AstraZeneca, BicycleTX Limited, Castle Biosciences, Eisai, Ideaya Biosciences, iTeos, Moderna, Pfizer. Hyunseok Kang: Grant or institutional research support: ACCRF, Ayala Pharmaceuticals, Elevar Therapeutics, Eli Lilly, Exelixis, NeoimmuneTech, PDS Biotechnology, Prelude Therapeutics, NRG Oncology. Consulting/Honoria: Bayer, Bertis, Coherus Biosciences, MitoImmune, LG Chem, Pin Therapeutics, Remix. Varun Monga: Grant or institutional research support: Amgen, Astex Pharmaceuticals, C4 Therapeutics, Deciphera, GSK, Hutchison Pharma, Prelude Therapeutics, Rising Tide Foundation, Theradex, Trillium Therapeutics. Honoraria for lectures as part of an educational event: Gundersen Foundation, Iowa Oncology Society. Data safety monitoring board: Astex Pharmaceuticals, Forma Therapeutics. Meeting attendance: GSK, Deciphera. Rajneesh Nath: No relevant conflicts of interest to declare. Neil Palmisiano: No relevant conflicts of interest to declare. Naveen Babbar: Employee of and owns equity in Prelude Therapeutics. William Sun: Prior employee of and owns equity in Prelude Therapeutics. Glenn J. Hanna: Grant or institutional research support: ACCRF, Actuate, Elevar, Gateway for Cancer Research, Genentech, V Foundation. Consulting/honoraria: Prelude Therapeutics, Remix., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Adolescents and young adults (AYAs, 15-39 years) with cancer experience disparities in care and outcomes compared with older/younger patients. AYAs receive care from medical and pediatric oncologists, however, little is known about the extent of training fellows receive. This needs assessment evaluating current AYA oncology (AYA-O) education in pediatric and medical oncology fellowship programs to identify knowledge gaps for curricular development. Methods: An anonymous, cross-sectional, web-based survey developed by pediatric and medical oncologists was sent to medical ( n  = 178) and pediatric ( n  = 119) hematology/oncology program directors (PDs) at 251 sites in the United States. PDs were asked to participate and distribute the survey to their fellows. Survey questions addressed current AYA curriculum, provider comfort, and priorities for future AYA educational content. Results: Participants from 69/251 programs responded (program response rate = 27%), including 51 PDs (32 pediatric, 19 medical oncology) and 58 fellows (33 pediatric, 25 medical oncology). Eighty-five percent of PDs (44/51) reported lacking formal AYA curricula. Of these, 80% (35/44) offer some topic-specific lectures, while 20% (9/44) provide little/no education for any topics. For nearly all topics, at least 45% of combined respondents reported little/no education. Respondents believe AYA topics are important for inclusion in future curricula. The most important topics for inclusion reported were oncofertility (82%), survivorship (78%), and communication (77%). Conclusions: There are large and actionable gaps in AYA-O education during fellowship training. Efforts are underway to develop AYA-O curriculum to provide both medical and pediatric oncology fellows with the knowledge and skills required to provide optimal AYA care.

Diabetes is a serious health threat across the globe, claiming millions of lives worldwide. Among the various strategies employed, inhibition of α-amylase is a therapeutic protocol for the management of Type 2 diabetes mellitus. α-Amylase is a crucial enzyme involved in the breakdown of dietary starch into simpler units. However, the clinically used α-amylase inhibitors have various drawbacks. Therefore, design and development of novel α-amylase inhibitors have gained significant attention. The pyrazole motif has been identified as a versatile scaffold in medicinal chemistry, and recent studies have led to the identification of various pyrazole-based α-amylase inhibitors. This review compiles therapeutic implications of pyrazole-appended α-amylase inhibitors; their synthesis, biological activities, structure-activity relationships and molecular docking studies are discussed.

Purpose: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans., Patients and Methods: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker., Results: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems., Conclusions: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255., (©2023 American Association for Cancer Research.)

Background: Extremity soft-tissue sarcomas (STS) are commonly treated with neoadjuvant radiation therapy followed by surgical resection. However, the pathological near-complete response rate is low (9-25%). Noninvasive imaging assessment that predicts treatment response before and during treatment is desirable to optimize treatment regimens. This pilot study aimed to investigate the application of a quantitative MRI parameter, T 2 *, in assessing neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS., Methods: This prospective cohort study included seven patients diagnosed with extremity STS and scheduled to receive neoadjuvant radiation therapy combined with pharmacological ascorbate. T 2 * maps were obtained from each patient before treatment (baseline MRI), two weeks after initiating treatment (on-treatment MRI), and before surgery (pre-surgery MRI). The T 2 * values within the tumor region were transformed into z-scores with respect to the normal- appearing tissue region. The voxel-wise z-scores within the tumor region were thresholded to generate masks representing significantly high (z-score>1.96) and low z-score (z-score<-1.96) voxels. The means of the total z-scores and within each of the significantly high and low z-score mask were computed. Their correlations with percent necrosis from pathological examination were evaluated using Spearman's rank correlation coefficient r. A correlation was considered as moderate or strong when r is higher than 0.6 and 0.8, respectively. A correlation was considered as fair or weak when r is below 0.6., Results: For the baseline and on-treatment MRIs, the means of the significantly high z-scores of the T 2 * measurements showed moderate correlations with percent necrosis (r = 0.68 and 0.6; p = 0.11 and 0.24). For the pre-surgery MRI, the means of the total and significantly high z-scores showed strong correlations with percent necrosis (r = 0.8 and 0.9; p = 0.13 and 0.08). Tumor volume and baseline MRI-based percent necrosis showed fair or weak correlations (r = 0.3-0.54; p = 0.24-0.68)., Conclusion: T 2 * measurements prior to treatment, two weeks after initiating treatment, and before surgery showed moderate to strong correlations with percent necrosis. These results support the potential for using T 2 * mapping to predict and assess response to neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Level of Evidence: IV ., Competing Interests: Disclosures: The authors report no potential conflicts of interest related to this study., (Copyright © The Iowa Orthopaedic Journal 2023.)

Nucleic acid represents the ideal drug candidate for protein targets that are hard to target or against which drug development is not easy. Peptide nucleic acids (PNAs) are synthesized by attaching modified peptide backbones generally derived from repetitive N-2-aminoethyl glycine units in place of the regular phosphodiester backbone and represent synthetic impersonator of nucleic acids that offers an exciting research field due to their fascinating spectrum of biotechnological, diagnostic and potential therapeutic applications. The semi-rigid peptide nucleic acid backbone serves as a nearly-perfect template for attaching complimentary base pairs on DNA or RNA in a sequence-dependent manner as described by Watson-Crick models. PNAs and their analogues are endowed with exceptionally high affinity and specificity for receptor sites, essentially due to their polyamide backbone's uncharged and flexible nature. The present review compiled various strategies to modify the polypeptide backbone for improving the target selectivity and stability of the PNAs in the body. The investigated biological activities carried out on PNAs have also been summarized in the present review., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Malaria is among one of the most devastating and deadliest parasitic disease in the world claiming millions of lives every year around the globe. It is a mosquito-borne infectious disease caused by various species of the parasitic protozoan of the genus Plasmodium. The indiscriminate exploitation of the clinically used antimalarial drugs led to the development of various drug-resistant and multidrug-resistant strains of plasmodium which severely reduces the therapeutic effectiveness of most frontline medicines. Therefore, there is urgent need to develop novel structural classes of antimalarial agents acting with unique mechanism of action(s). In this context, design and development of hybrid molecules containing pharmacophoric features of different lead molecules in a single entity represents a unique strategy for the development of next-generation antimalarial drugs. Research efforts by the scientific community over the past few years has led to the identification and development of several heterocyclic small molecules as antimalarial agents with high potency, less toxicity and desired efficacy. Triazole derivatives have become indispensable units in the medicinal chemistry due to their diverse spectrum of biological profiles and many triazole based hybrids and conjugates have demonstrated potential in vitro and in vivo antimalarial activities. The manuscript compiled recent developments in the medicinal chemistry of triazole based small heterocyclic molecules as antimalarial agents and discusses various reported biologically active compounds to lay the groundwork for the rationale design and discovery of triazole based antimalarial compounds. The article emphasised on biological activities, structure activity relationships, and molecular docking studies of various triazole based hybrids with heterocycles such as quinoline, artemisinins, naphthyl, naphthoquinone, etc. as potential antimalarial agents which could act on the dual stage and multi stage of the parasitic life cycle., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Boron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1α, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc., have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy, safety, and tolerability of topiramate for the treatment of posttraumatic stress disorder (PTSD) in civilians., Methods: This 12-week double-blind, randomized, placebo-controlled study enrolled 72 outpatients (aged 19-64 years) with a DSM-IV-TR diagnosis of non-combat-related PTSD and a score ≥ 50 on the Clinician-Administered PTSD Scale (CAPS). The primary efficacy endpoint, percent change in total CAPS score, and secondary efficacy measures were assessed by analysis of covariance. Safety assessments included monitoring of vital signs, physical examinations, clinical laboratory parameters, electrocardiograms, and adverse events (AEs). The study was conducted from October 2001 to March 2004., Results: The intent-to-treat (ITT) population (N = 68; mean age = 35 years; 87% women; 74% White) showed greater percent reduction in total CAPS scores with topiramate versus placebo (39.5% vs 29.5%), but the difference was not statistically significant ( P  = .31). Similarly, higher reductions with topiramate versus placebo were seen in the CAPS subscale scores for symptoms of reexperiencing (43.6% vs 34.8%), avoidance/numbing (38.3% vs 30.6%), and hyperarousal (36.6% vs 21.4%). However, these differences were not statistically significant. Six patients in the topiramate arm had a final CAPS score < 20, whereas only 2 in the placebo arm achieved the result ( P  = .075). The median final topiramate daily dose was 100 mg/d (range, 25-400 mg/d), and mean ± SD treatment duration was 55 ± 32 days, showing the tolerability of the medication. In topiramate-treated patients, treatment-emergent AEs included paresthesia, headache, fatigue, and insomnia; treatment-limiting AEs included influenza-like symptoms, agitation, cognitive problems not otherwise specified, and somnolence. However, a higher rate of AE-related discontinuation was seen in the placebo group than in the treatment group (26% vs 18%)., Conclusions: In this 12-week civilian PTSD study, topiramate improved the primary and secondary outcome measures at a higher rate than did placebo, but the difference did not reach statistical significance. Further adequately powered studies may be warranted., Trial Registration: Clinical Trials.gov identifier: NCT00208130., Prim Care Companion CNS Disord 2023;25(5):23m03555 ., Author affiliations are listed at the end of this article., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Competing Interests: None of the co-authors have responded with any conflict of interest pertaining to the research, writing, or publication of the aforementioned article. We remain fully committed to upholding the highest standards of ethical conduct and integrity in our research and academic pursuits. It is our aim to contribute to the advancement of medical knowledge with complete transparency and dedication to unbiased inquiry.

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models., Experimental Design: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response., Results: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression., Conclusions: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes., (©2023 American Association for Cancer Research.)

Objective: Compared to the general population, the risk of suicide is three times higher in patients with epilepsy and remains doubled for these patients even after adjusting for sociodemographic correlates of suicide in the absence of mental health comorbidities. Following the United States (US) Food and Drug Administration (FDA) alert prompting a black box warning regarding the association between suicidality and antiepileptic drugs (AEDs), several studies were conducted, the results of which have been ambiguous, with some demonstrating a positive association between suicidality and AEDs, while others did not. This systematic review of literature sought to study the relationship between suicidality and AEDs when used exclusively for treatment of epilepsy., Methods: A comprehensive literature search was conducted on PubMed without time limits using a predefined search language. The search results were then subjected to a systematic screening process. Eight out of a total of 443 articles satisfying predefined inclusion and exclusion criteria were included in the review for final data extraction., Results: Three studies found a significant association between suicide-related behavior and levetiracetam use in the treatment of epilepsy. One study reported a positive association of pregabalin use in patients with epilepsy under 40 years of age and high AED load with suicidality, independent of depression. The remaining four studies reported a significant association between positive family and personal history of psychiatric comorbidities and suicidality in epilepsy., Conclusion: Although there were several methodological limitations, this review found an association between levetiracetam use and mental health comorbidities and the occurrence of suicidality in epilepsy. Larger prospective, randomized studies that overcome the limitations of current studies are required to provide definitive evidence on the occurrence of suicidality in patients with epilepsy and AED use., Competing Interests: DISCLOSURES: The authors have no conflicts of interest relevant to the contents of this article., (Copyright © 2023. Matrix Medical Communications. All rights reserved.)

Tourette's syndrome (TS) patients experiencing severe tics and behavioral disturbances can have a rare complication called rhabdomyolysis (RML), which is characterized by the breakdown of muscle tissue. The occurrence of RML poses a significant physical and emotional risk to patients with TS by impacting the quality of life and in some cases causing severe damage. In this case report, we present the first documented case of RML resulting from severe tics in an adult with a diagnosis of TS. The patient exhibited severe tics and self-injurious behaviors that led to elevated creatine kinase and a subsequent diagnosis of RML requiring hospitalization with a complex hospital course. The patient did not have neuroleptic malignant syndrome as his laboratory parameters improved with the decrease in severity of tics. Our case highlights the potential complication of RML because of severe tics independent of neuroleptic drug use in a patient with TS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Monga et al.)

Introduction: The quinolone scaffold is a bicyclic benzene-pyridinic ring scaffold with nitrogen at the first position and a carbonyl group at the second or fourth position. It is endowed with a diverse spectrum of pharmacological activities, including antitumor activity, and has progressed into various development phases of clinical trials for their target-specific anticancer activity., Areas Covered: The present review covers both classes of quinolones, i.e. quinolin-2( H )-one and quinolin-4( H )-one as anticancer agents, along with their possible mode of binding. Furthermore, their structure-activity relationships, molecular mechanisms, and pharmacokinetic properties are also covered to provide insight into their structural requirements for their rational design as anticancer agents., Expert Opinion: Synthetic feasibility and ease of derivatization at multiple positions, has allowed medicinal chemists to explore quinolones and their chemical diversity to discover newer anticancer agents. The presence of both hydrogen bond donor (-NH) and acceptor (-C=O) functionality in the basic scaffold at two different positions, has broadened the research scope. In particular, substitution at the -NH functionality of the quinolone motif has provided ample space for suitable functionalization and appropriate substitution at the quinolone's third, sixth, and seventh carbons, resulting in selective anticancer agents binding specifically with various drug targets.

Observing cataplexy episodes during an office visit is extremely rare as they are usually triggered by laughter or emotional stress. Narcolepsy usually occurs in the younger population. We report a case of a 65-year-old Caucasian female with a past medical history of obesity who developed excessive daytime sleepiness, fatigue, and sleep attacks five weeks after getting influenza and pneumococcal vaccines. The presentation of cataplexy was atypical. Several episodes of cataplexy were observed during the office visit without any emotional trigger. Further workup, including polysomnography (PSG), was positive for obstructive sleep apnea, controlled with continuous positive airway pressure (CPAP) use. Later, she had PSG with CPAP use, which optimally controlled obstructive sleep apnea, followed by multiple sleep latency tests (MSLT) with CPAP use. It was positive for narcolepsy with a mean sleep latency of 1.6 minutes with sleep onset rapid eye movement (REM) in five out of five naps. Her cerebrospinal fluid (CSF) hypocretin level was extremely low at 50 pg/ml, usually seen in narcolepsy with cataplexy. She was also positive for human leukocyte antigen (HLA) DBQ1*06:02. The diagnosis of narcolepsy with cataplexy was made, which improved with medications for narcolepsy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Verma et al.)

Objective . Hydrocephalus is the leading indication for pediatric neurosurgical care worldwide. Identification of postinfectious hydrocephalus (PIH) verses non-postinfectious hydrocephalus, as well as the pathogen involved in PIH is crucial for developing an appropriate treatment plan. Accurate identification requires clinical diagnosis by neuroscientists and microbiological analysis, which are time-consuming and expensive. In this study, we develop a domain enriched AI method for computerized tomography (CT)-based infection diagnosis in hydrocephalic imagery. State-of-the-art (SOTA) convolutional neural network (CNN) approaches form an attractive neural engineering solution for addressing this problem as pathogen-specific features need discovery. Yet black-box deep networks often need unrealistic abundant training data and are not easily interpreted. Approach . In this paper, a novel brain attention regularizer is proposed, which encourages the CNN to put more focus inside brain regions in its feature extraction and decision making. Our approach is then extended to a hybrid 2D/3D network that mines inter-slice information. A new strategy of regularization is also designed for enabling collaboration between 2D and 3D branches. Main results . Our proposed method achieves SOTA results on a CURE Children's Hospital of Uganda dataset with an accuracy of 95.8% in hydrocephalus classification and 84% in pathogen classification. Statistical analysis is performed to demonstrate that our proposed methods obtain significant improvements over the existing SOTA alternatives. Significance . Such attention regularized learning has particularly pronounced benefits in regimes where training data may be limited, thereby enhancing generalizability. To the best of our knowledge, our findings are unique among early efforts in interpretable AI-based models for classification of hydrocephalus and underlying pathogen using CT scans., (Creative Commons Attribution license.)

As artificial intelligence (AI) continues to evolve and mature, it is increasingly finding applications in the field of healthcare, particularly in specialties like radiology that are data-heavy and image-focused. Language learning models (LLMs) such as OpenAI's Generative Pre-trained Transformer-4 (GPT-4) are new in the field of medicine and there is a paucity of literature regarding the possible utilities of GPT-4 given its novelty. We aim to present an in-depth exploration of the role of GPT-4, an advanced language model, in radiology. Giving the GPT-4 model prompts for generating reports, template generation, enhancing clinical decision-making, and suggesting captivating titles for research articles, patient communication, and education, can occasionally be quite generic, and at times, it may present factually incorrect content, which could lead to errors. The responses were then analyzed in detail regarding their potential utility in day-to-day radiologist workflow, patient education, and research processes. Further research is required to evaluate LLMs' accuracy and safety in clinical practice and to develop comprehensive guidelines for their implementation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Grewal et al.)

Serotonin syndrome, also known as serotonin toxicity, is associated with increased serotonergic activity in the central and the peripheral nervous system. The symptoms can range from mild to potentially life threatening. Given the widespread use of serotonergic agents, the number of cases is on the rise. It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning, but still known cases with monotherapy of selective serotonin reuptake inhibitors are uncommon. Another known fact is that elevated whole blood serotonin, or hyperserotonemia, is one of the first biomarkers identified in autism spectrum disorder and is present in more than 25% of affected children. We present a case of a 32-year-old male with a history of autism spectrum disorder and depressive disorder who presented to the emergency department with restless agitation, neuromuscular excitability, and autonomic instability. He had been prescribed sertraline 50 mg which he had taken daily as prescribed for 4 days. On the fourth day, he presented to the emergency department with diffuse muscle stiffness, upper extremity tremors, ocular clonus, and inducible ankle clonus. He was diagnosed with probable serotonin syndrome utilizing Hunter's criteria. Patient's symptoms resolved within 24 hours with intravenous fluids, lorazepam, and discontinuation of sertraline. This case highlights the importance of a high degree of clinical suspicion in patients even on monotherapy of selective serotonin reuptake inhibitors in therapeutic doses, especially in children and adults with autism spectrum disorder. Due to preexisting hyperserotonemia, they may be more susceptible to serotonin syndrome than the general population., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Rohit Madan et al.)

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery., Competing Interests: Declaration of competing interest Drs. Spitz and Allen acknowledge support for their laboratory efforts from a sponsored research agreement from Galera Therapeutics, Inc. Dr. Beardsley is an employee of and owns stock in, Galera Therapeutics, Inc. Dr. Holmlund owns stock in Galera Therapeutics, Inc. No potential conflicts of interest were disclosed by the other authors., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Rhodanine or 2-Thioxothiazolidin-4-one is a privileged heterocyclic compound offering a wide opportunity for structural modification, lead development, and modification. It is one of the highly decorated scaffolds in the drug discovery process. Rhodanine derivatives possess a plethora of biological activities due to their ability to interact with a diverse range of protein targets, which provide tremendous opportunities to discover new drugs with different modes of action. The most common strategy for developing novel rhodanine derivatives is the introduction of structurally diverse substituents at the C-5 or N-3, or both positions. Since the inception of Epralestat into the market in 1992, the exploration of rhodanine-3-acetic acids has led to the development of novel leads against different biological targets such as MRSA, HHV-6, Mycobacterial tuberculosis, dengue, etc. In the current pandemic era, some rhodanine compounds have been explored against SARS-CoV-2. In recent years, rhodanine and its derivatives have witnessed significant progress in developing new drug leads as potential antimicrobial and antiviral agents. Different synthetic methodologies and recent developments in the medicinal chemistry of rhodanine derivatives, including biological activities, their mechanistic aspects, structure-activity relationships, and in silico findings, have been compiled in the present review. This article will benefit the scientific community and offer perspectives on how these scaffolds as privileged structures might be exploited in the future for rational design and discovery of rhodanine-based bio-active molecules., (© 2022 John Wiley & Sons Ltd.)

Purpose: Adolescent and young adult (AYA) cancer patients frequently demonstrate sexual dysfunction; however, there is a lack of data quantifying the severity and frequency. Methods: Males aged 18-39 years, diagnosed with cancer of any kind and who were scheduled to begin, were actively receiving, or had completed cancer treatment within 6 months, were offered validated surveys during their oncology appointment. These surveys included the International Index of Erectile Function (IIEF-6), Masturbation Erection Index (MEI), 36-Item Short Form Survey, and 5-point Likert scales to assess their desire and ability to engage in sex and masturbation. Results: Forty subjects completed the IIEF survey with a mean score of 17.7 ± 11, erectile dysfunction (ED) prevalence accordingly was 58%. Thirty-eight subjects completed the MEI with a mean score of 25.3 ± 5.3, ED prevalence was again 58%. Age and IIEF scores demonstrated a statistically significant ( p  < 0.05, n  = 38) Pearson's correlation coefficient of 0.40, patients younger than 30 years had an ED prevalence of 72% (mean IIEF 13), whereas patients aged 30 years and older had an ED prevalence of 45% (mean IIEF 22). All treatment modalities had ED rates >30%: chemotherapy demonstrated the highest prevalence at 64% (mean IIEF 17), whereas radiation therapy had the lowest prevalence at 33% (mean IIEF 23). Conclusion: This study demonstrates that the prevalence of sexual dysfunction among male AYA patients undergoing treatment for cancer is high. AYA oncologists should discuss potential sexual health concerns when treating this population. The exact cause of ED (non-organic vs. organic) within this group should be explored further.

Purpose: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas., Patients and Methods: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy., Results: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events., Conclusion: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2 -mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Background: Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation., Methods: This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II., Results: Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each)., Conclusions: Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

The Cannabinoid (CB) signalling cascade is widely located in the human body and is associated with several pathophysiological processes. The endocannabinoid system comprises cannabinoid receptors CB1 and CB2, which belong to G-protein Coupled Receptors (GPCRs). CB1 receptors are primarily located on nerve terminals, prohibiting neurotransmitter release, whereas CB2 are present predominantly on immune cells, causing cytokine release. The activation of CB system contributes to the development of several diseases which might have lethal consequences, such as CNS disorders, cancer, obesity, and psychotic disorders on human health. Clinical evidence revealed that CB1 receptors are associated with CNS ailments such as Alzheimer's disease, Huntington's disease, and multiple sclerosis, whereas CB2 receptors are primarily connected with immune disorders, pain, inflammation, etc. Therefore, cannabinoid receptors have been proved to be promising targets in therapeutics and drug discovery. Experimental and clinical outcomes have disclosed the success story of CB antagonists, and several research groups have framed newer compounds with the binding potential to these receptors. In the presented review, we have summarized variously reported heterocycles with CB receptor agonistic/antagonistic properties against CNS disorders, cancer, obesity, and other complications. The structural activity relationship aspects have been keenly described along with enzymatic assay data. The specific outcomes of molecular docking studies have also been highlighted to get insights into the binding patterns of the molecules to CB receptors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Excess of androgens leads to various diseases such as Poly-Cystic Ovarian Syndrome, Prostate Cancer, Hirsutism, Obesity and Acne. 17β-Hydroxysteroid Dehydrogenase type 5 (17β-HSD5) converts androstenedione into testosterone peripherally, thereby significantly contributing to the development of these diseases. Indole-bearing scaffolds are reported as potential 17β-HSD5 inhibitors for the manifestation of diseases arising due to androgen excess. In the present work, we have extensively performed a combination of molecular docking, Gaussian field-based 3D-QSAR, Pharmacophore mapping and MD-simulation studies (100 ns) to identify the pharmacophoric features of indole-based compounds as potent 17β-HSD5 inhibitors. Molecular simulation studies of the most potent compound in the binding pocket of enzyme revealed that the compound 11 was stable in the binding pocket and showed good binding affinity through interactions with various residues of active site pocket. The Molecular mechanics Generalized Born surface area continuum solvation (MM/GBSA) and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations revealed that the compound 11 possessed a free binding energy of -36.36 kcal/mol and -7.00 kcal/mol, respectively, which was better as compared to reference compound Desmethyl indomethacin (DES). The developed pharmacophore will be helpful to design novel indole-based molecules as potent 17β-HSD5 inhibitors for the treatment of various androgenic disorders.Communicated by Ramaswamy H. Sarma.

Naringenin is flavorless, water insoluble active principle belonging to flavanone subclass. It exhibits a diverse pharmacological profile as well as divine nutraceutical values. Although several researchers have explored this phytoconstituent to evaluate its promising properties, still it has not gained recognition at therapeutic levels and more clinical investigations are still required. Also the neutraceutical potential has limited marketed formulations. This compilation includes the description of reported therapeutic potentials of naringenin in variety of pathological conditions alongwith the underlying mechanisms. Details of various analytical investigations carried on this molecule have been provided along with brief description of chemistry and structural activity relationship. In the end, various patents filed and clinical trial data has been provided. Naringenin has revealed promising pharmacological activities including cardiovascular diseases, neuroprotection, anti-diabetic, anticancer, antimicrobial, antiviral, antioxidant, anti-inflammatory and anti-platelet activity. It has been marketed in the form of nanoformulations, co-crystals, solid dispersions, tablets, capsules and inclusion complexes. It is also available in various herbal formulations as nutraceutical supplement. There are some pharmacokinetic issue with naringenin like poor absorption and low dissolution rate. Although these issues have been sorted out upto certain extent still further research to investigate the bioavailability of naringenin from herbal supplements and its clinical efficacy is essential.

The DNA methyltransferase inhibitor decitabine has classically been used to reactivate silenced genes and as a pretreatment for anticancer therapies. In a variation of this idea, this study explores the concept of adding low-dose decitabine (DAC) following administration of chemotherapy to bolster therapeutic efficacy. We find that addition of DAC following treatment with the chemotherapy agent gemcitabine improves survival and slows tumor growth in a mouse model of high-grade sarcoma. Unlike prior studies in epithelial tumor models, DAC did not induce a robust antitumor T cell response in sarcoma. Furthermore, DAC synergizes with gemcitabine independently of the immune system. Mechanistic analyses demonstrate that the combination therapy induces biphasic cell cycle arrest and apoptosis. Therapeutic efficacy was sequence dependent, with gemcitabine priming cells for treatment with DAC through inhibition of ribonucleotide reductase. This study identifies an apparently unique application of DAC to augment the cytotoxic effects of conventional chemotherapy in an immune-independent manner. The concepts explored in this study represent a promising paradigm for cancer treatment by augmenting chemotherapy through addition of DAC to increase tolerability and improve patient response. These findings have widespread implications for the treatment of sarcomas and other aggressive malignancies.

Background: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy., Methods: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations., Results: No significant differences in survival were identified between TSC-1 and TSC-2 mutated PEComa or TSC-1 / -2 versus other mutations. No significant difference was seen in progression-free survival (PFS) after first-line therapy between mTOR inhibition versus other systemic therapies., Conclusions: We were unable to detect differences in survival based on genomic alterations or PFS between mTOR inhibition versus other systemic therapies. Future studies should seek to identify other drivers of TSC-1/-2 silencing that could predict response to mTOR inhibition.

Background: Sarcomas are a diverse group of neoplasms that vary greatly in clinical presentation and responsiveness to treatment. Given the differences in the sites of involvement, rarity, and treatment modality, a multidisciplinary approach is required. Previous literature suggests patients with sarcoma suffer from poorer quality of life (QoL) especially physical and functional wellbeing. Adolescent and young adult (AYA) patients are an underrepresented population in cancer research and have differing factors influencing QoL., Methods: Retrospective analysis of Young Adult patients (age 18-39) enrolled in the Sarcoma Tissue Repository at University of Iowa. QoL was assessed using the self-report FACT-G questionnaire at enrollment and 12 months post-diagnosis; overall scores and the 4 wellbeing subscales (Physical, Emotional, Social, Functional) were calculated. Linear mixed effects models were used to measure the association between the rate of change in FACT-G subscale scores and baseline clinical, comorbidity, and treatment characteristics., Results: 49 patients were identified. 57.1% of patients had a malignancy involving an extremity. Mean FACT-G scores of overall wellbeing improved from baseline to 12 months (76.4 vs. 85.4, p < 0.01). Social and emotional wellbeing did not differ significantly between baseline and 12 months. Physical wellbeing (18.8 vs. 23.9, p < 0.01) and functional wellbeing (16.8 vs. 20.0, p < 0.01) scores improved from baseline to 12 months. No difference was seen for FACT-G overall scores for age, sex, laterality, marital status, performance status, having children, clinical stage, limb surgery, chemotherapy, or tumor size. A difference was demonstrated in physical wellbeing scores for patients with baseline limitation (ECOG 1-3) compared to those with no baseline limitation (ECOG 0) ( p = 0.03). A difference was demonstrated in social wellbeing based on anatomical site ( p = 0.02)., Conclusion: Young adults with sarcoma treated at a tertiary center had improvements in overall reported QoL at 12 months from diagnosis. Overall baseline QoL scores on FACT-G were lower than the general adult population for YA patients with sarcoma but at 12 months became in line with general population norms. The improvements seen merit further investigation to evaluate how these change over the continuum of care. Quality of life changes may be useful outcomes of interest in sarcoma trials., Competing Interests: VM received research funding from Gateway Foundation, Rising Tide Cancer Research Foundation, Amgen. Advisory Board—Forma Therapeutics and Astex Pharmaceuticals. MM reports consultancy/advisory board for Blueprints Medicine, Immunocore, Amgen, Trieza, Array Biopharma, Biontech, and Novartis. The remaining 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., (Copyright © 2022 Day, Miller, Loeffler, Mott, Tanas, Curry, Davick, Milhem and Monga.)

2,4-Thiazolidinedione (2,4-TZD), commonly known as glitazone, is a ubiquitous heterocyclic pharmacophore possessing a plethora of pharmacological activities and offering a vast opportunity for structural modification. The diverse range of biological activities endowed with a novel mode of action, low cost, and easy synthesis has attracted the attention of medicinal chemists. Several researchers have integrated the TZD core with different structural fragments to develop a wide range of lead molecules against various clinical disorders. The most common sites for structural modifications at the 2,4-TZD nucleus are the N-3 and the active methylene at C-5. The review covers the recent development of TZD derivatives such as antimicrobial, anticancer, and antidiabetic agents. Various 2,4-TZD based agents or drugs, which are either under clinical development or in the market, are discussed in the study. Different synthetic methodologies for synthesizing the 2,4-TZD core are also included in the manuscript. The importance of various substitutions at N-3 and C-5 and the mechanisms of action and structure-activity relationships are also discussed. We hope this study will serve as a valuable tool for the scientific community engaged in the structural exploitation of the 2,4-TZD core for developing novel drug m\olecules for life-threatening ailments., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Pharmacological ascorbate (i.e., intravenous infusions of vitamin C reaching ~ 20 mM in plasma) is under active investigation as an adjuvant to standard of care anti-cancer treatments due to its dual redox roles as an antioxidant in normal tissues and as a prooxidant in malignant tissues. Immune checkpoint inhibitors (ICIs) are highly promising therapies for many cancer patients but face several challenges including low response rates, primary or acquired resistance, and toxicity. Ascorbate modulates both innate and adaptive immune functions and plays a key role in maintaining the balance between pro and anti-inflammatory states. Furthermore, the success of pharmacological ascorbate as a radiosensitizer and a chemosensitizer in pre-clinical studies and early phase clinical trials suggests that it may also enhance the efficacy and expand the benefits of ICIs., Competing Interests: 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., (Copyright © 2022 Zaher, Stephens, Miller, Hartwig, Stolwijk, Petronek, Zacharias, Wadas, Monga, Cullen, Furqan, Houtman, Varga, Spitz and Allen.)

Purpose: Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. Pre-clinical studies have reported that pharmacological ascorbate (P-AscH-) enhances NSCLC response to platinum-based therapy. We conducted a phase II clinical trial combining P-AscH- with carboplatin-paclitaxel chemotherapy., Experimental Design: Chemotherapy naïve advanced stage NSCLC patients received 75 g ascorbate twice per week intravenously with carboplatin and paclitaxel every three weeks for four cycles. The primary endpoint was to improve tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 compared to the historical control of 20%. The trial was conducted as an optimal Simon's two-stage design. Blood samples were collected for exploratory analyses., Results: The study enrolled 38 patients and met its primary endpoint with an objective response rate of 34.2% (p = 0.03). All were confirmed partial responses (cPR). The disease control rate was 84.2% (stable disease + cPR). Median progression-free and overall survival were 5.7 months and 12.8 months, respectively. Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 events (cytopenias). Cytokine and chemokine data suggest that the combination elicits an immune response. Immunophenotyping of peripheral blood mononuclear cells demonstrated an increase in effector CD8 T-cells in patients with a progression-free survival (PFS) ≥ 6 months., Conclusions: The addition of P-AscH- to platinum-based chemotherapy improved tumor response in advanced stage NSCLC. P-AscH- appears to alter the host immune response and needs further investigation as a potential adjuvant to immunotherapy., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Glioma, characterized by neoplastic growth in the brain, is a life-threatening condition that, in most cases, ultimately leads to death. Typical analysis of glioma development involves observation of brain tissue in the form of a histology slide under a microscope. Although brain histology images have much potential for predicting patient outcomes such as overall survival (OS), they are rarely used as the sole predictors due challenges presented by unique characteristics of brain tissue histology. However, utilizing histology in predicting overall survival can be useful for treatment and quality-of-life for patients with early-stage glioma. In this study, we investigate the use of deep learning models on histology slides combined with simple descriptor data (age and glioma subtype) as a predictor of (OS) in patients with low-grade glioma (LGG). Using novel clinical data, we show that models which are more attentive to discriminative features of the image will confer better predictions than generic models (82.7 and 65.3 AUC RFD-Net and Baseline VGG16 model, respectively). Additionally, we show that adding age and subtype information to a histology image-based model may provide greater robustness in the model than using the image alone (3.8 and 4.3 stds for RFD-Net and Baseline VGG16 model with 3-fold CV, respectively), while a model based on image and age but not subtype may confer the best predictive results (83.7 and 82.0 AUC for RFD-Net + age and RFD-Net + age + subtype, respectively). Clinical relevance- This study establishes important criteria for deep learning models which predict OS using histology and basic clinical data from LGG patients.

Background: Cancer cells often have altered iron metabolism relative to non-malignant cells with increased transferrin receptor and ferritin expression. Targeting iron regulatory proteins as part of a cancer therapy regimen is currently being investigated in various malignancies. Anti-cancer therapies that exploit the differences in iron metabolism between malignant and non-malignant cells (e.g. pharmacological ascorbate and iron chelation therapy) have shown promise in various cancers, including glioblastoma, lung, and pancreas cancers. Non-invasive techniques that probe tissue iron metabolism may provide valuable information for the personalization of iron-based cancer therapies. T 2 * mapping is a clinically available MRI technique that assesses tissue iron content in the heart and liver. We aimed to investigate the capacity of T 2 * mapping to detect iron stores in soft tissue sarcomas (STS)., Methods: In this study, we evaluated T 2 * relaxation times ex vivo in five STS samples from subjects enrolled on a phase Ib/IIa clinical trial combining pharmacological ascorbate with neoadjuvant radiation therapy. Iron protein expression levels (ferritin, transferrin receptor, iron response protein 2) were evaluated by Western blot analysis. Bioinformatic data relating clinical outcomes in STS patients and iron protein expression levels were evaluated using the KMplotter database., Results: There was a high level of inter-subject variability in the expression of iron protein and T 2 * relaxation times. We identified that T 2 * relaxation time is capable of accurately detecting ferritin-heavy chain expression (r = -0.96) in these samples. Bioinformatic data acquired from the KMplot database revealed that transferrin receptor and iron-responsive protein 2 may be negative prognostic markers while ferritin expression may be a positive prognostic marker in the management of STS., Conclusion: These data suggest that targeting iron regulatory proteins may provide a therapeutic approach to enhance STS management. Additionally, T 2 * mapping has the potential to be used a clinically accessible, non-invasive marker of STS iron regulatory protein expression and influence cancer therapy decisions that warrants further investigation. Level of Evidence: IV ., (Copyright © The Iowa Orthopaedic Journal 2022.)

Adolescent and young adult (AYA) enrollment in cancer clinical trials (CCT) is suboptimal. Few studies have explored site level barriers and facilitators to AYA enrollment on CCTs and the efficacy of interventions to enhance enrollment. A cross sectional survey was developed by the COG AYA Oncology Discipline Committee Responsible Investigator (RI) Network to identify perceived barriers and facilitators to enrollment, as well as opportunities to improve enrollment. Associations of barriers and facilitators to enrollment with program demographics were assessed. The survey was sent to all AYA RI Network members (n = 143) and quantitative and thematic analyses were conducted. The overall response rate was 42% (n = 60/143). Participants represented diverse institutions based on size, presence or absence of dedicated AYA programs, and proximity and relationship between pediatric and medical oncology practices within the institution. The most frequently cited barriers to enrolling AYAs in CCTs were administrative logistical issues (45%), disparate enrollment practices (42%) and communication issues (27%) between pediatric and medical oncology and perceived limited trial availability (27%). The most frequently reported facilitators to enrollment included having strong communication between pediatric and medical oncology (48%), having a supportive research infrastructure (35%) and the presence of AYA champions (33%). Many barriers and facilitators were similar across institutions and AYA program types. Shared barriers and facilitators to AYA CCT enrollment exist across the landscape of cancer care settings. Interventions aimed at increasing coordination between pediatric and medical oncology clinical trials offices and providers have high potential to improve site-level AYA enrollment., (© 2022. The Author(s).)

Adolescents and young adults (AYAs; age 15-39 years) with cancer are under-represented in cancer clinical trials because of patient, provider, and institutional barriers. Health care technology is increasingly available to and highly used among AYAs and has the potential to improve cancer care delivery. The COVID-19 pandemic forced institutions to rapidly adopt novel approaches for enrollment and monitoring of patients on cancer clinical trials, many of which have the potential for improving AYA trial participation overall. This consensus statement from the Children's Oncology Group AYA Oncology Discipline Committee reviews opportunities to use technology to optimize AYA trial enrollment and study conduct, as well as considerations for widespread implementation of these practices. The use of remote patient eligibility screening, electronic informed consent, virtual tumor boards, remote study visits, and remote patient monitoring are recommended to increase AYA access to trials and decrease the burden of participation. Widespread adoption of these strategies will require new policies focusing on reimbursement for telehealth, license portability, facile communication between electronic health record systems and advanced safeguards to maintain patient privacy and security. Studies are needed to determine optimal approaches to further incorporate technology at every stage of the clinical trial process, from enrollment through study completion., Competing Interests: Varun MongaConsulting or Advisory Role: Forma TherapeuticsResearch Funding: Orbus Therapeutics (Inst), ImmunoCellular Therapeutics (Inst)¸ Newlink Genetics (Inst), Amgen (Inst), Prelude Therapeutics (Inst)Travel, Accommodations, Expenses: Deciphera (Inst), GlaxoSmithKline (Inst) Jamie E. FlerlageResearch Funding: Seattle Genetics (Inst) Michael A. TeraoOther Relationship: Sketchy MedicalUncompensated Relationships: theMednet Michael E. RothResearch Funding: Eisai, PfizerNo other potential conflicts of interest were reported.

Adenosine is an endogenous purine-based nucleoside expressed nearly in all body tissues. It regulates various body functions by activating four G-protein coupled receptors, A 1 , A 2A , A 2B , and A 3 . These receptors are widely acknowledged as drug targets for treating different neurological, metabolic, and inflammatory diseases. Although numerous adenosine receptor inhibitors have been developed worldwide, achieving target selectivity is still a big hurdle in drug development. However, the identification of specific radioligands-based affinity assay, fluorescent ligands, and MS-based ligand assay have contributed to the development of selective and potent adenosine ligands. In recent years various small heterocyclic-based molecules have shown some promising results. Istradefylline has been approved for treating Parkinson's in Japan, while preladenant, tozadenant, CVT-6883, MRS-1523, and many more are under different phases of clinical development. The present review is focused on the quest to develop potent and selective adenosine inhibitors from 2013 to early 2021 by various research groups. The review also highlights their biological activity, selectivity, structure-activity relationship, molecular docking, and mechanistic studies. A special emphsesis on drug designing strategies has been also given the manuscript. The comprehensive compilation of research work carried out in the field will provide inevitable scope for designing and developing novel adenosine inhibitors with improved selectivity and efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Sarcomas are a class of rare malignancies of mesenchymal origin with a heterogeneous histological spectrum. They are classically associated with poor outcomes, especially once metastasized. A path to improving clinical outcomes may be made through modifying the epigenome, where a variety of sarcomas demonstrate changes that contribute to their oncogenic phenotypes. This Perspective article identifies and describes changes in the sarcoma genome, while discussing specific epigenetic changes and their effect on clinical outcomes. Clinical attempts at modulating epigenetics in sarcoma are reviewed, as well as potential implications of these studies. Epigenetic targets to reverse and delay chemotherapy resistance are discussed. Future directions with primary next steps are proposed to invigorate the current understanding of epigenetic biomarkers to enact targeted therapies to epigenetic phenotypes of sarcoma subtypes. Modifications to prior studies, as well as proposed clinical steps, are also addressed., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2022.)