tbuckley/cabot-search huggingface dataset:
Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study
Authors: Maud Toulmonde, Mehdi Brahmi, Antoine Giraud, Camille Chakiba, Alban Bessede, Michèle Kind, Emilie Toulza, Marina Pulido, Sabrina Albert, Jean-Philippe Guégan, Sophie Cousin, Simone Mathoulin-Pelissier, Raul Perret, Sabrina Croce, Jean-Yves Blay, Isabelle Ray-Coquard, Anne Floquet, Antoine Italiano
Journal: Clinical Cancer Research (2021)

Trabectedin has shown preclinical synergy with immune checkpoint inhibitors in preclinical models.TRAMUNE is a phase Ib study investigating the combination of trabectedin with durvalumab through a dose escalation phase and two expansion cohorts, soft tissue sarcoma (STS) and ovarian carcinoma. Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2, and 1.5 mg/m2) on day 1, in combination with durvalumab, 1,120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses.A total of 40 patients were included (dose escalation, n = 9; STS cohort, n = 16; ovarian carcinoma cohort, n = 15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1-2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% [95% confidence interval (CI), 0.2-33.9], and the 6-month PFR was 28.6% (95% CI, 8.4-58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI, 4.7-50.8), and the 6-month PFR was 42.9% (95% CI, 17.7-71.1). Baseline levels of programmed death-ligand 1 expression and CD8-positive T-cell infiltrates were associated with PFS in patients with ovarian carcinoma.Combining trabectedin and durvalumab is manageable. Promising activity is observed in patients with platinum-refractory ovarian carcinoma. See related commentary by Digklia et al., p. 1745.
A 5-year look-back at the notification and management of vaccine supply shortages in Germany
Authors: Maria Auxiliadora Miranda-García, Marcus Hoffelner, Hagen Stoll, Dörte Ruhaltinger, Klaus Cichutek, Anette Siedler, Isabelle Bekeredjian-Ding
Journal: Eurosurveillance (2022)

BackgroundUnavailability of vaccines endangers the overall goal to protect individuals and whole populations against infections.MethodsThe German notification system includes the publication of vaccine supply shortages reported by marketing authorisation holders (MAH), information on the availability of alternative vaccine products, guidance for physicians providing vaccinations and an unavailability reporting tool to monitor regional distribution issues.AimThis study provides a retrospective analysis of supply issues and measures in the context of European and global vaccine supply constraints.Resultsbetween October 2015 and December 2020, the 250 notifications concerned all types of vaccines (54 products). Most shortages were caused by increased demand associated with immigration in Germany in 2015 and 2016, new or extended vaccine recommendations, increased awareness, or changes in global immunisation programmes. Shortages of a duration up to 30 days were mitigated using existing storage capacities. Longer shortages, triggered by high demand on a national level, were mitigated using alternative products and re-allocation; in a few cases, vaccines were imported. However, for long lasting supply shortages associated with increased global demand, often occurring in combination with manufacturing issues, few compensatory mechanisms were available. Nevertheless, only few critical incidents were identified: (i) shortage of hexavalent vaccines endangering neonatal immunisation programmes in 2015;(ii) distribution issues with influenza vaccines in 2018; and (iii) unmet demand for pneumococcal and influenza vaccines during the coronavirus disease (COVID)-19 pandemic.ConclusionVaccine product shortages in Germany resemble those present in neighbouring EU states and often reflect increased global demand not matched by manufacturing capacities.
Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms
Authors: Craig N. Morrell, Doran Mix, Anu Aggarwal, Rohan Bhandari, Matthew Godwin, Phillip Owens, Sean P. Lyden, Adam Doyle, Krystin Krauel, Matthew T. Rondina, Amy Mohan, Charles J. Lowenstein, Sharon Shim, Shaun Stauffer, Vara Prasad Josyula, Sara K. Ture, David I. Yule, Larry E. Wagner, John M. Ashton, Ayman Elbadawi, Scott J. Cameron
Journal: Journal of Clinical Investigation (2022)

As blood transitions from steady laminar flow (S-flow) in healthy arteries to disturbed flow (D-flow) in aneurysmal arteries, platelets are subjected to external forces. Biomechanical platelet activation is incompletely understood and is a potential mechanism behind antiplatelet medication resistance. Although it has been demonstrated that antiplatelet drugs suppress the growth of abdominal aortic aneurysms (AAA) in patients, we found that a certain degree of platelet reactivity persisted in spite of aspirin therapy, urging us to consider additional antiplatelet therapeutic targets. Transcriptomic profiling of platelets from patients with AAA revealed upregulation of a signal transduction pathway common to olfactory receptors, and this was explored as a mediator of AAA progression. Healthy platelets subjected to D-flow ex vivo, platelets from patients with AAA, and platelets in murine models of AAA demonstrated increased membrane olfactory receptor 2L13 (OR2L13) expression. A drug screen identified a molecule activating platelet OR2L13, which limited both biochemical and biomechanical platelet activation as well as AAA growth. This observation was further supported by selective deletion of the OR2L13 ortholog in a murine model of AAA that accelerated aortic aneurysm growth and rupture. These studies revealed that olfactory receptors regulate platelet activation in AAA and aneurysmal progression through platelet-derived mediators of aortic remodeling.
The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies
Authors: Pablo Berlanga, Gaelle Pierron, Ludovic Lacroix, Mathieu Chicard, Tiphaine Adam de Beaumais, Antonin Marchais, Anne C. Harttrampf, Yasmine Iddir, Alicia Larive, Aroa Soriano Fernandez, Imene Hezam, Cecile Chevassus, Virginie Bernard, Sophie Cotteret, Jean-Yves Scoazec, Arnaud Gauthier, Samuel Abbou, Nadege Corradini, Nicolas André, Isabelle Aerts, Estelle Thebaud, Michela Casanova, Cormac Owens, Raquel Hladun-Alvaro, Stefan Michiels, Olivier Delattre, Gilles Vassal, Gudrun Schleiermacher, Birgit Geoerger
Journal: Cancer Discovery (2022)

Abstract MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA). Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171
First Donepezil Transdermal Patch Approved for Alzheimer Disease
Authors: Howard D. Larkin
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Q&amp;A: Lisa Coussens on Her Leadership Year Ahead
Journal: Cancer Discovery (2022)

Lisa M. Coussens, PhD, of the Oregon Health and Science University in Portland, will formally assume a 1-year term as president of the American Association for Cancer Research at the organization's annual meeting in April 2022. In this interview, she offered an overview of her research and highlighted initiatives she aims to pursue during her tenure, such as boosting programs tied to education and mentoring and building a portal for imaging data.
Microbiota alterations in proline metabolism impact depression
Authors: Jordi Mayneris-Perxachs, Anna Castells-Nobau, María Arnoriaga-Rodríguez, Miquel Martin, Lisset de la Vega-Correa, Cristina Zapata, Aurelijus Burokas, Gerard Blasco, Clàudia Coll, Anira Escrichs, Carles Biarnés, José María Moreno-Navarrete, Josep Puig, Josep Garre-Olmo, Rafel Ramos, Salvador Pedraza, Ramón Brugada, Joan Carles Vilanova, Joaquín Serena, Jordi Gich, Lluís Ramió-Torrentà, Vicente Pérez-Brocal, Andrés Moya, Reinald Pamplona, Joaquim Sol, Mariona Jové, Wifredo Ricart, Manuel Portero-Otin, Gustavo Deco, Rafael Maldonado, José Manuel Fernández-Real
Journal: Cell Metabolism (2022)

The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment.
MS imaging and absorption methods visualizing sun filter skin spatial distribution and penetration
Authors: C. Jacques, F. Crépel, D. El Assad, T.B. Angerer, J. Bour, C. Jeanjean-Miquel, D. Redoules, D. Bacqueville, F. Pamelard, S. Bessou-Touya, G. Frache, H. Duplan
Journal: Journal of Controlled Release (2022)

Sunscreens must now be effective in protecting skin from ultraviolet, as well as visible/infrared radiation. Here, TriAsorB, a new broad-spectrum sun filter, was formulated with three other sunscreens and their distribution on human skin was studied using a standard penetration protocol and two novel mass spectrometry imaging techniques: atmospheric pressure matrix assisted laser desorption ionization (AP-MALDI) coupled to high resolution mass spectrometry and time of flight - secondary ion mass spectrometry (ToF-SIMS). The standard penetration protocol showed that sun filters absorption was very low, with most of the dose recovered at the surface (none entered the receptor fluid). Absorption was not increased in damaged skin. The results were confirmed by AP-MALDI and ToF-SIMS imaging of the spatial distribution of molecular species in cross-section samples of human skin. Each sun filter was detected on or in the stratum corneum, with a good homogenous coverage over the valleys and peaks of the skin, and correlated well with the distribution of endogenous biomarkers. In conclusion, conventional and novel imaging analysis methods showed that the sun filters remained mainly on the skin surface after topical application. Mass spectrometry imaging is a promising complementary approach to traditional skin penetration studies to visualize penetration of compounds.
Novel Approaches to Imaging the Pulmonary Vasculature and Right Heart
Authors: Fawaz Alenezi, Taylor A. Covington, Monica Mukherjee, Stephen C. Mathai, Paul B. Yu, Sudarshan Rajagopal
Journal: Circulation Research (2022)

There is an increased appreciation for the importance of the right heart and pulmonary circulation in several disease states across the spectrum of pulmonary hypertension and left heart failure. However, assessment of the structure and function of the right heart and pulmonary circulation can be challenging, due to the complex geometry of the right ventricle, comorbid pulmonary airways and parenchymal disease, and the overlap of hemodynamic abnormalities with left heart failure. Several new and evolving imaging modalities interrogate the right heart and pulmonary circulation with greater diagnostic precision. Echocardiographic approaches such as speckle-tracking and 3-dimensional imaging provide detailed assessments of regional systolic and diastolic function and volumetric assessments. Magnetic resonance approaches can provide high-resolution views of cardiac structure/function, tissue characterization, and perfusion through the pulmonary vasculature. Molecular imaging with positron emission tomography allows an assessment of specific pathobiologically relevant targets in the right heart and pulmonary circulation. Machine learning analysis of high-resolution computed tomographic lung scans permits quantitative morphometry of the lung circulation without intravenous contrast. Inhaled magnetic resonance imaging probes, such as hyperpolarized 129Xe magnetic resonance imaging, report on pulmonary gas exchange and pulmonary capillary hemodynamics. These approaches provide important information on right ventricular structure and function along with perfusion through the pulmonary circulation. At this time, the majority of these developing technologies have yet to be clinically validated, with few studies demonstrating the utility of these imaging biomarkers for diagnosis or monitoring disease. These technologies hold promise for earlier diagnosis and noninvasive monitoring of right heart failure and pulmonary hypertension that will aid in preclinical studies, enhance patient selection and provide surrogate end points in clinical trials, and ultimately improve bedside care.
Errors in Figures
Journal: JAMA Network Open (2022)

Ryon P. Graf, PhD; Virginia Fisher, PhD; Janick Weberpals, RPh, PhD; Ole Gjoerup, PhD; Marni B. Tierno, PhD, RN; Richard S. P. Huang, MD; Nicolas Sayegh, MD; Douglas I. Lin, MD, PhD; Kira Raskina, MD, MS; Alexa B. Schrock, PhD; Eric Severson, MD, PhD; James F. Haberberger, BS; Jeffrey S. Ross, MD; James Creeden, MD, PhD; Mia A. Levy, MD, PhD; Brian M. Alexander, MD, MPH; Geoffrey R. Oxnard, MD; Neeraj Agarwal, MD
Emerging evidence on heterologous COVID-19 vaccine schedules—To mix or not to mix?
Authors: Edward P K Parker, Shalini Desai, Melanie Marti, Katherine L O'Brien, David C Kaslow, Sonali Kochhar, Folake Olayinka, Alejandro Cravioto, Hanna Nohynek, Joachim Hombach, Annelies Wilder-Smith
Journal: The Lancet Infectious Diseases (2022)
Inhibition of DYRK1a Enhances Cardiomyocyte Cycling After Myocardial Infarction
Authors: Alexander Young, Leigh A. Bradley, Elizabeth Farrar, Helen O. Bilcheck, Svyatoslav Tkachenko, Jeffrey J. Saucerman, Stefan Bekiranov, Matthew J. Wolf
Journal: Circulation Research (2022)

DYRK1a (dual-specificity tyrosine phosphorylation-regulated kinase 1a) contributes to the control of cycling cells, including cardiomyocytes. However, the effects of inhibition of DYRK1a on cardiac function and cycling cardiomyocytes after myocardial infarction (MI) remain unknown.We investigated the impacts of pharmacological inhibition and conditional genetic ablation of DYRK1a on endogenous cardiomyocyte cycling and left ventricular systolic function in ischemia-reperfusion (I/R) MI using αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (RLTG) (denoted αDKRC::RLTG) and αMHC-Cre::Fucci2aR::DYRK1aflox/flox mice.We observed that harmine, an inhibitor of DYRK1a, improved left ventricular ejection fraction (39.5±1.6% and 29.1±1.6%, harmine versus placebo, respectively), 2 weeks after I/R MI. Harmine also increased cardiomyocyte cycling after I/R MI in αDKRC::RLTG mice, 10.8±1.5 versus 24.3±2.6 enhanced Green Fluorescent Protein (eGFP)+ cardiomyocytes, placebo versus harmine, respectively, P=1.0×10-3. The effects of harmine on left ventricular ejection fraction were attenuated in αDKRC::DTA mice that expressed an inducible diphtheria toxin in adult cycling cardiomyocytes. The conditional cardiomyocyte-specific genetic ablation of DYRK1a in αMHC-Cre::Fucci2aR::DYRK1aflox/flox (denoted DYRK1a k/o) mice caused cardiomyocyte hyperplasia at baseline (210±28 versus 126±5 cardiomyocytes per 40× field, DYRK1a k/o versus controls, respectively, P=1.7×10-2) without changes in cardiac function compared with controls, or compensatory changes in the expression of other DYRK isoforms. After I/R MI, DYRK1a k/o mice had improved left ventricular function (left ventricular ejection fraction 41.8±2.2% and 26.4±0.8%, DYRK1a k/o versus control, respectively, P=3.7×10-2). RNAseq of cardiomyocytes isolated from αMHC-Cre::Fucci2aR::DYRK1aflox/flox and αMHC-Cre::Fucci2aR mice after I/R MI or Sham surgeries identified enrichment in mitotic cell cycle genes in αMHC-Cre::Fucci2aR::DYRK1aflox/flox compared with αMHC-Cre::Fucci2aR.The pharmacological inhibition or cardiomyocyte-specific ablation of DYRK1a caused baseline hyperplasia and improved cardiac function after I/R MI, with an increase in cell cycle gene expression, suggesting the inhibition of DYRK1a may serve as a therapeutic target to treat MI.
Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy
Authors: A. Harrison Brody, Sarah Helena Nies, Fulin Guan, Levi M. Smith, Bandhan Mukherjee, Santiago A. Salazar, Suho Lee, Tu Kiet T. Lam, Stephen M. Strittmatter
Journal: Molecular Neurodegeneration (2022)

Genetic variation at the PTK2B locus encoding the protein Pyk2 influences Alzheimer's disease risk. Neurons express Pyk2 and the protein is required for Amyloid-β (Aβ) peptide driven deficits of synaptic function and memory in mouse models, but Pyk2 deletion has minimal effect on neuro-inflammation. Previous in vitro data suggested that Pyk2 activity might enhance GSK3β-dependent Tau phosphorylation and be required for tauopathy. Here, we examine the influence of Pyk2 on Tau phosphorylation and associated pathology.The effect of Pyk2 on Tau phosphorylation was examined in cultured Hek cells through protein over-expression and in iPSC-derived human neurons through pharmacological Pyk2 inhibition. PS19 mice overexpressing the P301S mutant of human Tau were employed as an in vivo model of tauopathy. Phenotypes of PS19 mice with a targeted deletion of Pyk2 expression were compared with PS19 mice with intact Pyk2 expression. Phenotypes examined included Tau phosphorylation, Tau accumulation, synapse loss, gliosis, proteomic profiling and behavior.Over-expression experiments from Hek293T cells indicated that Pyk2 contributed to Tau phosphorylation, while iPSC-derived human neuronal cultures with endogenous protein levels supported the opposite conclusion. In vivo, multiple phenotypes of PS19 were exacerbated by Pyk2 deletion. In Pyk2-null PS19 mice, Tau phosphorylation and accumulation increased, mouse survival decreased, spatial memory was impaired and hippocampal C1q deposition increased relative to PS19 littermate controls. Proteomic profiles of Pyk2-null mouse brain revealed that several protein kinases known to interact with Tau are regulated by Pyk2. Endogenous Pyk2 suppresses LKB1 and p38 MAPK activity, validating one potential pathway contributing to increased Tau pathology.The absence of Pyk2 results in greater mutant Tau-dependent phenotypes in PS19 mice, in part via increased LKB1 and MAPK activity. These data suggest that in AD, while Pyk2 activity mediates Aβ-driven deficits, Pyk2 suppresses Tau-related phenotypes.
Labile iron accumulation augments T follicular helper cell differentiation
Authors: Yogesh Scindia, Borna Mehrad, Laurence Morel
Journal: Journal of Clinical Investigation (2022)

T follicular helper (Tfh) cells are a subset of CD4+ T cells that are essential in the pathogenesis of systemic lupus erythematosus (SLE). Notably, iron is required for activated CD4+ T lymphocytes to sustain high proliferation and metabolism. In this issue of the JCI, Gao et al. showed that CD4+ T cells from patients with SLE accumulated iron, augmenting their differentiation into Tfh cells and correlating with disease activity. Using human cells and murine models, the authors demonstrated that miR-21 was overexpressed in lupus T cells and inhibited 3-hydroxybutyrate dehydrogenase-2 (BDH2). The subsequent loss of BDH2 drove labile iron to accumulate in the cytoplasm and promoted TET enzyme activity, BCL6 gene demethylation, and Tfh cell differentiation. This work identifies a role for iron in CD4+ T cell biology and the development of pathogenic effectors in SLE. We await future investigations that could determine whether modulating iron levels could regulate Tfh cells in human health and disease.
Trabectedin and Durvalumab Combination Is Feasible and Active in Relapsing Ovarian Cancer
Authors: Antonia Digklia, George Coukos, Krisztian Homicsko
Journal: Clinical Cancer Research (2022)

Summary The combination of chemotherapy and immune therapies still promises to synergize for prolonged tumor control. However, the quest for optimal combinations tailored for tumor histology remains ongoing. A recent study provides evidence on the feasibility of the trabectedin/durvalumab combination and reports on interesting preliminary efficacy. See related article by Toulmonde et al., p. 1765