tbuckley/cabot-search huggingface dataset:
Predictive features for effectiveness of dupilumab in elderly patients with atopic dermatitis: a real-world study
Authors: Qiqi Jia, Qiaozhi Cao, Cong Peng, Xinyu Shui, Jie Li
Journal: British Journal of Dermatology (2024)

In this study we retrospectively reviewed dupilumab’s efficacy and safety profile in treating elderly patients with atopic dermatitis (AD) and explored the predictive indicators for its efficacy. After analysing data from 181 patients we found that dupilumab appears to be effective and well-tolerated in treating AD among elderly patients. More importantly, we found that disease severity and early response to dupilumab are associated with complete remission at week 24 and may be used as potential predictive indicators for dupilumab’s efficacy.
Detection of colorectal cancer and advanced neoplasia during first surveillance interval after detection of adenomas in fecal immunochemical test cancer screening: a nationwide study
Authors: Pernille T. Larsen, Susanne F. Jørgensen, Rikke Hagemann-Madsen, Morten Rasmussen, Berit Andersen, Sisse H. Njor
Journal: Endoscopy (2024)

Abstract Background Adenoma surveillance guidelines are based on non-fecal immunochemical test (FIT)-based screening settings. However, colorectal cancer (CRC) risk may be different in FIT-positive screening populations. We evaluated the CRC and advanced adenoma risk within the recommended surveillance periods in the Danish FIT-based CRC screening program for participants with intermediate or high risk adenomas according to 2010 European guidelines. Furthermore, we estimated CRC risk for those who were not recommended surveillance according to European Society of Gastrointestinal Endoscopy (ESGE) 2020 guidelines. Methods Using nationwide health registries, we identified 17 936 FIT-screening participants from 2014–2017 with adenomas undergoing surveillance (high risk 1 year, intermediate risk 3 years). Participants with a follow-up examination were included (N = 10 068). Relative risk (RR) of CRC and advance adenoma was compared between intermediate and high risk groups and between intermediates who were recommended surveillance (S) or no surveillance (NS) according to 2020 ESGE guidelines. Results During surveillance, CRC occurred in 0.59% of the high risk group and 1.11% of the intermediate risk group (RR 0.53 [95%CI 0.34–0.84]). The high risk group had a 24% increased risk of advanced adenoma. CRC occurred in 1.69% of the intermediateNS group and 0.87% of the intermediateS group (RR 1.94 [95%CI 1.18–3.21]), and RR for advanced adenoma was 1.19 (95%CI 1.03–1.37). Conclusion CRC detection was lower among participants rated at higher risk at initial CRC screening. Findings at first screen-derived colonoscopy might not be as good a predictor of CRC risk in a FIT-positive screening population.
Diagnosis and management of Evans syndrome in adults: first consensus recommendations
Authors: Bruno Fattizzo, Monia Marchetti, Marc Michel, Silvia Cantoni, Henrik Frederiksen, Giulio Giordano, Andreas Glenthøj, Tomás José González-López, Irina Murakhovskaya, Mariasanta Napolitano, Maria-Eva Mingot, Maria Arguello, Andrea Patriarca, Simona Raso, Nicola Vianelli, Wilma Barcellini
Journal: The Lancet Haematology (2024)
Concomitant use of antidepressants and benzodiazepines during pregnancy and associated risk of congenital malformations: a population-based cohort study in Taiwan
Authors: Hui-Min Chuang, Lin-Chieh Meng, Chih-Wan Lin, Wen-Wen Chen, Yi-Yung Chen, Chi-Yung Shang, Liang-Kung Chen, Fei-Yuan Hsiao
Journal: The Lancet Psychiatry (2024)
An interpretable two-branch bi-coordinate network based on multi-grained domain knowledge for classification of thyroid nodules in ultrasound images
Authors: Mingyu Wang, Chao Chen, Ziyue Xu, Lang Xu, Weiwei Zhan, Jing Xiao, Yiqing Hou, Bingsheng Huang, Lingyun Huang, Shuo Li
Journal: Medical Image Analysis (2024)
Environmental challenges facing athletes, stakeholders and spectators at Paris 2024 Olympic and Paralympic Games: an evidence-based review of mitigation strategies and recommendations
Authors: Loïs Mougin, Valérie Bougault, Sébastien Racinais, Margo L Mountjoy, Ben Stephenson, Sarah Carter, Lewis J James, Stephen A Mears, Lee Taylor
Journal: British Journal of Sports Medicine (2024)

The upcoming Paris 2024 Olympic and Paralympic Games could face environmental challenges related to heat, air quality and water quality. These challenges will pose potential threats to athletes and impact thousands of stakeholders and millions of spectators. Recognising the multifaceted nature of these challenges, a range of strategies will be essential for mitigating adverse effects on participants, stakeholders and spectators alike. From personalised interventions for athletes and attendees to comprehensive measures implemented by organisers, a holistic approach is crucial to address these challenges and the possible interplay of heat, air and water quality factors during the event. This evidence-based review highlights various environmental challenges anticipated at Paris 2024, offering strategies applicable to athletes, stakeholders and spectators. Additionally, it provides recommendations for Local Organising Committees and the International Olympic Committee that may be applicable to future Games. In summary, the review offers solutions for consideration by the stakeholders responsible for and affected by the anticipated environmental challenges at Paris 2024.
International Union of Basic and Clinical Pharmacology. CXV: The Class F of G Protein-Coupled Receptors.
Authors: Gunnar Schulte
Journal: Pharmacological Reviews (2024)

The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD1-10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. SIGNIFICANCE STATEMENT: The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification, and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds.
Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids
Authors: Matteo Fiorenza, Antonio Checa, Rasmus M. Sandsdal, Simon B.K. Jensen, Christian R. Juhl, Mikkel H. Noer, Nicolai P. Bogh, Julie R. Lundgren, Charlotte Janus, Bente M. Stallknecht, Jens Juul Holst, Sten Madsbad, Craig E. Wheelock, Signe S. Torekov
Journal: Cell Reports Medicine (2024)

Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.
lnc-Rps4l-encoded peptide RPS4XL regulates RPS6 phosphorylation and inhibits the proliferation of PASMCs caused by hypoxia
Authors: Yiying Li, Junting Zhang, Hanliang Sun, Yujie Chen, Wendi Li, Xiufeng Yu, Xijuan Zhao, Lixin Zhang, Jianfeng Yang, Wei Xin, Yuan Jiang, Guilin Wang, Wenbin Shi, Daling Zhu
Journal: Molecular Therapy (2024)
Implications of noncoding regulatory functions in the development of insulinomas
Authors: Mireia Ramos-Rodríguez, Marc Subirana-Granés, Richard Norris, Valeria Sordi, Ángel Fernández, Georgina Fuentes-Páez, Beatriz Pérez-González, Clara Berenguer Balaguer, Helena Raurell-Vila, Murad Chowdhury, Raquel Corripio, Stefano Partelli, Núria López-Bigas, Silvia Pellegrini, Eduard Montanya, Montserrat Nacher, Massimo Falconi, Ryan Layer, Meritxell Rovira, Abel González-Pérez, Lorenzo Piemonti, Lorenzo Pasquali
Journal: Cell Genomics (2024)

Insulinomas are rare neuroendocrine tumors arising from pancreatic β cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in β cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of β cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.
Performance of spleen stiffness measurement to rule out high-risk varices in patients with porto-sinusoidal vascular disorder
Authors: Lucile Moga, Valérie Paradis, Joel Ferreira-Silva, Koushik Gudavalli, Federica Indulti, Elton Dajti, Oana Nicoara-Farcau, Giulia Tosetti, Antonina Antonenko, Andreea Fodor, Judit Vidal-González, Laura Turco, Francisco Capinha, Laure Elkrief, Teresa Monllor-Nunell, Odile Goria, Lorenz Balcar, Adrien Lannes, Vincent Mallet, Armelle Poujol-Robert, Dominique Thabut, Pauline Houssel-Debry, Yu Jun Wong, Maxime Ronot, Valérie Vilgrain, Sai Prasanth Rampally, Audrey Payancé, Laurent Castera, Thomas Reiberger, José Ferrusquía-Acosta, Carlos Noronha Ferreira, Giovanni Vitale, Macarena Simon-Talero, Bogdan Procopet, Annalisa Berzigotti, Riccardo Caccia, Fanny Turon, Filippo Schepis, Federico Ravaioli, Antonio Colecchia, Arun Valsan, Guilherme Macedo, Aurélie Plessier, Pierre-Emmanuel Rautou
Journal: Hepatology (2024)

Background and Aims: Baveno VII consensus suggests that screening endoscopy can be spared in patients with compensated cirrhosis when spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) is ≤40 kPa as they have a low probability of high-risk varices (HRV). Conversely, screening endoscopy is required in all patients with porto-sinusoidal vascular disorder (PSVD). This study aimed to evaluate the performance of SSM-VCTE to rule out HRV in patients with PSVD and signs of portal hypertension. Approach and Results: We retrospectively included patients with PSVD, ≥1 sign of portal hypertension, without a history of variceal bleeding, who underwent an SSM-VCTE within 2 years before or after an upper endoscopy in 21 VALDIG centers, divided into a derivation and a validation cohort. One hundred fifty-four patients were included in the derivation cohort; 43% had HRV. By multivariable logistic regression analysis, SSM-VCTE &gt;40 kPa and serum bilirubin ≥1 mg/dL were associated with HRV. SSM-VCTE ≤40 kPa combined with bilirubin &lt;1 mg/dL had a sensitivity of 96% to rule out HRV and could spare 38% of screening endoscopies, with 4% of HRV missed, and a 95% negative predictive value. In the validation cohort, including 155 patients, SSM combined with bilirubin could spare 21% of screening endoscopies, with 4% of HRV missed and a 94% negative predictive value. Conclusions: This study gathering a total of 309 patients with PSVD showed that SSM-VCTE ≤40 kPa combined with bilirubin &lt;1 mg/dL identifies patients with PSVD and portal hypertension with a probability of HRV &lt;5%, in whom screening endoscopy can be spared.
Role of Point-of-Care ultrasound (POCUS) in clinical hepatology
Authors: Madhumita Premkumar, Constantine J. Karvellas, Anand V. Kulkarni, Harish Bhujade, K. Rajender Reddy
Journal: Hepatology (2024)

Hospitalized patients with cirrhosis frequently require critical care management for sepsis, HE, respiratory failure, acute variceal bleeding, acute kidney injury (AKI), shock, and optimization for liver transplantation, while outpatients have unique care considerations. Point-of-care ultrasonography (POCUS) enhances bedside examination of the hepatobiliary system and relevant extrahepatic sites. POCUS includes cardiac US and is used to assess volume status and hemodynamic parameters like cardiac output, systemic vascular resistance, cardiac contractility, and pulmonary artery pressure, which aid in the early and accurate diagnosis of heart failure, cirrhotic cardiomyopathy, porto-pulmonary hypertension, hepatopulmonary syndrome, arrhythmia, and pulmonary embolism. This also helps in fluid management and vasopressor use in the resuscitation of patients with cirrhosis. Lung ultrasound (LUS) can help in differentiating pneumonia, effusion, and edema. Further, US guides interventions such as line placement, drainage of abdominal collections/abscesses, relief of tension pneumothorax, drainage of pleural and pericardial effusions, and biliary drainage in cholangitis. Additionally, its role is essential to assess liver masses foci of sepsis, for appropriate sites for paracentesis, and to assess for vascular disorders such as portal vein or hepatic vein thrombosis. Renal US can identify renal and postrenal causes of AKI and aid in diagnosis of prerenal AKI through volume assessment. In this review, we address the principles and methods of POCUS in hospitalized patients and in outpatients with cirrhosis and discuss the application of this diverse modality in clinical hepatology.
Reduction of Z alpha-1 antitrypsin polymers in human iPSC-hepatocytes and mice by LRRK2 inhibitors
Authors: Deniz Kent, Soon Seng Ng, Adam M. Syanda, Payam Khoshkenar, Riccardo Ronzoni, Chao Zheng Li, Marina Zieger, Cindy Greer, Stephanie Hatch, Joe Segal, Samuel J.I. Blackford, Yu Ri Im, Vivek Chowdary, Taylor Ismaili, Davide Danovi, Patrick A. Lewis, James A. Irving, Sunil Sahdeo, David A. Lomas, Daniel Ebner, Christian Mueller, S. Tamir Rashid
Journal: Hepatology (2024)

Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by the inheritance of the serpin family A member 1 "Z" genetic variant driving alpha-1 antitrypsin (AAT) protein misfolding in hepatocytes. There are no approved medicines for this disease.
Neural representation of human experimenters in the bat hippocampus
Authors: Madeleine C. Snyder, Kevin K. Qi, Michael M. Yartsev
Journal: Nature Neuroscience (2024)

Abstract Here we conducted wireless electrophysiological recording of hippocampal neurons from Egyptian fruit bats in the presence of human experimenters. In flying bats, many neurons modulated their activity depending on the identity of the human at the landing target. In stationary bats, many neurons carried significant spatial information about the position and identity of humans traversing the environment. Our results reveal that hippocampal activity is robustly modulated by the presence, movement and identity of human experimenters.
Author Correction: Pembrolizumab and cabozantinib in recurrent metastatic head and neck squamous cell carcinoma: a phase 2 trial
Authors: Nabil F. Saba, Conor E. Steuer, Asari Ekpenyong, Ashley McCook-Veal, Kelly Magliocca, Mihir Patel, Nicole C. Schmitt, William Stokes, James E. Bates, Soumon Rudra, Jill Remick, Mark McDonald, Marin Abousaud, Aik Choon Tan, Muhammad Zaki Hidayatullah Fadlullah, Ritu Chaudhary, Jameel Muzaffar, Kedar Kirtane, Yuan Liu, Georgia Z. Chen, Dong M. Shin, Yong Teng, Christine H. Chung
Journal: Nature Medicine (2024)
Denosumab Prevents Bone Loss and Microarchitectural Deterioration in Premenopausal Women With Breast Cancer Receiving Estradiol Suppression Therapy: A Randomized Controlled Trial
Authors: Sabashini K. Ramchand, Ali Ghasem-Zadeh, Rudolf Hoermann, Shane White, Belinda Yeo, Prudence A. Francis, Cecilia L.H. Xu, Olivia Coleman, Cat Shore-Lorenti, Peter R. Ebeling, Jeffrey D. Zajac, Ego Seeman, Mathis Grossmann
Journal: Journal of Clinical Oncology (2024)

PURPOSE Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)–positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women. METHODS In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437). RESULTS Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm 3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm 3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm 3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm 2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm 2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm 2 [95% CI, 0.05 to 0.07]) were also prevented. All P &lt; .001 unless otherwise noted. CONCLUSION Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.
Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma
Authors: Paul A. Meyers, Noah Federman, Najat Daw, Peter. M. Anderson, Lara E. Davis, AeRang Kim, Margaret E. Macy, Angela Pietrofeso, Ravin Ratan, Richard F. Riedel, Matteo Trucco, James B. Breitmeyer, Jeffrey A. Toretsky, Joseph A. Ludwig
Journal: Journal of Clinical Oncology (2024)

PURPOSE Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES. PATIENTS AND METHODS TK216 was administered intravenously as a continuous infusion to patients with R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators’ choice. The trial used a 3 + 3 design with an expansion cohort at the recommended phase II dose (RP2D). RESULTS A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m 2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11. CONCLUSION TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.
Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors
Authors: Andrea B. Apolo, Daniel M. Girardi, Scot A. Niglio, Rosa Nadal, Andre R. Kydd, Nicholas Simon, Lisa Ley, Lisa M. Cordes, Elias Chandran, Seth M. Steinberg, Sunmin Lee, Min-Jung Lee, Shraddha Rastogi, Nahoko Sato, Liang Cao, A. Rouf Banday, Salah Boudjadi, Maria J. Merino, Antoun Toubaji, Dilara Akbulut, Bernadette Redd, Hadi Bagheri, Rene Costello, Sandeep Gurram, Piyush K. Agarwal, Heather J. Chalfin, Vladimir Valera, Howard Streicher, John Joseph Wright, Elad Sharon, William D. Figg, Howard L. Parnes, James L. Gulley, Biren Saraiya, Sumanta K. Pal, David Quinn, Mark N. Stein, Primo N. Lara, Donald P. Bottaro, Amir Mortazavi
Journal: Journal of Clinical Oncology (2024)

Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts.