tbuckley/cabot-search huggingface dataset:
Mechanism of Musashi2 affecting radiosensitivity of lung cancer by modulating DNA damage repair
Authors: Hongjin Qu, Xiong Shi, Ying Xu, Hongran Qin, Junshi Li, Shanlin Cai, Jianpeng Zhao, Bingbing Wan, Yanyong Yang, Bailong Li
Journal: MedComm (2024)

Abstract Identifying new targets for overcoming radioresistance is crucial for improving the efficacy of lung cancer radiotherapy, given that tumor cell resistance is a leading cause of treatment failure. Recent research has spotlighted the significance of Musashi2 (MSI2) in cancer biology. In this study, we first demonstrated that MSI2 plays a key function in regulating the radiosensitivity of lung cancer. The expression of MSI2 is negatively correlated with overall survival in cancer patients, and the knockdown of MSI2 inhibits tumorigenesis and increases radiosensitivity of lung cancer cells. Cellular radiosensitivity, which is closely linked to DNA damage, is influenced by MSI2 interaction with ataxia telangiectasia mutated and Rad3‐related kinase (ATR) and checkpoint kinase 1 (CHK1) post‐irradiation; moreover, knockdown of MSI2 inhibits the ATR‐mediated DNA damage response pathway. RNA‐binding motif protein 17 (RBM17), which is implicated in DNA damage repair, exhibits increased interaction with MSI2 post‐irradiation. We found that knockdown of RBM17 disrupted the interaction between MSI2 and ATR post‐irradiation and increased the radiosensitivity of lung cancer cells. Furthermore, we revealed the potential mechanism of MSI2 recruitment into the nucleus with the assistance of RBM17 to activate ATR to promote radioresistance. This study provides novel insights into the potential application of MSI2 as a new target in lung cancer radiotherapy.
Right ventricular volume and function by three‐dimensional echocardiography: results of the echocardiographic measurements in normal Chinese adults (EMINCA) II
Authors: Yu Zhang, Ying‐Bin Wang, Gui‐Hua Yao, Hong Tang, Li‐Xin Chen, Li‐Xue Yin, Tian‐Gang Zhu, Jian‐Jun Yuan, Wei Han, Jun Yang, Xian‐Hong Shu, Ya Yang, Yu‐Lin Wei, Yan‐Li Guo, Wei‐Dong Ren, Dong‐Mei Gao, Gui‐Lin Lu, Ji Wu, Hong‐Ning Yin, Yu‐Ming Mu, Jia‐Wei Tian, Li‐Jun Yuan, Xiao‐Jing Ma, Hong‐Yan Dai, Yun‐Chuan Ding, Ming‐Yan Ding, Qing Zhou, Hao Wang, Di Xu, Mei Zhang, Yun Zhang
Journal: MedComm (2024)

Abstract Three‐dimensional (3D) echocardiography is an emerging technique for assessing right ventricular (RV) volume and function, but 3D‐RV normal values from a large Chinese population are still lacking. The aim of the present study was to establish normal values of 3D‐RV volume and function in healthy Chinese volunteers. A total of 1117 Han Chinese volunteers from 28 laboratories in 20 provinces of China were enrolled, and 3D‐RV images of 747 volunteers with optimal image quality were ultimately analyzed by a core laboratory. Both vendor‐dependent and vendor‐independent software platforms were used to analyze the 3D‐RV images. We found that men had larger RV volumes than women did in the whole population, even after indexing to body surface area, and older individuals had smaller RV volumes. The normal RV volume was significantly smaller than that recommended by the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines in both sexes. There were significant differences in 3D‐RV measurements between the two vendor ultrasound systems and the different software platforms. The echocardiographic measurements in normal Chinese adults II study revealed normal 3D‐RV volume and function in a large Chinese population, and there were significant differences between the sexes, ages, races, and vendor groups. Thus, normal 3D‐RV values should be stratified by sex, age, race, and vendor.
<i>RAS/RAF</i>landscape in monoclonal plasma cell conditions.
Authors: Anais Schavgoulidze, Jill Corre, Mehmet Kemal Samur, Celine Mazzotti, Luka Pavageau, Aurore Perrot, Titouan Cazaubiel, Xavier Leleu, Margaret Macro, Karim Belhadj, Murielle Roussel, Sabine Brechignac, Lydia Montes, Denis Caillot, Laurent Frenzel, Philippe Rey, Jean-Marc Schiano de Colella, Thomas Chalopin, Caroline Jacquet, Valentine Richez, Frederique Orsini-Piocelle, Jean Fontan, Salomon Manier, Ludovic Martinet, Adam Sciambi, Mohamad Mohty, Herve Avet-Loiseau
Journal: Blood (2024)
BCR::ABL1 Kinase N-lobe Mutants Confer Moderate to High Degrees of Resistance to Asciminib
Authors: Ariel Leyte-Vidal, Diego Garrido Ruiz, RosaAnna DeFilippis, Inga B. Leske, Delphine Rea, Stacey Phan, Kaeli B. Miller, Feifei Hu, Anjeli Mase, Yibing Shan, Oliver Hantschel, Matthew P. Jacobson, Neil P. Shah
Journal: Blood (2024)
Ibrutinib as part of risk-stratified treatment for post-transplant lymphoproliferative disorder: The phase 2 TIDaL trial
Authors: Sridhar Chaganti, Shanna Maycock, Graham McIlroy, Aimee E Jackson, Rebecca Bishop, Sarah Johnson, Edward Kanfer, Shireen Kassam, Kate Cwynarski, David J Wrench, Arvind Arumainathan, Christopher P Fox, Rod J Johnson, Pamela McKay, Shankara Paneesha, Clare Rowntree, Constantine Balotis, Graham P. Collins, Andrew J Davies, Josh Wright, Sarah Burns, Arian Dominic John Laurence, Keith Wheatley, Tobias Menne
Journal: Blood (2024)
A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome
Authors: Raffaele Badolato, Laia Alsina, Antoine Azar, Yves Bertrand, Audrey A. Bolyard, David Dale, Àngela Deyà-Martínez, Kathryn E. Dickerson, Navid Ezra, Henrik Hasle, Hyoung Jin Kang, Sorena Kiani-Alikhan, Taco W. Kuijpers, Alexander Kulagin, Daman Langguth, Carina Levin, Olaf Neth, Peter Olbrich, Jane Peake, Yulia Rodina, Caroline E. Rutten, Anna Shcherbina, Teresa K. Tarrant, Matthias G. Vossen, Christian A. Wysocki, Andrea Belschner, Gary J. Bridger, Kelly Chen, Susan Dubuc, Yanping Hu, Honghua Jiang, Sunny Li, Rick MacLeod, Murray Stewart, Arthur G. Taveras, Tina Yan, Jean Donadieu
Journal: Blood (2024)

We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/μL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/μL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/μL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.
Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT
Authors: Juan Montoro, Dirk-Jan Eikema, Joe Tuffnell, Victoria Potter, Krzysztof Kalwak, Constantijn J. M. Halkes, Alexander Kulagin, Matthew Collin, Robert F. Wynn, Stephen Robinson, Emma Nicholson, Henrik Sengeloev, Jennifer Clay, Khalid Halahleh, Elena Skorobogatova, Jaime Sanz, Jakob Passweg, Stephan Mielke, Samppa Ryhänen, Ben Carpenter, Tobias Gedde-Dahl, Eleni Tholouli, Renato Fanin, Philippe Lewalle, Austin Kulasekararaj, Antonio Risitano, Régis Peffault de Latour
Journal: Blood (2024)
Integrative single-cell chromatin and transcriptome analysis of human plasma cell differentiation
Authors: Elina Alaterre, Sara Ovejero, Caroline Bret, Laure Dutrieux, Dassou Sika, Raul Fernandez Perez, Marion Espéli, Thierry Fest, Michel Cogné, José Ignacio Martin-Subero, Pierre Milpied, Giacomo Cavalli, Jérôme Moreaux
Journal: Blood (2024)

Abstract Plasma cells (PCs) are highly specialized cells representing the end stage of B-cell differentiation. We have shown that PC differentiation can be reproduced in vitro using elaborate culture systems. The molecular changes occurring during PC differentiation are recapitulated in this in vitro differentiation model. However, a major challenge exists to decipher the spatiotemporal epigenetic and transcriptional programs that drive the early stages of PC differentiation. We combined single cell (sc) RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with high throughput sequencing (scATAC-seq) to decipher the trajectories involved in PC differentiation. ScRNA-seq experiments revealed a strong heterogeneity of the preplasmablastic and plasmablastic stages. Among genes that were commonly identified using scATAC-seq and scRNA-seq, we identified several transcription factors with significant stage specific potential importance in PC differentiation. Interestingly, differentially accessible peaks characterizing the preplasmablastic stage were enriched in motifs of BATF3, FOS and BATF, belonging to activating protein 1 (AP-1) transcription factor family that may represent key transcriptional nodes involved in PC differentiation. Integration of transcriptomic and epigenetic data at the single cell level revealed that a population of preplasmablasts had already undergone epigenetic remodeling related to PC profile together with unfolded protein response activation and are committed to differentiate in PC. These results and the supporting data generated with our in vitro PC differentiation model provide a unique resource for the identification of molecular circuits that are crucial for early and mature PC maturation and biological functions. These data thus provide critical insights into epigenetic- and transcription–mediated reprogramming events that sustain PC differentiation.
Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection
Authors: Kai Luo, Brandilyn A. Peters, Jee-Young Moon, Xiaonan Xue, Zheng Wang, Mykhaylo Usyk, David B. Hanna, Alan L. Landay, Michael F. Schneider, Deborah Gustafson, Kathleen M. Weber, Audrey French, Anjali Sharma, Kathryn Anastos, Tao Wang, Todd Brown, Clary B. Clish, Robert C. Kaplan, Rob Knight, Robert D. Burk, Qibin Qi
Journal: Genome Medicine (2024)

Abstract Background Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. Methods We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women’s Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria–diabetes associations are explained by altered metabolites and proteins. Results Seven gut bacterial genera were identified to be associated with diabetes (FDR-q &lt; 0.1), with positive associations for Shigella , Escherichia , Megasphaera , and Lactobacillus , and inverse associations for Adlercreutzia , Ruminococcus , and Intestinibacter . Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus , were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q &lt; 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera–diabetes associations, particularly for those of Adlercreutzia and Escherichia . Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. Conclusion Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera–diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.
Harnessing beta cell regeneration biology for diabetes therapy
Authors: Stephanie Bourgeois, Sophie Coenen, Laure Degroote, Lien Willems, Annelore Van Mulders, Julie Pierreux, Yves Heremans, Nico De Leu, Willem Staels
Journal: Trends in Endocrinology and Metabolism (2024)

The pandemic scale of diabetes mellitus is alarming, its complications remain devastating, and current treatments still pose a major burden on those affected and on the healthcare system as a whole. As the disease emanates from the destruction or dysfunction of insulin-producing pancreatic β-cells, a real cure requires their restoration and protection. An attractive strategy is to regenerate β-cells directly within the pancreas; however, while several approaches for β-cell regeneration have been proposed in the past, clinical translation has proven challenging. This review scrutinizes recent findings in β-cell regeneration and discusses their potential clinical implementation. Hereby, we aim to delineate a path for innovative, targeted therapies to help shift from 'caring for' to 'curing' diabetes.
Efficacy and safety of withholding antimicrobial therapy in children with cancer, fever, and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial
Authors: Juan P. Torres, Carolina Ibañez, Romina Valenzuela, Salome Rivera, Veronica De la Maza, Milena Villarroel, Paulina Coria, Veronica Contardo, Ana M. Álvarez, Carmen M. Zubieta, Valentina Gutierrez, Karen Ducasse, Daniela Martínez, Maria E. Santolaya
Journal: Clinical Microbiology and Infection (2024)

Objectives To validate the efficacy and safety of withholding antimicrobial therapy in a new cohort of children with cancer and febrile neutropenia (FN) having a demonstrated viral respiratory tract infection (RTI). Methods Prospective, multicenter, non-inferiority, randomized study, approved by the ethical committee, in children presenting with FN at seven hospitals in Chile, evaluated at admission for diagnosis of bacterial and viral pathogens. Children who were positive for a respiratory virus (RV), negative for a bacterial pathogen and had a favorable evolution after 48-72 hours of antimicrobial therapy were randomized to either maintain or withhold antimicrobial therapy. The primary endpoint was the percentage of episodes with uneventful resolution, whereas the secondary endpoints were days of fever/hospitalization, requirement of antimicrobial treatment readministration, sepsis, pediatric intensive care unit (PICU) admission and death. Results A total of 301 of 939 children with FN episodes recruited between March 2021 and December 2023 had a RV as a unique identified microorganism, of which 139 had a favorable evolution at 48-72 hours and were randomized, 70 to maintain and 69 to withdraw antimicrobial therapy. The median days of antimicrobial therapy was 5 (IQR 3-6) versus 3 (IQR 3-6) days (p<0.001), with similar frequency of uneventful resolution (66/70 (94%) and 66/69 (96%), RR 1.01, (95% CI 0.93-1.09), absolute risk difference 0.01, (95% CI -0.05-0.08) and similar number of days of fever and days of hospitalization. No cases of sepsis, PICU admission or death were reported. Conclusions We validated the strategy of withdrawal antimicrobial therapy in children with FN and viral RTI, based on clinical and microbiological/molecular diagnostic criteria. This will enable advances in antimicrobial stewardship strategies with a possible future impact on antimicrobial resistance.
Current Standards for Training in Robot-assisted Surgery and Endourology: A Systematic Review
Authors: Giuseppe Basile, Andrea Gallioli, Pietro Diana, Anthony Gallagher, Alessandro Larcher, Markus Graefen, Nina Harke, Olivier Traxer, Derya Tilki, Henk Van Der Poel, Esteban Emiliani, Oriol Angerri, Christian Wagner, Francesco Montorsi, Peter Wiklund, Bhaskar Somani, Nicolò Buffi, Alex Mottrie, Evangelos Liatsikos, Alberto Breda
Journal: European Urology (2024)
8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia
Authors: Jiamin Guo, Ralf Buettner, Li Du, Zhenlong Li, Wei Liu, Rui Su, Zhenhua Chen, Yuan Che, Yi Zhang, Rui Ma, Le Xuan Truong Nguyen, Roger E. Moore, Pathak Khyatiben, Min-Hsuan Chen, Pirrotte Patrick, Xiwei Wu, Guido Marcucci, Lili Wang, David Horne, Jianjun Chen, Yanzhong Yang, Steven T. Rosen
Journal: Leukemia (2024)

Abstract Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.
Summary Paper on Underactive Bladder from the European Association of Urology Guidelines on Non-neurogenic Male Lower Urinary Tract Symptoms
Authors: Michael Baboudjian, Hashim Hashim, Nikita Bhatt, Massimiliano Creta, Cosimo De Nunzio, Mauro Gacci, Thomas Herrmann, Markos Karavitakis, Sachin Malde, Lisa Moris, Christopher Netsch, Malte Rieken, Vasileios Sakalis, Natasha Schouten, Manuela Tutolo, Jean-Nicolas Cornu
Journal: European Urology (2024)
Deep and Durable Prostate-specific Antigen Response to Darolutamide with Androgen Deprivation Therapy and Docetaxel, and Association with Clinical Outcomes for Patients with High- or Low-volume Metastatic Hormone-sensitive Prostate Cancer: Analyses of the Randomized Phase 3 ARASENS Study
Authors: Fred Saad, Maha H.A. Hussain, Bertrand Tombal, Karim Fizazi, Cora N. Sternberg, E. David Crawford, Luke T. Nordquist, Martin Bögemann, Ronald Tutrone, Neal D. Shore, Laurence Belkoff, Todd Fralich, Jay Jhaveri, Shankar Srinivasan, Rui Li, Frank Verholen, Iris Kuss, Matthew R. Smith
Journal: European Urology (2024)

Addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) in ARASENS (NCT02799602). Here we report on prostate-specific antigen (PSA) responses and their association with outcomes. ARASENS is an international, double-blind, phase 3 study in patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), both with ADT + docetaxel. The proportion of patients with undetectable PSA (<0.2 ng/ml) and time to PSA progression (≥25% relative and ≥2 ng/ml absolute increase from nadir) were compared between groups in prespecified exploratory analyses. PSA outcomes by disease volume and the association of undetectable PSA with OS and times to castration-resistant prostate cancer (CRPC) and PSA progression were assessed in post hoc analyses. The proportion of patients with undetectable PSA at any time was more than doubled with darolutamide versus placebo, at 67% versus 29% in the overall population, 62% versus 26% in the high-volume subgroup, and 84% versus 38% in the low-volume subgroup. Darolutamide delayed time to PSA progression versus placebo, with hazard ratios of 0.26 (95% confidence interval [CI] 0.21–0.31) in the overall population, 0.30 (95% CI 0.24–0.37) in the high-volume subgroup, and 0.093 (95% CI 0.047–0.18) in the low-volume subgroup. Undetectable PSA at 24 wk was associated with longer OS, with a hazard ratio of 0.49 (95% CI 0.37–0.65) in the darolutamide group, as well as longer times to CRPC and PSA progression, with similar findings in the disease volume subgroups. Darolutamide + ADT + docetaxel led to deep and durable PSA responses in patients with high- or low-volume mHSPC. Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes. For patients with metastatic hormone-sensitive prostate cancer being treated with androgen deprivation therapy and docetaxel, PSA (prostate-specific antigen) became undetectable (below 0.2 ng/ml) in 67% of those also receiving darolutamide versus 29% of patients also receiving placebo. On average, patients achieving undetectable PSA lived longer than patients with detectable PSA.