tbuckley/cabot-search huggingface dataset:
Genomic and immune determinants of resistance to daratumumab-based therapy in relapsed refractory multiple myeloma
Authors: Bachisio Ziccheddu, Claudia Giannotta, Mattia D'Agostino, Giuseppe Bertuglia, Elona Saraci, Stefania Oliva, Elisa Genuardi, Marios Papadimitriou, Benjamin Diamond, Paolo Corradini, David Coffey, Ola Landgren, Niccolò Bolli, Benedetto Bruno, Mario Boccadoro, Massimo Massaia, Francesco Maura, Alessandra Larocca
Journal: Blood Cancer Journal (2024)

Abstract Targeted immunotherapy combinations, including the anti-CD38 monoclonal antibody (MoAb) daratumumab, have shown promising results in patients with relapsed/refractory multiple myeloma (RRMM), leading to a considerable increase in progression-free survival. However, a large fraction of patients inevitably relapse. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676). We conducted an integrated analysis using whole-genome sequencing (WGS) and flow cytometry in patients with RRMM. WGS before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss, APOBEC mutagenesis, and gain of function structural variants involving MYC and chromothripsis. Flow cytometry on 202 blood samples, collected every 3 months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38-positive NK cells, persistence of T-cell exhaustion, and reduced depletion of regulatory T cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd in patients with RRMM.
Myeloid neoplasms arising after methotrexate therapy for autoimmune rheumatological diseases do not exhibit poor-risk molecular features
Authors: Mihir D Wechalekar, Lin-Pierre Zhao, Monika M Kutyna, Lih En Hong, Joule Li, Kevin Hung, Hamish S Scott, Anna Brown, Christopher C Hahn, Karin Kassahn, Dariusz Ladon, David T Yeung, Daniel Thomas, Mrinal Patnaik, Susanna Proudman, Lionel Ades, Mithun V Shah, Chung H Kok, Devendra K Hiwase
Journal: Blood Cancer Journal (2024)

Myeloid neoplasms arising after methotrexate
Performance of the 2023 <scp>ACR</scp>/<scp>EULAR</scp> classification criteria for antiphospholipid syndrome in a Mexican cohort
Authors: Erik Cimé‐Aké, Gabriela Hernández‐Molina, Amaya Llorente‐Chávez, Eduardo Martín‐Nares
Journal: Arthritis & Rheumatology (2024)

The objective is to assess the performance of the 2023 American College of Rheumatology/EULAR classification criteria (2023 AECC) for antiphospholipid syndrome (APS) in a Mexican cohort.
Acquired Temozolomide Resistance Instructs Patterns of Glioblastoma Behavior in Gelatin Hydrogels
Authors: Victoria A. Kriuchkovskaia, Ela K. Eames, Rebecca B. Riggins, Brendan A. C. Harley
Journal: Advanced Healthcare Materials (2024)

Abstract Acquired drug resistance in glioblastoma (GBM) presents a major clinical challenge and is a key factor contributing to abysmal prognosis, with less than 15 months median overall survival. Aggressive chemotherapy with the frontline therapeutic, temozolomide (TMZ), ultimately fails to kill residual highly invasive tumor cells after surgical resection and radiotherapy. Here, a 3D engineered model of acquired TMZ resistance is reported using two isogenically matched sets of GBM cell lines encapsulated in gelatin methacrylol hydrogels. Response of TMZ‐resistant versus TMZ‐sensitive GBM cell lines within the gelatin‐based extracellular matrix platform is benchmarked and drug response at physiologically relevant TMZ concentrations is further validated. The changes in drug sensitivity, cell invasion, and matrix‐remodeling cytokine production are shown as the result of acquired TMZ resistance. This platform lays the foundation for future investigations targeting key elements of the GBM tumor microenvironment to combat GBM's devastating impact by advancing the understanding of GBM progression and treatment response to guide the development of novel treatment strategies.
Decisive reversal of lethal coronavirus disease 2019 in senescent hamster by synchronic antiviral and immunoregulatory intervention
Authors: Xuan Liu, Ming Zhou, Mujing Fang, Ying Xie, Peiwen Chen, Rirong Chen, Kun Wu, Jianghui Ye, Che Liu, Huachen Zhu, Tong Cheng, Lunzhi Yuan, Hui Zhao, Yi Guan, Ningshao Xia
Journal: MedComm (2024)

The poor prognosis observed in elderly individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a serious clinical burden and the underlying mechanism is unclear, which necessities detailed investigation of disease characteristics and research for efficient countermeasures. To simulate lethal coronavirus disease 2019 (COVID-19) in senescent human patients, 80-week-old male hamsters are intranasally inoculated with different doses of SARS-CoV-2 Omicron BA.5 variant. Exposure to a low dose of the Omicron BA.5 variant results in early activation of the innate immune response, followed by rapid viral clearance and minimal lung damage. However, a high dose of BA.5 results in impaired interferon signaling, cytokine storm, uncontrolled viral replication, and severe lung injury. To decrease viral load and reverse the deterioration of COVID-19, a new bio-mimic decoy called CoVR-MV is used as a preventive or therapeutic agent. Administration of CoVR-MV as a preventive or therapeutic intervention in the early stages of infection can effectively suppress viral load, regulate the immune response, and rescue animals from death and critical illness. These findings underscore the risk associated with SARS-CoV-2 Omicron BA.5 exposure in senescent hamsters and highlight the importance of early intervention to prevent disease progression.
Gut Microbiome and Osteoarthritis: Insights From the Naturally Occurring Canine Model of Osteoarthritis
Authors: Christina Stevens, Samantha Norris, Liubov Arbeeva, Scott Carter, Masataka Enomoto, Amanda E. Nelson, B. Duncan X. Lascelles
Journal: Arthritis & Rheumatology (2024)

Objective The purpose of this study was to enhance the current knowledge of the relationship between the gut microbiome and osteoarthritis (OA) and associated pain using pet dogs as a clinically relevant translational model. Methods Fecal samples were collected from 93 owned pet dogs. Dogs were designated as either clinically healthy or OA pain using validated methods. Metagenomic profiling was performed through shotgun sequencing using the Illumina NovaSeq platform. MetaPhlAn2 and HUMAnN2 were used to evaluate bacterial taxonomic and pathway relative abundance. Comparisons between healthy and OA‐pain groups were performed individually for each taxa using nonparametric tests following Benjamini and Hochberg adjustment for multiple comparisons. Permutation analysis of variance was performed using Bray‐Curtis distance matrices. All downstream analyses were completed in R. Results No significant differences between healthy and OA‐pain dogs were observed for alpha and beta diversity. We found 13 taxa with nominally significant ( P &lt; 0.05) associations with OA case status, but none of the associations remained significant after adjustment for multiple comparisons. No differences in alpha or beta diversities or the Firmicutes to Bacteroidetes ratio were found regarding pain severity, mobility or activity level, age, or body composition score. Conclusion Similar to recent studies in humans, the present study did not demonstrate a significant difference in the fecal microbial communities between dogs with OA pain and healthy control dogs. Future research in this naturally occurring model should expand on these data and relate the gut microbiome to gut permeability and circulating proinflammatory and anti‐inflammatory molecules to better understand the influence of the gut microbiome on OA and OA pain.
Development of a genome atlas for discriminating benign, preinvasive, and invasive lung nodules
Authors: Peng Liang, Minhua Peng, Jinsheng Tao, Bo Wang, Jinwang Wei, Lixuan Lin, Bo Cheng, Shan Xiong, Jianfu Li, Caichen Li, Ziwen Yu, Chunyan Li, Jun Wang, Hui Li, Zhiwei Chen, Jian‐Bing Fan, Wenhua Liang, Jianxing He
Journal: MedComm (2024)

Abstract To tackle misdiagnosis in lung cancer screening with low‐dose computed tomography (LDCT), we aimed to compile a genome atlas for differentiating benign, preinvasive, and invasive lung nodules and characterize their molecular pathogenesis. We collected 432 lung nodule tissue samples from Chinese patients, spanning benign, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). We performed comprehensive sequencing, examining somatic variants, gene expressions, and methylation levels. Our findings uncovered EGFR and TP53 mutations as key drivers in ‐ early lung cancer development, with EGFR mutation frequency increasing with disease progression. Both EGFR mutations and EGF/EGFR hypo‐methylation activated the EGFR pathway, fueling cancer growth. Transcriptome analysis identified four lung nodule subtypes (G1‐4) with distinct molecular features and immune cell infiltrations: EGFR‐driven G1, EGFR/TP53 co‐mutation G2, inflamed G3, stem‐like G4. Estrogen/androgen response was associated with the EGFR pathway, proposing a new therapy combining tyrosine kinase inhibitors with antiestrogens. Preinvasive nodules exhibited stem cell pathway enrichment, potentially hindering invasion. Epigenetic regulation of various genes was essential for lung cancer initiation and development. This study provides insights into the molecular mechanism of neoplastic progression and identifies potential diagnostic biomarkers and therapeutic targets for lung cancer.
Dual‐Barb Microneedle with JAK/STAT Inhibitor‐Loaded Nanovesicles Encapsulation for Tendinopathy
Authors: Minhao Chen, Fengkai Zou, Pei Wang, Wenbo Hu, Peng Shen, Xinyuan Wu, Hua Xu, Yunfeng Rui, Xiansong Wang, Youhua Wang
Journal: Advanced Healthcare Materials (2024)

Tendon stem/progenitor cells (TSPCs) are crucial for tendon repair, regeneration, and homeostasis. Dysfunction of TSPCs, due to aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, contributes to tendinopathy. Unfortunately, the effectiveness of conventional subcutaneous injection targeting at suppressing JAK/STAT signaling pathway is limited due to the passive diffusion of drugs away from the injury site. Herein, a novel poly-gamma-glutamic acid (γ-PGA) dual-barb microneedle (MN) path loaded with TSPCs-derived nanovesicles (NVs) containing JAK/STAT inhibitor WP1066 (MN-WP1066-NVs) for tendinopathy treatment is designed. The dual-barb design of the MN ensures firm adhesion to the skin, allowing for sustained and prolonged release of WP1066-NVs, facilitating enhanced TSPCs self-renewal, migration, and stemness in tendinopathy. In vitro and in vivo experiments demonstrate that the degradation of γ-PGA patch tips facilitates the gradual release of WP1066-NVs at the lesion site. This release alleviates inflammation, suppresses extracellular matrix degradation, and restores normal tendon histological structure by inhibiting the JAK/STAT pathway. These findings suggest that the multifunctional dual-barb MN patch offers a novel and effective therapeutic strategy for tendinopathy treatment.
Trash into Treasure: Nano‐coating of Catheter Utilizes Urine to Deprive H<sub>2</sub>S Against Persister and Rip Biofilm Matrix
Authors: Zhiming Hou, Xinyu Ren, Zhuangzhuang Sun, Ruoqi An, Mingzhi Huang, Cen Gao, Mengying Yin, Guangxiu Liu, Dengqi He, Hongliang Du, Rongbing Tang
Journal: Advanced Healthcare Materials (2024)

Abstract Bacteria‐derived hydrogen sulfide (H 2 S) often contributes to the emergence of antibiotic‐recalcitrant bacteria, especially persister (a sub‐population of dormant bacteria), thus causing the treatment failure of Catheter‐associated urinary tract infection (CAUTI). Here, an H 2 S harvester nanosystem to prevent the generation of persister bacteria and disrupt the dense biofilm matrix by the self‐adaptive ability of shape‐morphing is prepared. The nanosystem possesses a core‐shell structure that is composed of liquid metal nanoparticle (LM NP), AgNPs, and immobilized urease. The nanosystem decomposes urea contained in urine to generate ammonia for eliminating bacteria‐derived H 2 S. Depending on the oxidative layer of liquid metal, the nanosystem also constitutes a long‐lasting reservoir for temporarily storing bacteria‐derived H 2 S, when urease transiently overloads or in the absence of urine in a catheter. Depriving H 2 S can prevent the emergence of persistent bacteria, enhancing the bacteria‐killing efficiency of Ga 3+ and Ag + ions. Even when the biofilm has formed, the urine flow provides heat to trigger shape morphing of the LM NP, tearing the biofilm matrix. Collectively, this strategy can turn trash (urea) into treasure (H 2 S scavengers and biofilm rippers), and provides a new direction for the antibacterial materials application in the medical field.
Integration of Genetic and Clinical Risk Factors for Risk Classification of Uveitis in Patients With Juvenile Idiopathic Arthritis
Authors: Melissa Tordoff, Samantha L. Smith, Saskia Lawson‐Tovey, Andrew D. Dick, Michael W. Beresford, Athimalaipet V. Ramanan, Kimme L Hyrich, Andrew P Morris, Stephen Eyre, Lucy R Wedderburn, John Bowes
Journal: Arthritis & Rheumatology (2024)

Objective Juvenile idiopathic arthritis (JIA)–associated uveitis (JIAU) is a serious JIA comorbidity that can result in vision impairment. This study aimed to identify genetic risk factors within the major histocompatibility complex for JIAU and evaluate their contribution for improving risk classification when combined with clinical risk factors. Methods Data on single nucleotide polymorphisms, amino acids, and classical HLA alleles were available for 2,497 patients with JIA without uveitis and 579 patients with JIAU (female 2,060, male 1,015). Analysis was restricted to patients with inferred European ancestry. Forward conditional logistic regression identified genetic markers exceeding a Bonferroni‐corrected significance (6 × 10 −6 ). Multivariable logistic regression estimated the effects of clinical and genetic risk factors, and a likelihood ratio test calculated the improvement in model fit when adding genetic factors. Uveitis risk classification performance of a model integrating genetic and clinical risk factors was estimated using area under the receiver operator characteristic curve and compared with a model of clinical risk factors alone. Results Three genetic risk factors were identified, mapping to HLA‐DRB1 , HLA‐DPB1 , and HLA‐A . These markers were statistically independent from clinical risk factors and significantly improved the fit of a model when included with clinical risk factors ( P = 3.3 × 10 −23 ). The addition of genetic markers improved the classification of JIAU compared with a model of clinical risk factors alone (area under the curve 0.75 vs 0.71). Conclusion Integration of a genetic and clinical risk prediction model outperforms a model based solely on clinical risk factors. Future JIAU risk prediction models should include genetic risk factors.
Targeting N4‐acetylcytidine suppresses hepatocellular carcinoma progression by repressing eEF2‐mediated HMGB2 mRNA translation
Authors: Hailing Liu, Lei Xu, Shiwei Yue, Hongfei Su, Xing Chen, Qiumeng Liu, Hui Li, Huifang Liang, Xiaoping Chen, Jiefeng He, Zeyang Ding, Bixiang Zhang
Journal: Cancer Communications (2024)

Abstract Background N4‐acetylcytidine (ac4C) represents a novel messenger RNA (mRNA) modification, and its associated acetyltransferase N‐acetyltransferase 10 (NAT10) plays a crucial role in the initiation and progression of tumors by regulating mRNA functionality. However, its role in hepatocellular carcinoma (HCC) development and prognosis is largely unknown. This study aimed to elucidate the role of NAT10‐mediated ac4C in HCC progression and provide a promising therapeutic approach. Methods The ac4C levels were evaluated by dot blot and ultra‐performance liquid chromatography‐tandem mass spectrometry with harvested HCC tissues. The expression of NAT10 was investigated using quantitative real‐time polymerase chain reaction, western blotting, and immunohistochemical staining across 91 cohorts of HCC patients. To explore the underlying mechanisms of NAT10‐ac4C in HCC, we employed a comprehensive approach integrating acetylated RNA immunoprecipitation and sequencing, RNA sequencing and ribosome profiling analyses, along with RNA immunoprecipitation, RNA pull‐down, mass spectrometry, and site‐specific mutation analyses. The drug affinity responsive targets stability, cellular thermal shift assay, and surface plasmon resonance assays were performed to assess the specific binding of NAT10 and Panobinostat. Furthermore, the efficacy of targeting NAT10‐ac4C for HCC treatment was elucidated through in vitro experiments using HCC cells and in vivo HCC mouse models. Results Our investigation revealed a significant increase in both the ac4C RNA level and NAT10 expression in HCC. Notably, elevated NAT10 expression was associated with poor outcomes in HCC patients. Functionally, silencing NAT10 suppressed HCC proliferation and metastasis in vitro and in vivo. Mechanistically, NAT10 stimulates the ac4C modification within the coding sequence (CDS) of high mobility group protein B2 (HMGB2), which subsequently enhances HMGB2 translation by facilitating eukaryotic elongation factor 2 (eEF2) binding to the ac4C sites on HMGB2 mRNA's CDS. Additionally, high‐throughput compound library screening revealed Panobinostat as a potent inhibitor of NAT10‐mediated ac4C modification. This inhibition significantly attenuated HCC growth and metastasis in both in vitro experiments using HCC cells and in vivo HCC mouse models. Conclusions Our study identified a novel oncogenic epi‐transcriptome axis involving NAT10‐ac4C/eEF2‐HMGB2, which plays a pivotal role in regulating HCC growth and metastasis. The drug Panobinostat validates the therapeutic potential of targeting this axis for HCC treatment.
A benchmark of computational methods for correcting biases of established and unknown origin in CRISPR-Cas9 screening data
Authors: Alessandro Vinceti, Raffaele M. Iannuzzi, Isabella Boyle, Lucia Trastulla, Catarina D. Campbell, Francisca Vazquez, Joshua M. Dempster, Francesco Iorio
Journal: Genome biology (2024)

Abstract Background CRISPR-Cas9 dropout screens are formidable tools for investigating biology with unprecedented precision and scale. However, biases in data lead to potential confounding effects on interpretation and compromise overall quality. The activity of Cas9 is influenced by structural features of the target site, including copy number amplifications (CN bias). More worryingly, proximal targeted loci tend to generate similar gene-independent responses to CRISPR-Cas9 targeting (proximity bias), possibly due to Cas9-induced whole chromosome-arm truncations or other genomic structural features and different chromatin accessibility levels. Results We benchmarked eight computational methods, rigorously evaluating their ability to reduce both CN and proximity bias in the two largest publicly available cell-line-based CRISPR-Cas9 screens to date. We also evaluated the capability of each method to preserve data quality and heterogeneity by assessing the extent to which the processed data allows accurate detection of true positive essential genes, established oncogenetic addictions, and known/novel biomarkers of cancer dependency. Our analysis sheds light on the ability of each method to correct biases under different scenarios. AC-Chronos outperforms other methods in correcting both CN and proximity biases when jointly processing multiple screens of models with available CN information, whereas CRISPRcleanR is the top performing method for individual screens or when CN information is not available. In addition, Chronos and AC-Chronos yield a final dataset better able to recapitulate known sets of essential and non-essential genes. Conclusions Overall, our investigation provides guidance for the selection of the most appropriate bias-correction method, based on its strengths, weaknesses and experimental settings.
Large language models outperform mental and medical health care professionals in identifying obsessive-compulsive disorder
Authors: Jiyeong Kim, Kimberly G. Leonte, Michael L. Chen, John B. Torous, Eleni Linos, Anthony Pinto, Carolyn I. Rodriguez
Journal: npj Digital Medicine (2024)

Despite the promising capacity of large language model (LLM)-powered chatbots to diagnose diseases, they have not been tested for obsessive-compulsive disorder (OCD). We assessed the diagnostic accuracy of LLMs in OCD using vignettes and found that LLMs outperformed medical and mental health professionals. This highlights the potential benefit of LLMs in assisting in the timely and accurate diagnosis of OCD, which usually entails a long delay in diagnosis and treatment.
Generation of non-genetically modified, CAR-like, NK cells
Authors: Loïs Coënon, Emilie Rigal, Hortense Courot, Caroline Multrier, Sara Zemiti, Jennifer Lambour, Martine Pugnière, Marion de Toledo, Guillaume Bossis, Guillaume Cartron, Bruno Robert, Pierre Martineau, Bénédicte Fauvel, Jessy Presumey, Martin Villalba
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Natural killer (NK) cell therapy is considered an attractive and safe strategy for anticancer therapy. Nevertheless, when autologous or allogenic NK cells are used alone, the clinical benefit has been disappointing. This is partially due to the lack of target specificity. Recently, CD19-specific chimeric antigen receptor (CAR)-NK cells have proven to be safe and potent in patients with B-cell tumors. However, the generation of CAR-NK cells is a complicated manufacturing process. We aim at developing a targeted NK cell therapy without the need for cellular genetic modifications. We took advantage of the natural expression of the IgG Fc receptor CD16a (FcγRIIIa) to induce strong antigen-specific effector functions through antibody-dependent cell-mediated cytotoxicity (ADCC). We have generated the new technology “Pin”, which enables the arming of modified monoclonal antibodies (mAbs) onto the CD16a of ex vivo expanded NK (eNK) cells. Methods Ex vivo eNK were prepared from umbilical cord blood cells and expanded using interleukin (IL)-2/IL-15 and Epstein-Barr virus (EBV)-transformed B-lymphoblastoid feeder cells. mAbs were engineered with four substitutions called Pin mutations to increase their affinity to CD16a. eNK were incubated with anti-CD20 or anti-CD19 Pin-mAbs to generate “armed” eNK and were used to assess effector functions in vitro on cancer cell lines, lymphoma patient cells and in vivo. Results CD16a/Pin-mAb interaction is stable for several days and Pin-mAb eNK inherit the mAb specificity and exclusively induce ADCC against targets expressing the cognate antigen. Hence, Pin-mAbs confer long-term selectivity to eNK, which allows specific elimination of the target cells in several in vivo mouse models. Finally, we showed that it is possible to arm eNK with at least two Pin-mAbs simultaneously, to increase efficacy against heterogenous cancer cell populations. Conclusions The Pin technology provides an off-the-shelf NK cell therapy platform to generate CAR-like NK cells, without genetic modifications, that easily target multiple tumor antigens.