tbuckley/cabot-search huggingface dataset:
Abstract 5305: M9657, a tumor-targeted anti-CD137 agonist, induced significant antitumor immunity in combination with anti-PD-1 antibody
Authors: Chunxiao Xu, Sireesha Yalavarthi, Hong Zhang, Uma Mahesh Gundra, Clotilde Bourin, Laura Helming
Journal: Cancer Research (2024)

Abstract Background: M9657, a first-in-class tumor-targeted conditional immune agonist, was developed to boost antitumor immune responses in the tumor microenvironment (TME) by targeting CD137. The immune agonism potency of M9657 was validated through in vitro assays and in vivo efficacy studies in syngeneic tumor models using the surrogate antibody FS122m. Combining CD137 agonists and antiPD(L)-1 antibodies presents a novel therapeutic strategy to overcome immune checkpoint inhibitor (ICI) resistance and enhance antitumor activity via complementary mechanisms. Anti-PD-(L)-1 antibodies can reverse the suppressive immune signals, and CD137 agonists can boost T cell activation, improving antigen presentation and cytokine release. Methods: The antitumor immunity of M9657 + pembrolizumab (anti-PD-1 antibody) combination therapy was assessed using in-vitro luciferase and ex-vivo functional assays. In vivo antitumor efficacy was investigated with the M9657 surrogate (FS122m) and anti-mPD-1 in syngeneic tumor models expressing Mesothelin (MSLN). Results: The combination of M9657 and pembrolizumab displayed dose-dependent immune agonism potency and significantly enhanced tumor cell cytotoxicity and CD8+ T cell cytokine release relative to single agent treatments. In various syngeneic tumor models, the combination of FS122m with antimPD1 significantly increased antitumor efficacy relative to monotherapies, with more mice achieving complete tumor regression and prolonged median survival. Tumor-cured mice after combination treatment exhibited resistance to the primary tumor rechallenge, indicating the generation of tumor antigen-specific antitumor immunity and long-term immune protectivity. Conclusion: The combination of M9657 with anti-PD-(L)1 could overcome primary ICI therapy resistance and improve the antitumor efficacy of current anti-PD-(L)1 therapy in the clinic. Our findings support a combination strategy to combine M9657 with anti-PD-(L)1 in a clinical setting, potentially leading to enhanced antitumor immunity and improved patient outcomes. Future studies should investigate the safety and efficacy of this combination therapy in human patients. Sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) Citation Format: Chunxiao Xu, Sireesha Yalavarthi, Hong Zhang, Uma Mahesh Gundra, Clotilde Bourin, Laura Helming. M9657, a tumor-targeted anti-CD137 agonist, induced significant antitumor immunity in combination with anti-PD-1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5305.
mNFE: microbiome network flow entropy for detecting pre-disease states of type 1 diabetes
Authors: Rong Gao, Peiluan Li, Yueqiong Ni, Xueqing Peng, Jing Ren, Luonan Chen
Journal: Gut Microbes (2024)

In the development of Type 1 diabetes (T1D), there are critical states just before drastic changes, and identifying these pre-disease states may predict T1D or provide crucial early-warning signals. Unlike gene expression data, gut microbiome data can be collected noninvasively from stool samples. Gut microbiome sequencing data contain different levels of phylogenetic information that can be utilized to detect the tipping point or critical state in a reliable manner, thereby providing accurate and effective early-warning signals. However, it is still difficult to detect the critical state of T1D based on gut microbiome data due to generally non-significant differences between healthy and critical states. To address this problem, we proposed a new method - microbiome network flow entropy (mNFE) based on a single sample from each individual - for detecting the critical state before seroconversion and abrupt transitions of T1D at various taxonomic levels. The numerical simulation validated the robustness of mNFE under different noise levels. Furthermore, based on real datasets, mNFE successfully identified the critical states and their dynamic network biomarkers (DNBs) at different taxonomic levels. In addition, we found some high-frequency species, which are closely related to the unique clinical characteristics of autoantibodies at the four levels, and identified some non-differential 'dark species' play important roles during the T1D progression. mNFE can robustly and effectively detect the pre-disease states at various taxonomic levels and identify the corresponding DNBs with only a single sample for each individual. Therefore, our mNFE method provides a new approach not only for T1D pre-disease diagnosis or preventative treatment but also for preventative medicine of other diseases by gut microbiome.
Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation
Authors: Tao Liu, Siqi Liu, Xianliang Rui, Ye Cao, Julian Hecker, Feng Guo, Yihan Zhang, Lu Gong, Yihan Zhou, Yuzhen Yu, Nandini Krishnamoorthyni, Samuel Bates, Sung Chun, Nathan Boyer, Shuang Xu, Jin-Ah Park, Mark A. Perrella, Bruce D. Levy, Scott T. Weiss, Hongmei Mou, Benjamin A. Raby, Xiaobo Zhou
Journal: European Respiratory Journal (2024)

Rationale Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes ( ISGs ). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning ISG induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown. Objectives To decipher the functions of gasdermin B (encoded by GSDMB ) in respiratory virus-induced lung inflammation. Methods In two independent cohorts, we analysed expression correlation between GSDMB and ISG s . In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated GSDMB -overexpressing and GSDMB -deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISG induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of GSDMB in respiratory syncytial virus-induced lung inflammation in vivo . Results GSDMB is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB in mouse airway epithelium led to enhanced ISGs induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection. Conclusions GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.
N6‐methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer
Authors: Jiayao Wang, Jiehao Zhang, Hao Liu, Lingnan Meng, Xianchun Gao, Yihan Zhao, Chen Wang, Xiaoliang Gao, Ahui Fan, Tianyu Cao, Daiming Fan, Xiaodi Zhao, Yuanyuan Lu
Journal: Cancer Communications (2024)

Abstract Background Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6‐methyladenosine (m 6 A)‐binding protein involved in a variety of cancers. However, whether m 6 A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance. Methods The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry. Results Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug‐resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5‐fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m 6 A‐dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/β‐catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non‐responders compared with responders. Conclusion Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/β‐catenin pathway and exacerbate chemoresistance in GC.
Genetic regulation of carnitine metabolism controls lipid damage repair and aging RBC hemolysis in vivo and in vitro
Authors: Travis Nemkov, Alicia Key, Daniel Stephenson, Eric J. Earley, Gregory R. Keele, Ariel Hay, Pascal Amireault, Madeleine Casimir, Michaël Dussiot, Monika Dzieciatkowska, Julie A. Reisz, Xutao Deng, Mars Stone, Steve Kleinman, Steven L. Spitalnik, Kirk C. Hansen, Philip J. Norris, Gary A. Churchill, Michael P. Busch, Nareg Roubinian, Grier P. Page, James C. Zimring, Arduino Arduini, Angelo D’Alessandro
Journal: Blood (2024)
Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043 patient/years analysis
Authors: Carmelo Gurnari, Hussein Awada, Simona Pagliuca, Danai Dima, Fauzia Ullah, Naomi Kawashima, Yasuo Kubota, Ceylan Colak, Valeria Visconte, Bhumika J. Patel, Vikram Dhillon, Naimisha Marneni, Suresh Kumar Balasubramanian, Ashwin Kishtagari, Taha Bat, Jaroslaw P. Maciejewski
Journal: Blood (2024)
Landscape of driver mutations and their clinical effects on Down syndrome–related myeloid neoplasms
Authors: Tomohiko Sato, Kenichi Yoshida, Tsutomu Toki, Rika Kanezaki, Kiminori Terui, Ryunosuke Saiki, Masami Ojima, Yotaro Ochi, Seiya Mizuno, Masaharu Yoshihara, Tamayo Uechi, Naoya Kenmochi, Shiro Tanaka, Jun Matsubayashi, Kenta Kisai, Ko Kudo, Kentaro Yuzawa, Yuka Takahashi, Tatsuhiko Tanaka, Yohei Yamamoto, Akie Kobayashi, Takuya Kamio, Shinya Sasaki, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Hideki Muramatsu, Asahito Hama, Daisuke Hasegawa, Atsushi Sato, Katsuyoshi Koh, Shuhei Karakawa, Masao Kobayashi, Junichi Hara, Yuichi Taneyama, Chihaya Imai, Daiichiro Hasegawa, Naoto Fujita, Masahiro Yoshitomi, Shotaro Iwamoto, Genki Yamato, Satoshi Saida, Nobutaka Kiyokawa, Takao Deguchi, Masafumi Ito, Hidemasa Matsuo, Souichi Adachi, Yasuhide Hayashi, Takashi Taga, Akiko M. Saito, Keizo Horibe, Kenichiro Watanabe, Daisuke Tomizawa, Satoru Miyano, Satoru Takahashi, Seishi Ogawa, Etsuro Ito
Journal: Blood (2024)
The Global Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among Patients With Type 2 Diabetes
Authors: Zobair M. Younossi, Pegah Golabi, Jillian Kallman Price, Soroor Owrangi, Nagashree Gundu-Rao, Romona Satchi, James M. Paik
Journal: Clinical Gastroenterology and Hepatology (2024)
Sex differences in sleep, circadian rhythms, and metabolism: Implications for precision medicine
Authors: Renske Lok, Jingyi Qian, Sarah L. Chellappa
Journal: Sleep Medicine Reviews (2024)

The number of individuals experiencing sleep loss has exponentially risen over the past decades. Extrapolation of laboratory findings to the real world suggests that females are more affected by extended wakefulness and circadian misalignment than males are. Therefore, long-term effects such as sleep and metabolism disorders are likely to be more prevalent in females than in males. Despite emerging evidence for sex differences in key aspects of sleep-wake and circadian regulation, much remains unknown, as females are often underrepresented in sleep and circadian research. This brief communication is intended to highlight 1) how sex differences systematically impinge on the sleep-wake and circadian regulation in humans, 2) how sex differences in sleep and circadian factors modulate metabolism, and 3) the meaning of these differences for precision medicine. Ultimately, the findings justify factoring in sex differences when optimizing individually targeted sleep and circadian interventions in humans.
An analysis of multidrug multicomponent crystals as tools for drug development
Authors: Oisín N. Kavanagh
Journal: Journal of Controlled Release (2024)

In a typical tablet or capsule formulation, the active drug is often present as a crystalline solid. This solid emerges from the relationships between the individual atoms within the crystal, which confer a distinct set of physical properties. Then, it follows that if we modify the packing arrangement of the individual molecules within these crystals, we can modulate their properties. This can be achieved by crystal engineering. Crystal engineering has also seen teams arrange multiple drug molecules within the same crystal, resulting in dramatic improvements to drug properties in the lab. The success of drugs like SEGLENTIS® and Entresto® have revitalised interest in these forms, but controversy surrounding their translation has prompted this reconsideration of their clinical utility. I reflect on the current academic, clinical, and commercial interest in multidrug multicomponent crystals, drawing parallels with developments pre-Bragg, contributing to a nuanced understanding of the potential and limitations of crystal engineering in pharmaceutical applications.
Antimicrobial sensitisers: Gatekeepers to avoid the development of multidrug-resistant bacteria
Authors: Hanfei Wang, Yingying Yang, Simeng Wang, Sara Badawy, Irma Ares, Marta Martínez, Bernardo Lopez-Torres, María-Rosa Martínez-Larrañaga, Xu Wang, Arturo Anadón, María-Aránzazu Martínez
Journal: Journal of Controlled Release (2024)

The resistance of multidrug-resistant bacteria to existing antibiotics forces the continued development of new antibiotics and antibacterial agents, but the high costs and long timeframe involved in the development of new agents renders the hope that existing antibiotics may again play a part. The "antibiotic adjuvant" is an indirect antibacterial strategy, but its vague concept has, in the past, limited the development speed of related drugs. In this review article, we put forward an accurate concept of a "non-self-antimicrobial sensitisers (NSAS)", to distinguish it from an "antibiotic adjuvant", and then discuss several scientific methods to restore bacterial sensitivity to antibiotics, and the sources and action mechanism of existing NSAS, in order to guide the development and further research of NSAS.
Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse
Authors: Mengnuo Chen, Sara Mainardi, Cor Lieftink, Arno Velds, Iris de Rink, Chen Yang, Hendrik J. Kuiken, Ben Morris, Finn Edwards, Fleur Jochems, Olaf van Tellingen, Manon Boeije, Natalie Proost, Robin A. Jansen, Shifan Qin, Haojie Jin, J.C. Koen van der Mijn, Arnout Schepers, Subramanian Venkatesan, Wenxin Qin, Roderick L. Beijersbergen, Liqin Wang, René Bernards
Journal: Cell Reports Medicine (2024)

Drug-tolerant persisters (DTPs) are a rare subpopulation of cells within a tumor that can survive therapy through nongenetic adaptive mechanisms to develop relapse and repopulate the tumor following drug withdrawal. Using a cancer cell line with an engineered suicide switch to kill proliferating cells, we perform both genetic screens and compound screens to identify the inhibition of bromodomain and extraterminal domain (BET) proteins as a selective vulnerability of DTPs. BET inhibitors are especially detrimental to DTPs that have reentered the cell cycle (DTEPs) in a broad spectrum of cancer types. Mechanistically, BET inhibition induces lethal levels of ROS through the suppression of redox-regulating genes highly expressed in DTPs, including GPX2, ALDH3A1, and MGST1. In vivo BET inhibitor treatment delays tumor relapse in both melanoma and lung cancer. Our study suggests that combining standard of care therapy with BET inhibitors to eliminate residual persister cells is a promising therapeutic strategy.
Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation
Authors: Weize Zhu, Ying Hong, Zhaowei Tong, Xiaofang He, Yan Li, Hao Wang, Xinxin Gao, Pengtao Song, Xianshan Zhang, Xiaochang Wu, Zhenhua Tan, Wenjin Huang, Zekun Liu, Yiyang Bao, Junli Ma, Ningning Zheng, Cen Xie, Xisong Ke, Wen Zhou, Wei Jia, Mingxiao Li, Jing Zhong, Lili Sheng, Houkai Li
Journal: Cell Reports Medicine (2024)

Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy.
KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial
Authors: Yuanyuan Zhao, Gang Chen, Xingya Li, Jingxun Wu, Baoping Chang, Sheng Hu, Shujun Yang, Ting Xu, Yilan Liu, Ni Wang, Li Zhang, Yan Huang
Journal: Cell Reports Medicine (2024)

KN046, a bispecific antibody targeting PD-L1 and CTLA-4, presents a promising therapeutic option for metastatic non-small cell lung cancer (NSCLC). In this multicenter phase 2 trial, patients with nonsquamous (non-sq) NSCLC receive pemetrexed, whereas those with sq-NSCLC receive paclitaxel, plus KN046 and carboplatin. Following four cycles, maintenance therapy includes KN046 with pemetrexed for non-sq-NSCLC and KN046 for sq-NSCLC. The objective response rate is 46.0%, and the median duration of response is 8.1 months. The median progression-free and overall survival are 5.8 and 26.6 months, respectively. The common adverse events include anemia (87.4%), loss of appetite (72.4%), and neutropenia (70.1%). The most prevalent immune-related adverse event is pruritus (28.7%). These findings indicate that first-line treatment with KN046 and chemotherapy is effective and tolerable in metastatic NSCLC patients, warranting further investigation in a larger phase 3 trial. The trial is registered at ClinicalTrials.gov (NCT04054531).
SARS-CoV-2 BA.1 and BA.2 breakthrough infections boost antibody responses to early Omicron subvariants but not BQ.1.1 or XBB.1.5
Authors: Anass Abbad, Temima Yellin, Gagandeep Singh, Miriam Fried, Ariel Raskin, Johnstone Tcheou, Brian Monahan, Charles Gleason, Dalles Andre, Maria C. Bermúdez-González, Dominika Bielak, Gianna Cai, Christian Cognigni, Yuexing Chen, Hyun Min Kang, Giulio Kleiner, Neko Lyttle, Jacob Mauldin, Sara Morris, Jessica Nardulli, Annika Oostenink, Ashley-Beathrese Salimbangon, Komal Srivastava, Leeba Sullivan, Morgan Van Kesteren, Viviana Simon, Juan Manuel Carreño, Florian Krammer
Journal: Cell Reports Medicine (2024)

Subvariants of the Omicron lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) efficiently escape neutralizing antibody responses induced by both vaccination and infection with antigenically distinct variants. Here, we describe the potency and breadth of neutralizing and binding antibody responses against a large panel of variants following an Omicron BA.1 or BA.2 breakthrough infection in a heterogeneous cohort of individuals with diverse exposure histories. Both BA.1 and BA.2 breakthrough infections significantly boost antibody levels and broaden antibody reactivity. However, this broader immunity induced by BA.1 and BA.2 breakthrough infections does not neutralize Omicron BQ and XBB subvariants efficiently. While these subvariants are not neutralized well by post-breakthrough sera, suggesting escape, binding non-neutralizing antibody responses are sustained. In summary, our data suggest that while BA.1 and BA.2 breakthrough infections broaden the immune response to SARS-CoV-2 spike, the induced neutralizing antibody response is still outpaced by viral evolution.
STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma
Authors: Nicole Prutsch, Shuning He, Alla Berezovskaya, Adam D. Durbin, Neekesh V. Dharia, Kelsey A. Maher, Jamie D. Matthews, Lucy Hare, Suzanne D. Turner, Kimberly Stegmaier, Lukas Kenner, Olaf Merkel, A. Thomas Look, Brian J. Abraham, Mark W. Zimmerman
Journal: Cell Reports Medicine (2024)

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.
Federated machine learning in healthcare: A systematic review on clinical applications and technical architecture
Authors: Zhen Ling Teo, Liyuan Jin, Nan Liu, Siqi Li, Di Miao, Xiaoman Zhang, Wei Yan Ng, Ting Fang Tan, Deborah Meixuan Lee, Kai Jie Chua, John Heng, Yong Liu, Rick Siow Mong Goh, Daniel Shu Wei Ting
Journal: Cell Reports Medicine (2024)