tbuckley/cabot-search huggingface dataset:
Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts
Authors: Kojiro Suda, Yohsuke Moriyama, Nurhanani Razali, Yatzu Chiu, Yumiko Masukagami, Koutarou Nishimura, Hunter Barbee, Hiroshi Takase, Shinju Sugiyama, Yuta Yamazaki, Yoshikatsu Sato, Tetsuya Higashiyama, Yoshikazu Johmura, Makoto Nakanishi, Keiko Kono
Journal: Nature Aging (2024)

Plasma membrane damage (PMD) occurs in all cell types due to environmental perturbation and cell-autonomous activities. However, cellular outcomes of PMD remain largely unknown except for recovery or death. In this study, using budding yeast and normal human fibroblasts, we found that cellular senescence-stable cell cycle arrest contributing to organismal aging-is the long-term outcome of PMD. Our genetic screening using budding yeast unexpectedly identified a close genetic association between PMD response and replicative lifespan regulations. Furthermore, PMD limits replicative lifespan in budding yeast; upregulation of membrane repair factors ESCRT-III (SNF7) and AAA-ATPase (VPS4) extends it. In normal human fibroblasts, PMD induces premature senescence via the Ca
Cellular senescence: Neither irreversible nor reversible
Authors: Maurice Reimann, Soyoung Lee, Clemens A. Schmitt
Journal: The Journal of Experimental Medicine (2024)

Cellular senescence is a critical stress response program implicated in embryonic development, wound healing, aging, and immunity, and it backs up apoptosis as an ultimate cell-cycle exit mechanism. In analogy to replicative exhaustion of telomere-eroded cells, premature types of senescence—referring to oncogene-, therapy-, or virus-induced senescence—are widely considered irreversible growth arrest states as well. We discuss here that entry into full-featured senescence is not necessarily a permanent endpoint, but dependent on essential maintenance components, potentially transient. Unlike a binary state switch, we view senescence with its extensive epigenomic reorganization, profound cytomorphological remodeling, and distinctive metabolic rewiring rather as a journey toward a full-featured arrest condition of variable strength and depth. Senescence-underlying maintenance-essential molecular mechanisms may allow cell-cycle reentry if not continuously provided. Importantly, senescent cells that resumed proliferation fundamentally differ from those that never entered senescence, and hence would not reflect a reversion but a dynamic progression to a post-senescent state that comes with distinct functional and clinically relevant ramifications.
Reply to Behnam Shakiba’s Letter to the Editor re: Emilien Seizilles de Mazancourt, Juliette Cotte, Caroline Plassais, et al. Sexual and Moral Harassment of French Urologists in Training and Barriers to Reporting: Results from a National Survey. Eur Urol. 2024;85:e162–e163
Authors: Emilien Seizilles de Mazancourt, Kevin Kaulanjan
Journal: European Urology (2024)
Understanding the clinical implications of the “non-classical” microbiome in chronic lung disease: a viewpoint
Authors: Steven L. Taylor, Aurélie Crabbé, Luke R. Hoffman, James D. Chalmers, Geraint B. Rogers
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>Descriptive lung microbiome studies are not sufficient to contribute to clinical understanding. Research now requires systematic exploration to identify the contribution of non-classical bacteria to chronic lung disease.</b>https://bit.ly/3UbgVCs
Unravelling the “frequent exacerbator” phenotype in cystic fibrosis
Authors: Raya Cohen, Michal Shteinberg
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>Exacerbation frequency among people with CF is correlated to an abnormal inflammatory/anti-inflammatory activity balance, and is evident in stable state as well as during pulmonary exacerbations</b> https://bit.ly/3Hqzyuw
Dyspnoea in acutely ill mechanically ventilated adult patients: an ERS/ESICM statement
Authors: Alexandre Demoule, Maxens Decavele, Massimo Antonelli, Luigi Camporota, Fekri Abroug, Dan Adler, Elie Azoulay, Metin Basoglu, Margaret Campbell, Giacomo Grasselli, Margaret Herridge, Miriam J. Johnson, Lionel Naccache, Paolo Navalesi, Paolo Pelosi, Richard Schwartzstein, Clare Williams, Wolfram Windisch, Leo Heunks, Thomas Similowski
Journal: European Respiratory Journal (2024)

This statement outlines a review of the literature and current practice concerning the prevalence, clinical significance, diagnosis and management of dyspnoea in critically ill, mechanically ventilated adult patients. It covers the definition, pathophysiology, epidemiology, short- and middle-term impact, detection and quantification, and prevention and treatment of dyspnoea. It represents a collaboration of the European Respiratory Society and the European Society of Intensive Care Medicine. Dyspnoea ranks among the most distressing experiences that human beings can endure. Approximately 40% of patients undergoing invasive mechanical ventilation in the intensive care unit (ICU) report dyspnoea, with an average intensity of 45 mm on a visual analogue scale from 0 to 100 mm. Although it shares many similarities with pain, dyspnoea can be far worse than pain in that it summons a primal fear response. As such, it merits universal and specific consideration. Dyspnoea must be identified, prevented and relieved in every patient. In the ICU, mechanically ventilated patients are at high risk of experiencing breathing difficulties because of their physiological status and, in some instances, because of mechanical ventilation itself. At the same time, mechanically ventilated patients have barriers to signalling their distress. Addressing this major clinical challenge mandates teaching and training, and involves ICU caregivers and patients. This is even more important because, as opposed to pain which has become a universal healthcare concern, very little attention has been paid to the identification and management of respiratory suffering in mechanically ventilated ICU patients.
Characterization of the generic mutant p53-rescue compounds in a broad range of assays
Authors: Shujun Xiao, Fangfang Shi, Huaxin Song, Jingyi Cui, Derun Zheng, Hesong Zhang, Kai Tan, Jiaqi Wu, Xueqin Chen, Jiale Wu, Yigang Tang, Yuting Dai, Min Lu
Journal: Cancer Cell (2024)
The synthetic future of algal genomes
Authors: Hugh D. Goold, Jeffrey L. Moseley, Kyle J. Lauersen
Journal: Cell Genomics (2024)

Algae are diverse organisms with significant biotechnological potential for resource circularity. Taking inspiration from fermentative microbes, engineering algal genomes holds promise to broadly expand their application ranges. Advances in genome sequencing with improvements in DNA synthesis and delivery techniques are enabling customized molecular tool development to confer advanced traits to algae. Efforts to redesign and rebuild entire genomes to create fit-for-purpose organisms currently being explored in heterotrophic prokaryotes and eukaryotic microbes could also be applied to photosynthetic algae. Future algal genome engineering will enhance yields of native products and permit the expression of complex biochemical pathways to produce novel metabolites from sustainable inputs. We present a historical perspective on advances in engineering algae, discuss the requisite genetic traits to enable algal genome optimization, take inspiration from whole-genome engineering efforts in other microbes for algal systems, and present candidate algal species in the context of these engineering goals.
Disruption of the Na+/K+-ATPase-purinergic P2X7 receptor complex in microglia promotes stress-induced anxiety
Authors: Songqiang Huang, Wanting Dong, Xiaoqian Lin, Kangtai Xu, Kun Li, Siping Xiong, Zilong Wang, Xiaowei Nie, Jin-Song Bian
Journal: Immunity (2024)
Mechanisms of sex differences in Alzheimer’s disease
Authors: Chloe Lopez-Lee, Eileen Ruth S. Torres, Gillian Carling, Li Gan
Journal: Neuron (2024)

Alzheimer's disease (AD) and the mechanisms underlying its etiology and progression are complex and multifactorial. The higher AD risk in women may serve as a clue to better understand these complicated processes. In this review, we examine aspects of AD that demonstrate sex-dependent effects and delve into the potential biological mechanisms responsible, compiling findings from advanced technologies such as single-cell RNA sequencing, metabolomics, and multi-omics analyses. We review evidence that sex hormones and sex chromosomes interact with various disease mechanisms during aging, encompassing inflammation, metabolism, and autophagy, leading to unique characteristics in disease progression between men and women.
SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase
Authors: Komal Srivastava, Juan Manuel Carreño, Charles Gleason, Brian Monahan, Gagandeep Singh, Anass Abbad, Johnstone Tcheou, Ariel Raskin, Giulio Kleiner, Harm van Bakel, Emilia Mia Sordillo, Florian Krammer, Viviana Simon, Hala Alshammary, Angela A. Amoako, Dalles Andre, Mahmoud Awawda, Maria C. Bermúdez-González, Katherine F. Beach, Dominika Bielak, Gianna Y. Cai, Rachel L. Chernet, Christian Cognigni, Yuexing Chen, Lily Q. Eaker, Emily D. Ferreri, Daniel L. Floda, Miriam Fried, Joshua Z. Hamburger, Denise Jurczyszak, Hyun Min Kang, Neko Lyttle, Julia C. Matthews, Jacob Mauldin, Wanni A. Mendez, Jacob Mischka, Sara Morris, Lubbertus C.F. Mulder, Ismail Nabeel, Jessica R. Nardulli, Jose Polanco, Annika Oostenink, Aria Rooker, Kayla T. Russo, Ashley-Beathrese Salimbangon, Miti S. Saksena, Amber A. Shin, Levy A. Sominsky, Daniel Stadlbauer, Leeba Sullivan, Morgan van Kesteren, Temima Yellin, Ania Wajnberg
Journal: Immunity (2024)

It is thought that mRNA-based vaccine-induced immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wanes quickly, based mostly on short-term studies. Here, we analyzed the kinetics and durability of the humoral responses to SARS-CoV-2 infection and vaccination using >8,000 longitudinal samples collected over a 3-year period in New York City. Upon primary immunization, participants with pre-existing immunity mounted higher antibody responses faster and achieved higher steady-state antibody titers than naive individuals. Antibody kinetics were characterized by two phases: an initial rapid decay, followed by a stabilization phase with very slow decay. Booster vaccination equalized the differences in antibody concentration between participants with and without hybrid immunity, but the peak antibody titers decreased with each successive antigen exposure. Breakthrough infections increased antibodies to similar titers as an additional vaccine dose in naive individuals. Our study provides strong evidence that SARS-CoV-2 antibody responses are long lasting, with initial waning followed by stabilization.
Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer
Authors: Xinyuan Tong, Ayushi S. Patel, Eejung Kim, Hongjun Li, Yueqing Chen, Shuai Li, Shengwu Liu, Julien Dilly, Kevin S. Kapner, Ningxia Zhang, Yun Xue, Laura Hover, Suman Mukhopadhyay, Fiona Sherman, Khrystyna Myndzar, Priyanka Sahu, Yijun Gao, Fei Li, Fuming Li, Zhaoyuan Fang, Yujuan Jin, Juntao Gao, Minglei Shi, Satrajit Sinha, Luonan Chen, Yang Chen, Thian Kheoh, Wenjing Yang, Itai Yanai, Andre L. Moreira, Vamsidhar Velcheti, Benjamin G. Neel, Liang Hu, James G. Christensen, Peter Olson, Dong Gao, Michael Q. Zhang, Andrew J. Aguirre, Kwok-Kin Wong, Hongbin Ji
Journal: Cancer Cell (2024)

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
Groundbreaking TIL Therapy OK’d for Melanoma
Authors: Alissa Poh
Journal: Cancer Discovery (2024)

After decades of research, the first tumor-infiltrating lymphocyte therapy was greenlighted by the FDA to treat patients with inoperable or metastatic melanoma—Iovance’s lifileucel (Amtagvi). The agency’s approval is not only the first for a cellular immunotherapy but also for a solid tumor.
Glucose Fuel Cells: Electricity from Blood Sugar
Authors: Robert G. Gloeb-McDonald, Gene Fridman
Journal: IEEE Reviews in Biomedical Engineering (2024)

Harvesting energy from the human body is an area of growing interest. While several techniques have been explored, the focus in the field is converging on using Glucose Fuel Cells (GFCs) that use glucose oxidation reactions at an anode and oxygen reduction reactions (ORRs) at a cathode to create a voltage gradient that can be stored as power. To facilitate these reactions, catalysts are immobilized at an anode and cathode that result in electrochemistry that typically produces two electrons, a water molecule, and gluconic acid. There are two competing classes of these catalysts: enzymes, which use organic proteins, and abiotic options, which use reactive metals. Enzymatic catalysts show better specificity towards glucose, whereas abiotic options show superior operational stability. The most advanced enzymatic test showed a maximum power density of 119 μW/cm
A Novel Human Interleukin‐23A Overexpressing Mouse Model of Systemic Lupus Erythematosus
Authors: Eleni Christodoulou‐Vafeiadou, Christina Geka, Lida Iliopoulou, Lydia Ntari, Maria C. Denis, Niki Karagianni, George Kollias
Journal: Arthritis & Rheumatology (2024)

Interleukin-23 (IL-23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases such as psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model overexpressing human IL-23A (TghIL-23A), providing a valuable tool for investigating the pathogenic role of human IL-23A and evaluating the efficacy of anti-human IL-23A therapeutics.
Animal Models of Human Diabetic Polyneuropathy—Reply
Authors: George L. King
Journal: JAMA (2003)

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Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation
Authors: Simran Pherwani, David Connolly, Qiuyu Sun, Qutuba G. Karwi, Michael Carr, Kim L. Ho, Cory S. Wagg, Liyan Zhang, Jody Levasseur, Heidi Silver, Jason R.B. Dyck, Gary D. Lopaschuk
Journal: Metabolism (2024)
Safety of the novel oral poliovirus vaccine type 2 (nOPV2) in infants and young children aged 1 to &lt;5 years and lot-to-lot consistency of the immune response to nOPV2 in infants in The Gambia: a phase 3, double-blind, randomised controlled trial
Authors: Magnus Ochoge, Ahmed Cherno Futa, Ama Umesi, Lucy Affleck, Larry Kotei, Baboucarr Daffeh, Ebrima Saidy-Jah, Anna Njie, Oluwafemi Oyadiran, Bassey Edem, Musa Jallow, Edrissa Jallow, Simon A Donkor, Erman Tritama, Talha Abid, Kathryn A V Jones, Bernardo A Mainou, John O Konz, Alan Fix, Chris Gast, Ed Clarke
Journal: The Lancet (2024)

Novel oral poliovirus vaccine type 2 (nOPV2) has been engineered to improve the genetic stability of Sabin oral poliovirus vaccine (OPV) and reduce the emergence of circulating vaccine-derived polioviruses. This trial aimed to provide key safety and immunogenicity data required for nOPV2 licensure and WHO prequalification.
First-line treatment with camrelizumab plus famitinib in advanced or metastatic NSCLC patients with PD-L1 TPS ≥1%: results from a multicenter, open-label, phase 2 trial
Authors: Shengxiang Ren, Xicheng Wang, Bao-Hui Han, Yueyin Pan, Jun Zhao, Yufeng Cheng, Sheng Hu, Tianshu Liu, Yalun Li, Ying Cheng, Jifeng Feng, Shanyong Yi, Shanzhi Gu, Shegan Gao, Yongzhong Luo, Ying Liu, Caigang Liu, Huijie Duan, Shuni Wang, Xinfeng Yang, Jia Fan, Caicun Zhou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. Methods Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. Results Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1–49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. Conclusion Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. Trial registration number NCT04346381 .
The biotherapeutic <i>Clostridium butyricum</i> MIYAIRI 588 strain potentiates enterotropism of Rorγt <sup>+</sup> Treg and PD-1 blockade efficacy
Authors: Thomas Paz Del Socorro, Kentaro Oka, Olivier Boulard, Motomichi Takahashi, Lionel Franz Poulin, Atsushi Hayashi, Mathias Chamaillard
Journal: Gut Microbes (2024)

Immune checkpoint inhibitors (ICI) have been positioned as a standard of care for patients with advanced non-small-cell lung carcinomas (NSCLC). A pilot clinical trial has reflected optimistic association between supplementation with Clostridium butyricum MIYAIRI 588 (CBM588) and ICI efficacy in NSCLC. However, it remains to be established whether this biotherapeutic strain may be sufficient to heighten the immunogenicity of the tumor draining lymph nodes to overcome resistance to ICI. Herein, we report that supplementation with CBM588 led to an improved responsiveness to antibody targeting programmed cell death protein 1 (aPD-1). This was statistically associated with a significant decrease in α-diversity of gut microbiota from CBM588-treated mice upon PD-1 blockade. At the level of the tumor-draining lymph node, such combination of treatment significantly lowered the frequency of microbiota-modulated subset of regulatory T cells that express Retinoic Orphan Receptor gamma t (Rorγt+ Treg). Specifically, this strongly immunosuppressive was negatively correlated with the abundance of bacteria that belong to the family of Ruminococcaceae. Accordingly, the colonic expression of both indoleamine 2,3-Dioxygenase 1 (IDO-1) and interleukin-10 (IL-10) were heightened in mice with greater PD-1 blockade efficacy. The CBM588-induced ability to secrete Interleukin-10 of lamina propria mononuclear cells was heightened in tumor bearers when compared with cancer-free mice. Conversely, blockade of interleukin-10 signaling preferentially enhanced the capacity of CD8+ T cells to secrete Interferon gamma when being cocultured with CBM588-primed lamina propria mononuclear cells of tumor-bearing mice. Our results demonstrate that CBM588-centered intervention can adequately improve intestinal homeostasis and efficiently overcome resistance to PD-1 blockade in mice.
Socioeconomic Deprivation and the Risk of Sight-Threatening Diabetic Retinopathy: A Population-Based Cohort Study in the U.K.
Authors: Luyuan Tan, Jingya Wang, Jieun Han, Christopher Sainsbury, Alastair K. Denniston, Francesca L. Crowe, Konstantinos A. Toulis, Muhammad Ali Karamat, Mi Yao, Krishnarajah Nirantharakumar
Journal: Diabetes Care (2024)

To evaluate the associations between socioeconomic deprivation and sight-threatening diabetic retinopathy (STDR) in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D).