tbuckley/cabot-search huggingface dataset:
Impact of pembrolizumab treatment duration on overall survival and prognostic factors in advanced non-small cell lung cancer: a nationwide retrospective cohort study
Authors: Adrien Rousseau, Stefan Michiels, Noémie Simon-Tillaux, Alexandre Lolivier, Julia Bonastre, David Planchard, Fabrice Barlesi, Jordi Remon, Pernelle Lavaud, Mihaela Aldea, Maxime Frelaut, Cecile Le Pechoux, Angela Botticella, Antonin Levy, Anas Gazzah, Stephanie Foulon, Benjamin Besse
Journal: The Lancet Regional Health - Europe (2024)

The efficacy of front-line pembrolizumab has been established in studies that limit treatment duration to 2 years, but decision to stop pembrolizumab after 2 years is often at physician's discretion. ATHENA is a retrospective cohort study using a comprehensive administrative database aimed firstly at exploring the optimal duration of pembrolizumab and secondly real-life prognosis factors in patients with advanced non-small cell lung cancer (NSCLC). Using the French National Health Insurance database (SNDS), we identified patients with incident lung cancer in France from 2015 to 2022. Treatments and patients' characteristics were extracted or inferred from hospital, outpatient care, pharmacy delivery reports. The duration's hazard ratio (HR) was estimated with Cox model weighted by inverse of propensity score to account for confounding. Prognostics factors in first line population were identified with Cox model selected by a LASSO procedure. 391,106 patients with lung cancer were identified, of whom 43,359 received up-front pembrolizumab for an advanced disease. There were 67% (29,040/43,359) of male and the median age at diagnosis was 65 years old. After a median follow-up time of 25.9 months (min-max, [0-97.6]), the median overall survival (OS) after pembrolizumab initiation in first line was 15.7 [CI 95, 15.3-16.0] months. In multivariable analysis, several covariables were independently associated with worse OS, including male sex with chemo-immunotherapy, age, hospital category, high deprivation index, inpatient hospitalization for first pembrolizumab, and history of diabetes, diuretic, beta blocker, painkiller prescription. At landmark time of 29 months after pembrolizumab initiation, continuation beyond 2 years was not associated with better OS than a fixed 2-year treatment, HR = 0.97 [0.75-1.26] p = 0.95. This study supports the notion that stopping pembrolizumab after 2 years could be safe for patients with advanced NSCLC. However, because observational studies are prone to confounding and selection bias, causality cannot be affirmed. This study did not receive any specific grant.
Beyond ribosomal function: RPS6 deficiency suppresses cholangiocarcinoma cell growth by disrupting alternative splicing
Authors: Wenkang Fu, Yanyan Lin, Mingzhen Bai, Jia Yao, Chongfei Huang, Long Gao, Ningning Mi, Haidong Ma, Liang Tian, Ping Yue, Yong Zhang, Jinduo zhang, Yanxian Ren, Liyun Ding, Lunzhi Dai, Joseph W. Leung, Jinqiu Yuan, Wenhua Zhang, Wenbo Meng
Journal: Acta Pharmaceutica Sinica B (2024)

Cholangiocarcinoma (CCA) is a bile duct malignancy with a dismal prognosis. This study systematically investigated the role of the ribosomal protein S6 (
Integration of STING activation and COX-2 inhibition via steric-hindrance effect tuned nanoreactors for cancer chemoimmunotherapy
Authors: Pengfei Zhang, Di Zhong, Yongbo Yu, Lupeng Wang, Yifan Li, Ye Liang, Yanfeng Shi, Meilin Duan, Bing Li, Haitao Niu, Yuanhong Xu
Journal: Biomaterials (2024)
Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer
Authors: A Di Federico, S L Alden, J W Smithy, B Ricciuti, J V Alessi, X Wang, F Pecci, G Lamberti, M M Gandhi, V R Vaz, L F Spurr, L M Sholl, K L Pfaff, S J Rodig, Y Y Li, A D Cherniack, M Nishino, B E Johnson, M M Awad
Journal: Annals of Oncology (2024)
The immune and metabolic milieu of the choroid plexus as a potential target in brain protection
Authors: Afroditi Tsitsou-Kampeli, Stefano Suzzi, Michal Schwartz
Journal: Trends in Neurosciences (2024)

The brain's choroid plexus (CP), which operates as an anatomical and functional 'checkpoint', regulates the communication between brain and periphery and contributes to the maintenance of healthy brain homeostasis throughout life. Evidence from mouse models and humans reveals a link between loss of CP checkpoint properties and dysregulation of the CP immune milieu as a conserved feature across diverse neurological conditions. In particular, we suggest that an imbalance between different immune signals at the CP, including CD4
Publications in the <i>BJD</i>: the impact of being read (and cited)
Authors: John A McGrath
Journal: British Journal of Dermatology (2024)

Abstract The BJD prides itself on the quality and breadth of its content. Our current publications span the Journal’s key domains of translational research, clinical trials, epidemiology, global health, evidence-based dermatology, and outcomes and qualitative research, with the editorial aim of publishing the best clinically relevant science, advances in dermatology and items of clinical or practical value and interest to dermatologists and other colleagues working in related disciplines.
Microbial Metabolites and Gut Immunology
Authors: Tadashi Takeuchi, Yumiko Nakanishi, Hiroshi Ohno
Journal: Annual Review of Immunology (2024)

The intestine is the largest peripheral lymphoid organ in animals, including humans, and interacts with a vast array of microorganisms called the gut microbiota. Comprehending the symbiotic relationship between the gut microbiota and our immune system is essential not only for the field of immunology but also for understanding the pathogenesis of various systemic diseases, including cancer, cardiometabolic disorders, and extraintestinal autoimmune conditions. Whereas microbe-derived antigens are crucial for activating the intestinal immune system, particularly T and B cells, as environmental cues, microbes and their metabolites play a critical role in directing the differentiation of these immune cells. Microbial metabolites are regarded as messengers from the gut microbiota, since bacteria have the ability to produce unique molecules that humans cannot, and many immune cells in the intestine express receptors for these molecules. This review highlights the distinct relationships between microbial metabolites and the differentiation and function of the immune system.
The Multifaceted Role of Tissue-Resident Memory T Cells
Authors: Susan N. Christo, Simone L. Park, Scott N. Mueller, Laura K. Mackay
Journal: Annual Review of Immunology (2024)

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell–mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain.
Poxvirus Immune Evasion
Authors: Bruno Hernaez, Antonio Alcamí
Journal: Annual Review of Immunology (2024)

Poxviruses have evolved a wide array of mechanisms to evade the immune response, and we provide an overview of the different immunomodulatory strategies. Poxviruses prevent the recognition of viral DNA that triggers the immune responses and inhibit signaling pathways within the infected cell. A unique feature of poxviruses is the production of secreted proteins that mimic cytokines and cytokine receptors, acting as decoy receptors to neutralize the activity of cytokines and chemokines. The capacity of these proteins to evade cellular immune responses by inhibiting cytokine activation is complemented by poxviruses' strategies to block natural killer cells and cytotoxic T cells, often through interfering with antigen presentation pathways. Mechanisms that target complement activation are also encoded by poxviruses. Virus-encoded proteins that target immune molecules and pathways play a major role in immune modulation, and their contribution to viral pathogenesis, facilitating virus replication or preventing immunopathology, is discussed.
Ovarian microenvironment: challenges and opportunities in protecting against chemotherapy-associated ovarian damage
Authors: Yican Guo, Liru Xue, Weicheng Tang, Jiaqiang Xiong, Dan Chen, Yun Dai, Chuqing Wu, Simin Wei, Jun Dai, Meng Wu, Shixuan Wang
Journal: Human Reproduction Update (2024)

Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy.
Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19
Authors: R.K. Subbarao Malireddi, Bhesh Raj Sharma, Thirumala-Devi Kanneganti
Journal: Annual Review of Immunology (2024)

The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.
Neuroimmune Interactions in the Intestine
Authors: Antonia Wallrapp, Isaac M. Chiu
Journal: Annual Review of Immunology (2024)

Recent advances have contributed to a mechanistic understanding of neuroimmune interactions in the intestine and revealed an essential role of this cross talk for gut homeostasis and modulation of inflammatory and infectious intestinal diseases. In this review, we describe the innervation of the intestine by intrinsic and extrinsic neurons and then focus on the bidirectional communication between neurons and immune cells. First, we highlight the contribution of neuronal subtypes to the development of colitis and discuss the different immune and epithelial cell types that are regulated by neurons via the release of neuropeptides and neurotransmitters. Next, we review the role of intestinal inflammation in the development of visceral hypersensitivity and summarize how inflammatory mediators induce peripheral and central sensitization of gut-innervating sensory neurons. Finally, we outline the importance of immune cells and gut microbiota for the survival and function of different neuronal populations at homeostasis and during bacterial and helminth infection.
Circadian Rhythms in Anticancer Immunity: Mechanisms and Treatment Opportunities
Authors: Robert Pick, Chen Wang, Qun Zeng, Zeynep Melis Gül, Christoph Scheiermann
Journal: Annual Review of Immunology (2024)

Circadian rhythms of approximately 24 h have emerged as important modulators of the immune system. These oscillations are important for mounting short-term, innate immune responses, but surprisingly also long-term, adaptive immune responses. Recent data indicate that they play a central role in antitumor immunity, in both mice and humans. In this review, we discuss the evolving literature on circadian antitumor immune responses and the underlying mechanisms that control them. We further provide an overview of circadian treatment regimens-chrono-immunotherapies-that harness time-of-day differences in immunity for optimal efficacy. Our aim is to provide an overview for researchers and clinicians alike, for a better understanding of the circadian immune system and how to best harness it for chronotherapeutic interventions. This knowledge is important for a better understanding of immune responses per se and could revolutionize the way we approach the treatment of cancer and a range of other diseases, ultimately improving clinical practice.
Ontogeny and Function of Plasmacytoid Dendritic Cells
Authors: Nicholas M. Adams, Annesa Das, Tae Jin Yun, Boris Reizis
Journal: Annual Review of Immunology (2024)

Plasmacytoid dendritic cells (pDCs) represent a unique cell type within the innate immune system. Their defining property is the recognition of pathogen-derived nucleic acids through endosomal Toll-like receptors and the ensuing production of type I interferon and other soluble mediators, which orchestrate innate and adaptive responses. We review several aspects of pDC biology that have recently come to the fore. We discuss emerging questions regarding the lineage affiliation and origin of pDCs and argue that these cells constitute an integral part of the dendritic cell lineage. We emphasize the specific function of pDCs as innate sentinels of virus infection, particularly their recognition of and distinct response to virus-infected cells. This essential evolutionary role of pDCs has been particularly important for the control of coronaviruses, as demonstrated by the recent COVID-19 pandemic. Finally, we highlight the key contribution of pDCs to systemic lupus erythematosus, in which therapeutic targeting of pDCs is currently underway.
Gut microbiota-mediated polyphenol metabolism is restrained by parasitic whipworm infection and associated with altered immune function in mice
Authors: Audrey Inge Schytz Andersen-Civil, Pankaj Arora, Ling Zhu, Laura J. Myhill, Nilay Büdeyri Gökgöz, Josue L. Castro-Mejia, Milla M. Leppä, Lars H. Hansen, Jacob Lessard-Lord, Juha-Pekka Salminen, Stig M. Thamsborg, Dennis Sandris Nielsen, Yves Desjardins, Andrew R. Williams
Journal: Gut Microbes (2024)

Polyphenols are phytochemicals commonly found in plant-based diets which have demonstrated immunomodulatory and anti-inflammatory properties. However, the interplay between polyphenols and pathogens at mucosal barrier surfaces has not yet been elucidated in detail. Here, we show that proanthocyanidin (PAC) polyphenols interact with gut parasites to influence immune function and gut microbial-derived metabolites in mice. PAC intake inhibited mastocytosis during infection with the small intestinal roundworm Heligmosomoides polygyrus, and altered the host tissue transcriptome at the site of infection with the large intestinal whipworm Trichuris muris, with a notable enhancement of type-1 inflammatory and interferon-driven gene pathways. In the absence of infection, PAC intake promoted the expansion of Turicibacter within the gut microbiota, increased fecal short chain fatty acids, and enriched phenolic metabolites such as phenyl-γ-valerolactones in the cecum. However, these putatively beneficial effects were reduced in PAC-fed mice infected with T. muris, suggesting concomitant parasite infection can attenuate gut microbial-mediated PAC catabolism. Collectively, our results suggest an inter-relationship between a phytonutrient and infection, whereby PAC may augment parasite-induced inflammation (most prominently with the cecum dwelling T. muris), and infection may abrogate the beneficial effects of health-promoting phytochemicals.
Intratumoral microbiome is associated with gastric cancer prognosis and therapy efficacy
Authors: Gangjian Wang, Haojie Wang, Xin Ji, Tong Wang, Ye Zhang, Wenjie Jiang, Lin Meng, Hua-Jun Wu, Xiaofang Xing, Jiafu Ji
Journal: Gut Microbes (2024)

The role of the intratumoral microbiome in gastric cancer (GC) has not been comprehensively assessed. Here, we explored the relationship between the microbial community and GC prognosis and therapy efficacy. Several cancer-associated microbial characteristics were identified, including increased α-diversity, differential β-diversity, and decreased
White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models
Authors: Liang Li, Brian J. Feldman
Journal: Journal of Clinical Investigation (2024)

Healthy adipose tissue is essential for normal physiology. There are 2 broad types of adipose tissue depots: brown adipose tissue (BAT), which contains adipocytes poised to burn energy through thermogenesis, and white adipose tissue (WAT), which contains adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell-specific properties that have important implications. For example, the subcutaneous and visceral WAT confers divergent risk for metabolic disease. Further, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood. Here, we found that the transcription factor KLF15 is required for maintaining white adipocyte properties selectively within the subcutaneous WAT. We revealed that deletion of Klf15 is sufficient to induce beige adipocyte properties and that KLF15's direct regulation of Adrb1 is a critical molecular mechanism for this process. We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells. Our results elucidate a pathway for depot-specific maintenance of white adipocyte properties that could enable the development of therapies for obesity and associated diseases.
NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy
Authors: Stephen P. Chelko, Vinay R. Penna, Morgan Engel, Emily A. Shiel, Ann M. Centner, Waleed Farra, Elisa N. Cannon, Maicon Landim-Vieira, Niccole Schaible, Kory Lavine, Jeffrey E. Saffitz
Journal: Journal of Clinical Investigation (2024)
Disordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders
Authors: Sulayman D. Dib-Hajj, Stephen G. Waxman
Journal: Journal of Clinical Investigation (2024)

Multiple approaches have targeted voltage-gated sodium (Nav) channels for analgesia. In this issue of the JCI, Shin et al. identified a peptide aptamer, NaViPA1, carrying a short polybasic motif flanked by serine residues in a structurally disordered region of loop 1 in tetrodotoxin-sensitive (TTX-S) but not tetrodotoxin-resistant (TTX-R) channels. NaViPA1h inhibited TTX-S NaV channels and attenuated excitability of sensory neurons. Delivery of NaViPA1 in vivo via adeno-associated virions restricted its expression to peripheral sensory neurons and induced analgesia in rats. Targeting of short linear motifs in this manner may provide a gene therapy modality, with minimal side effects due to its peripherally-restricted biodistribution, which opens up a therapeutic strategy for hyperexcitability disorders, including pain.
Hearts apart: sex differences in cardiac remodeling in health and disease
Authors: Thomas G. Martin, Leslie A. Leinwand
Journal: Journal of Clinical Investigation (2024)

Biological sex is an important modifier of physiology and influences pathobiology in many diseases. While heart disease is the number one cause of death worldwide in both men and women, sex differences exist at the organ and cellular scales, affecting clinical presentation, diagnosis, and treatment. In this Review, we highlight baseline sex differences in cardiac structure, function, and cellular signaling and discuss the contribution of sex hormones and chromosomes to these characteristics. The heart is a remarkably plastic organ and rapidly responds to physiological and pathological cues by modifying form and function. The nature and extent of cardiac remodeling in response to these stimuli are often dependent on biological sex. We discuss organ- and molecular-level sex differences in adaptive physiological remodeling and pathological cardiac remodeling from pressure and volume overload, ischemia, and genetic heart disease. Finally, we offer a perspective on key future directions for research into cardiac sex differences.
NK cell heparanase controls tumor invasion and immune surveillance
Authors: Eva M. Putz, Alyce J. Mayfosh, Kevin Kos, Deborah S. Barkauskas, Kyohei Nakamura, Liam Town, Katharine J. Goodall, Dean Y. Yee, Ivan K.H. Poon, Nikola Baschuk, Fernando Souza-Fonseca-Guimaraes, Mark D. Hulett, Mark J. Smyth
Journal: Journal of Clinical Investigation (2024)
A little ER stress isn’t bad: the IRE1α/XBP1 pathway shapes ILC3 functions during intestinal inflammation
Authors: Cinzia Fionda, Giuseppe Sciumè
Journal: Journal of Clinical Investigation (2024)

Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.
The other pandemic: lessons from 40 years of HIV research
Authors: Mary E. Klotman, Barton F. Haynes
Journal: Journal of Clinical Investigation (2024)

Since 1983, the JCI has consistently published papers that have contributed to much of today's understanding of the immunopathogenesis of HIV-1-host interactions.A representative subset of papers published in the JCI since the inception of the AIDS pandemic will be highlighted here.These reports have had a major impact on the understanding of pathogenesis and the clinical management of HIV-1 infection and have opened the door to current and future research, promising to better prevent, manage, and even cure HIV-1 infection.