tbuckley/cabot-search huggingface dataset:
B cells require DOCK8 to elicit and integrate T cell help when antigen is limiting
Authors: Mukta Deobagkar-Lele, Greg Crawford, Tanya L. Crockford, Jennifer Back, Rose Hodgson, Aneesha Bhandari, Katherine R. Bull, Richard J. Cornall
Journal: Science Immunology (2024)

Dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome is characterized by a failure of the germinal center response, a process involving the proliferation and positive selection of antigen-specific B cells. Here, we describe how DOCK8-deficient B cells are blocked at a light-zone checkpoint in the germinal centers of immunized mice, where they are unable to respond to T cell–dependent survival and selection signals and consequently differentiate into plasma cells or memory B cells. Although DOCK8-deficient B cells can acquire and present antigen to initiate activation of cognate T cells, integrin up-regulation, B cell–T cell conjugate formation, and costimulation are insufficient for sustained B cell and T cell activation when antigen availability is limited. Our findings provide an explanation for the failure of the humoral response in DOCK8 immunodeficiency syndrome and insight into how the level of available antigen modulates B cell–T cell cross-talk to fine-tune humoral immune responses and immunological memory.
Internal world models in humans, animals, and AI
Authors: Ilka Diester, Marlene Bartos, Joschka Bödecker, Adam Kortylewski, Christian Leibold, Johannes Letzkus, Matthew M. Nour, Monika Schönauer, Andrew Straw, Abhinav Valada, Andreas Vlachos, Thomas Brox
Journal: Neuron (2024)
Age-related patterns of microbial dysbiosis in multiplex inflammatory bowel disease families
Authors: Jonathan P Jacobs, Elizabeth A Spencer, Drew S Helmus, Julianne C Yang, Venu Lagishetty, Gerold Bongers, Graham Britton, Kyle Gettler, Pamela Reyes-Mercedes, Jianzhong Hu, Amy Hart, Esi Lamousé-Smith, Jan Wehkamp, Carol Landers, Philip Debbas, Joana Torres, Jean-Frederic Colombel, Judy Cho, Inga Peter, Jeremiah Faith, Jonathan Braun, Marla Dubinsky
Journal: Gut (2024)

IBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives).
Regenerative Role of Lrig1 + Cells in Kidney Repair
Authors: Yura Lee, Kwang H. Kim, Jihwan Park, Hyun Mi Kang, Sung-Hee Kim, Haengdueng Jeong, Buhyun Lee, Nakyum Lee, Yejin Cho, Gyeong Dae Kim, Seyoung Yu, Heon Yung Gee, Jinwoong Bok, Maxwell S. Hamilton, Leslie Gewin, Bruce J Aronow, Kyung-Min Lim, Robert J. Coffey, Ki Taek Nam
Journal: Journal of the American Society of Nephrology (2024)

Key Points Lrig1 + cells exist long term during kidney homeostasis and become activated upon injury, contributing to regeneration. Lrig1 + cells and their progeny emerge during tubulogenesis and contribute to proximal tubule and inner medullary collecting duct development. Lrig1 + cells expand and differentiate into a mature nephron lineage in response to AKI to repair the proximal tubule. Background In response to severe kidney injury, the kidney epithelium displays remarkable regenerative capabilities driven by adaptable resident epithelial cells. To date, it has been widely considered that the adult kidney lacks multipotent stem cells; thus, the cellular lineages responsible for repairing proximal tubule damage are incompletely understood. Leucine-rich repeats and immunoglobulin-like domain protein 1–expressing cells ( Lrig1 + cells) have been identified as a long-lived cell in various tissues that can induce epithelial tissue repair. Therefore, we hypothesized that Lrig1 + cells participate in kidney development and tissue regeneration. Methods We investigated the role of Lrig1 + cells in kidney injury using mouse models. The localization of Lrig1 + cells in the kidney was examined throughout mouse development. The function of Lrig1 + progeny cells in AKI repair was examined in vivo using a tamoxifen-inducible Lrig1 -specific Cre recombinase-based lineage tracing in three different kidney injury mouse models. In addition, we conducted single-cell RNA sequencing to characterize the transcriptional signature of Lrig1 + cells and trace their progeny. Results Lrig1 + cells were present during kidney development and contributed to formation of the proximal tubule and collecting duct structures in mature mouse kidneys. In three-dimensional culture, single Lrig1 + cells demonstrated long-lasting propagation and differentiated into the proximal tubule and collecting duct lineages. These Lrig1 + proximal tubule cells highly expressed progenitor-like and quiescence-related genes, giving rise to a novel cluster of cells with regenerative potential in adult kidneys. Moreover, these long-lived Lrig1 + cells expanded and repaired damaged proximal tubule in response to three types of AKIs in mice. Conclusions These findings highlight the critical role of Lrig1 + cells in kidney regeneration.
HER2 antibody-drug conjugates are active against desmoplastic small round cell tumor
Authors: Tom Zhang, Christopher A. Febres-Aldana, Zebing Liu, Jenna-Marie Dix, Ryan Cheng, Raymond G. Dematteo, Allan J.W. Lui, Inna Khodos, Leo Gili, Marissa S. Mattar, Jeanine Lisanti, Charlene Kwong, Irina Linkov, Murray J. Tipping, Elisa de Stanchina, Igor Odintsov, Marc Ladanyi, Romel Somwar
Journal: Clinical Cancer Research (2024)

Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target.
US Surgeon General Vivek Murthy: To Protect Adolescents, Social Media Needs Warning Labels
Authors: Jennifer Abbasi, Yulin Hswen
Journal: JAMA (2024)

This Medical News article is an interview with US Surgeon General Vivek Murthy, MD, MBA, and JAMA Editor in Chief Kirsten Bibbins-Domingo, PhD, MD, MAS, about his call for a warning label on social media platforms.
GLP-1 RA Drugs Not Associated With Increased Suicidal Thoughts
Authors: Samantha Anderer
Journal: JAMA (2024)

Given the past decade's dramatic increase in glucagon-like peptide-1 receptor agonist (GLP-1 RA) use among people with type 2 diabetes, clinicians have raised concerns about whether the drugs, which target reward areas in the brain, could lead to suicidal thoughts.
Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication
Authors: Jayaprakash Mandal, Tiffany Nicole Jones, Juliane Marie Liberto, Stephanie Gaillard, Tian-Li Wang, Ie-Ming Shih
Journal: Cancer Research (2024)

Targeting multiple signaling pathways has been proposed as a strategy to overcome resistance to single-pathway inhibition in cancer therapy. A previous study in epithelial ovarian cancers identified hyperactivity of spleen tyrosine kinase (SYK) and EGFR, which mutually phosphorylate and activate each other. Given the potential for pharmacologic inhibition of both kinases with clinically available agents, this study aimed to assess the antitumor efficacy of both pharmacologic and genetic SYK and EGFR coinhibition using a multifaceted approach. We assessed the coinactivation effects in chemoresistant ovarian cancer cell lines, patient-derived organoids, and xenograft models. Dual inhibition of SYK and EGFR in chemoresistant ovarian cancer cells elicited a synergistic antitumor effect. Notably, the combined inhibition activated the DNA damage response, induced G1 cell-cycle arrest, and promoted apoptosis. The phosphoproteomic analysis revealed that perturbation of SYK and EGFR signaling induced a significant reduction in both phosphorylated and total protein levels of cell division cycle 6, a crucial initiator of DNA replication. Together, this study provides preclinical evidence supporting dual inhibition of SYK and EGFR as a promising treatment for chemoresistant ovarian cancer by disrupting DNA synthesis and impairing formation of the prereplication complex. These findings warrant further clinical investigation to explore the potential of this combination therapy in overcoming drug resistance and improving patient outcomes. Significance: SYK and EGFR coinhibition exerts synergistic anticancer effects in chemoresistant ovarian cancer, providing a strategy to treat chemotherapy-resistant ovarian cancers using clinically available agents by targeting critical signaling pathways involved in DNA replication.
E-Cigarette Nicotine Delivery Among Young Adults by Nicotine Form, Concentration, and Flavor
Authors: Yoo Jin Cho, Toral Mehta, Alice Hinton, Ruth Sloan, Jean Nshimiyimana, Alayna P. Tackett, Megan E. Roberts, Marielle C. Brinkman, Theodore L. Wagener
Journal: JAMA Network Open (2024)

Concerns have been raised about the abuse liability of modern e-cigarettes that use acidic additives to form nicotine salts, making the inhalation of nicotine smoother than freebase nicotine.
Multiple faces of anxiety: a frontal lobe perspective
Authors: Angela C. Roberts, Kevin G. Mulvihill
Journal: Trends in Neurosciences (2024)

Marked dysregulation of the human prefrontal cortex (PFC) and anterior cingulate cortex (ACC) characterises a variety of anxiety disorders, and its amelioration is a key feature of treatment success. Overall treatment response, however, is highly variable, and about a third of patients are resistant to treatment. In this review we hypothesise that a major contributor to this variation in treatment response are the multiple faces of anxiety induced by distinct forms of frontal cortex dysregulation. Comparison of findings from humans and non-human primates reveals marked similarity in the functional organisation of threat regulation across the frontal lobes. This organisation is discussed in relation to the 'predatory imminence continuum' model of threat and the differential engagement of executive functions at the core of both emotion generation and regulation strategies.
An Immune‐Enhancing Injectable Hydrogel Loaded with Esketamine and DDP Promotes Painless Immunochemotherapy to Inhibit Breast Cancer Growth
Authors: Xiali Yin, Yaohua Ke, Ying Liang, Shuxian Zhang, Ziqi Chen, Lixia Yu, Ming Jiang, Qin Liu, Xiaoping Gu
Journal: Advanced Healthcare Materials (2024)

Abstract Chemotherapy is the cornerstone of triple‐negative breast cancer. The poor effectiveness and severe neuropathic pain caused by it have a significant impact on the immune system. Studies confirmed that immune cells in the tumor microenvironment (TME), have critical roles in tumor immune regulation and prognosis. In this study, it is revealed that the painless administration of Esketamine, combined with Cisplatin (DDP), can exert an anti‐tumor effect, which is further boosted by the hydrogel delivery system. It is also discovered that Esketamine combined with DDP co‐loaded in Poloxamer Hydrogel (PDEH) induces local immunity by increasing mature Dendritic Cells (mDCs) and activated T cells in PDEH group while the regulatory T cells (Tregs) known as CD4 + CD25 + FoxP3 + decreased significantly. Finally, , CD8 + and CD4 + T cells in the spleen exhibited a significant increase, suggesting a lasting immune impact of PDEH. This study proposes that Esketamine can serve as a painless immune modulator, enhancing an anti‐tumor effect while co‐loaded in poloxamer hydrogel with DDP. Along with improving immune cells in the microenvironment, it can potentially alleviate anxiety and depression. With its outstanding bio‐safety profile, it offers promising new possibilities for painless clinical therapy.
Environmental impact of single-use versus reusable gastroscopes
Authors: Mathieu Pioche, Heiko Pohl, João A Cunha Neves, Arthur Laporte, Mikael Mochet, Jérôme Rivory, Raphaelle Grau, Jérémie Jacques, Daniel Grinberg, Mathilde Boube, Robin Baddeley, Pierre-Jean Cottinet, Marion Schaefer, Enrique Rodríguez de Santiago, Arthur Berger
Journal: Gut (2024)

The environmental impact of endoscopy is a topic of growing interest. This study aimed to compare the carbon footprint of performing an esogastroduodenoscopy (EGD) with a reusable (RU) or with a single-use (SU) disposable gastroscope.
Structure and Function of Somatostatin and Its Receptors in Endocrinology
Authors: Bo Zhang, Li Xue, Zhe Bao Wu
Journal: Endocrine Reviews (2024)

Abstract Somatostatin analogs, such as octreotide, lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors. Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy combined with the protein structure prediction platform AlphaFold has been used to determine the 3-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the 3-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.
Exercise and nutrition to improve cancer Treatment-Related outcomes (ENICTO)
Authors: Kathryn H Schmitz, Justin C Brown, Melinda L Irwin, Kim Robien, Jessica M Scott, Nathan A Berger, Bette Caan, Andrea Cercek, Tracy E Crane, Scott R Evans, Jennifer A Ligibel, Jeffrey A Meyerhardt, Tanya Agurs-Collins, Karen Basen-Engquist, Jennifer W Bea, Sheng F Cai, Brenda Cartmel, Vernon M Chinchilli, Wendy Demark-Wahnefried, Christina M Dieli-Conwright, Loretta DiPietro, Shawna E Doerksen, Sharon L Edelstein, Joanne Elena, William Evans, Leah M Ferrucci, Julia Foldi, Sarah Freylersythe, Helena Furberg, Lee W Jones, Ross Levine, Chaya S Moskowitz, Cynthia Owusu, Frank Penedo, Borsika A Rabin, Elena Ratner, Margaret Rosenzweig, Talya Salz, Tara Sanft, Matthew Schlumbrecht, Guillaume Spielmann, Cynthia A Thomson, Ashley H Tjaden, Martin R Weiser, Shengping Yang, Anthony F Yu, Frank M Perna
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Chemotherapy treatment-related side-effects are common and increase the risk of suboptimal outcomes. Exercise interventions during cancer treatment improve self-reported physical functioning, fatigue, anxiety, and depression, but it is unclear whether these interventions improve important clinical outcomes, such as chemotherapy relative dose intensity (RDI). The National Cancer Institute funded the Exercise and Nutrition to Improve Cancer Treatment-Related Outcomes (ENICTO) Consortium, to address this knowledge gap. This paper describes the mechanisms hypothesized to underpin intervention effects on clinically-relevant treatment outcomes, briefly outlines each project’s distinct research aims, summarizes the scope and organizational structure of ENICTO, and provides an overview of the integrated common data elements used to pursue research questions collectively. In addition, the paper includes a description of consortium-wide activities and broader research community opportunities for collaborative research. Findings from the ENICTO Consortium have the potential to accelerate a paradigm shift in oncology care such that cancer patients could receive exercise and nutrition programming as the standard of care in tandem with chemotherapy to improve RDI for a curative outcome.
Impact of linked color imaging on the proximal adenoma miss rate: useful or not?
Authors: Naohisa Yoshida
Journal: Endoscopy (2024)

In this issue of Endoscopy, Karsenti et al. present an impressive randomized controlled trial investigating the impact of linked color imaging (LCI) on the proximal adenoma miss rate in a multicenter tandem setting [1]. The study examined whether LCI could detect more adenomas than white-light imaging (WLI) in the right-sided colon. The detection and resection of colorectal adenomas by colonoscopy is performed worldwide because it helps prevent colorectal cancer deaths. Routine colonoscopy is mainly performed under WLI. However, in a meta-analysis of 51 reports, the adenoma miss rate (AMR) of WLI was 26% (95%CI 23%–30%) [2].
Effect of indoor residual spraying on sandfly abundance and incidence of visceral leishmaniasis in India, 2016–22: an interrupted time-series analysis and modelling study
Authors: Luc E Coffeng, Sake J de Vlas, Rudra Pratap Singh, Ananthu James, Joy Bindroo, Niteen K Sharma, Asgar Ali, Chandramani Singh, Sadhana Sharma, Michael Coleman
Journal: The Lancet Infectious Diseases (2024)
Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial
Authors: Paul Kim, Ana M Sanchez, Taylor J R Penke, Hannah H Tuson, James C Kime, Robert W McKee, William L Slone, Nicholas R Conley, Lana J McMillan, Cameron J Prybol, Paul M Garofolo
Journal: The Lancet Infectious Diseases (2024)
The panzootic spread of highly pathogenic avian influenza H5N1 sublineage 2.3.4.4b: a critical appraisal of One Health preparedness and prevention
Authors: Marion P G Koopmans, Casey Barton Behravesh, Andrew A Cunningham, Wiku B Adisasmito, Salama Almuhairi, Pépé Bilivogui, Salome A Bukachi, Natalia Casas, Natalia Cediel Becerra, Dominique F Charron, Abhishek Chaudhary, Janice R Ciacci Zanella, Osman Dar, Nitish Debnath, Baptiste Dungu, Elmoubasher Farag, George F Gao, Margaret Khaitsa, Catherine Machalaba, John S Mackenzie, Wanda Markotter, Thomas C Mettenleiter, Serge Morand, Vyacheslav Smolenskiy, Lei Zhou, David T S Hayman
Journal: The Lancet Infectious Diseases (2024)
Adaptive radiotherapy (up to 74 Gy) or standard radiotherapy (66 Gy) for patients with stage III non-small-cell lung cancer, according to [18F]FDG-PET tumour residual uptake at 42 Gy (RTEP7–IFCT-1402): a multicentre, randomised, controlled phase 2 trial
Authors: Pierre Vera, Sébastien Thureau, Florence Le Tinier, Philippe Chaumet-Riffaud, Sébastien Hapdey, Hélène Kolesnikov-Gauthier, Etienne Martin, Alina Berriolo-Riedinger, Nicolas Pourel, Jean Marc Broglia, Pierre Boissellier, Sophie Guillemard, Naji Salem, Isabelle Brenot-Rossi, Cécile Le Péchoux, Céline Berthold, Etienne Giroux-Leprieur, Damien Moreau, Sophie Guillerm, Khadija Benali, Laurent Tessonnier, Clarisse Audigier-Valette, Delphine Lerouge, Elske Quak, Carole Massabeau, Frédéric Courbon, Patricia Moisson, Anne Larrouy, Romain Modzelewski, Pierrick Gouel, Nadia Ghazzar, Alexandra Langlais, Elodie Amour, Gérard Zalcman, Philippe Giraud
Journal: The Lancet Oncology (2024)
When I use a word . . . Utopias, dystopias, cacotopias, agathotopias, kalotopias, and the NHS
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

Sir Thomas More's "libellus vere aureus," his "golden little book," <i>Utopia</i>, introduced a word for a fictional place that was supposedly perfect, although such fictional places had been written about for hundreds of years before his book appeared in 1516. The name "Utopia" was a pun, coming as it might from Greek words for either "no place" or "goodly place" (οὔ τόπος or εὐ τόπος), a pun that More himself explicitly pointed out. Later, the term "dystopia" was coined as an antonym, in contrast to "eutopia" rather than "outopia." Then others suggested that "cacotopia" might be a better antonym. Later terms have included "agathotopia" and "kalotopia," respectively a good place and a beautiful place. Which, I wonder, should be applied to the NHS of today?
Cardiovascular Pharmacogenetics: From Discovery of Genetic Association to Clinical Adoption of Derived Test
Authors: Benoît Delabays, Katerina Trajanoska, Joshua Walonoski, Vincent Mooser
Journal: Pharmacological Reviews (2024)

Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies that investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies and the individual load of actionable PGx variants. Given the high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond. <h3>Significance Statement</h3> Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting PGx testing in the cardiovascular area is limited to a few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond.