tbuckley/cabot-search huggingface dataset:
DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma
Authors: Allison M. Kirk, Jeremy Chase Crawford, Ching-Heng Chou, Cliff Guy, Kirti Pandey, Tanya Kozlik, Ravi K. Shah, Shanzou Chung, Phuong Nguyen, Xiaoyu Zhang, Jin Wang, Matthew Bell, Robert C. Mettelman, E. Kaitlynn Allen, Mikhail V. Pogorelyy, Hyunjin Kim, Anastasia A. Minervina, Walid Awad, Resha Bajracharya, Toni White, Donald Long, Brittney Gordon, Michelle Morrison, Evan S. Glazer, Andrew J. Murphy, Yixing Jiang, Elizabeth A. Fitzpatrick, Mark Yarchoan, Praveen Sethupathy, Nathan P. Croft, Anthony W. Purcell, Sara M. Federico, Elizabeth Stewart, Stephen Gottschalk, Anthony E. Zamora, Christopher DeRenzo, Scott E. Strome, Paul G. Thomas
Journal: Cell Reports Medicine (2024)

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.
Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma
Authors: Ahmed Abu-Zaid, Jie Fang, Hongjian Jin, Shivendra Singh, Prahalathan Pichavaram, Qiong Wu, Heather Tillman, Laura Janke, Wojciech Rosikiewicz, Beisi Xu, Lee-Ann Van De Velde, Yian Guo, Yimei Li, Noha A.M. Shendy, Ian M. Delahunty, Zoran Rankovic, Taosheng Chen, Xiang Chen, Kevin W. Freeman, Mark E. Hatley, Adam D. Durbin, Peter J. Murray, Andrew J. Murphy, Paul G. Thomas, Andrew M. Davidoff, Jun Yang
Journal: Cell Reports Medicine (2024)

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.
Expression of a mutant CD47 protects against phagocytosis without inducing cell death or inhibiting angiogenesis
Authors: Lu Xu, Xiaodan Wang, Ting Zhang, Xiandi Meng, Wenjie Zhao, Chenchen Pi, Yong-Guang Yang
Journal: Cell Reports Medicine (2024)

CD47 is a ligand of SIRPα, an inhibitory receptor expressed by macrophages, dendritic cells, and natural killer (NK) cells, and, therefore, transgenic overexpression of CD47 is considered an effective approach to inhibiting transplant rejection. However, the detrimental effect of CD47 signaling is overlooked when exploring this approach. Here, we construct a mutant CD47 by replacing the transmembrane and intracellular domains with a membrane anchor (CD47-IgV). In both human and mouse cells, CD47-IgV is efficiently expressed on the cell surface and protects against phagocytosis in vitro and in vivo but does not induce cell death or inhibit angiogenesis. Furthermore, hematopoietic stem cells expressing transgenic CD47-IgV show no detectable alterations in engraftment or differentiation. This study provides a potentially effective means of achieving transgenic CD47 expression that may help to produce gene-edited pigs for xenotransplantation and hypoimmunogenic pluripotent stem cells for regenerative medicine.
Intervention with metabolites emulating endogenous cell transitions accelerates muscle regeneration in young and aged mice
Authors: Reyna Hernandez-Benitez, Chao Wang, Lei Shi, Yasuo Ouchi, Cuiqing Zhong, Tomoaki Hishida, Hsin-Kai Liao, Eric A. Magill, Sebastian Memczak, Rupa D. Soligalla, Chiara Fresia, Fumiyuki Hatanaka, Veronica Lamas, Isabel Guillen, Sanjeeb Sahu, Mako Yamamoto, Yanjiao Shao, Alain Aguirre-Vazquez, Estrella Nuñez Delicado, Pedro Guillen, Concepcion Rodriguez Esteban, Jing Qu, Pradeep Reddy, Steve Horvath, Guang-Hui Liu, Pierre Magistretti, Juan Carlos Izpisua Belmonte
Journal: Cell Reports Medicine (2024)

Tissue regeneration following an injury requires dynamic cell-state transitions that allow for establishing the cell identities required for the restoration of tissue homeostasis and function. Here, we present a biochemical intervention that induces an intermediate cell state mirroring a transition identified during normal differentiation of myoblasts and other multipotent and pluripotent cells to mature cells. When applied in somatic differentiated cells, the intervention, composed of one-carbon metabolites, reduces some dedifferentiation markers without losing the lineage identity, thus inducing limited reprogramming into a more flexible cell state. Moreover, the intervention enabled accelerated repair after muscle injury in young and aged mice. Overall, our study uncovers a conserved biochemical transitional phase that enhances cellular plasticity in vivo and hints at potential and scalable biochemical interventions of use in regenerative medicine and rejuvenation interventions that may be more tractable than genetic ones.
Characteristics and management of sclerosing skin diseases during immune checkpoint inhibitor therapy: An evidence-based review
Authors: Siddhartha Sood, Ahmed Bagit, Dana Taghaddos, Aliyah King, Khalad Maliyar, Muskaan Sachdeva, Asfandyar Mufti, Jensen Yeung
Journal: Journal of the American Academy of Dermatology (2024)
Executive Summary: From the Medical Board of the National Psoriasis Foundation: Perioperative management of immunomodulatory agents in patients with psoriasis and psoriatic arthritis
Authors: Warren A. James, Angela L. Rosenberg, Jashin J. Wu, Sylvia Hsu, April Armstrong, Elizabeth B. Wallace, Lara Wine Lee, Joseph Merola, Sergio Schwartzman, Dafna Gladman, Clive Liu, John Koo, Jason E. Hawkes, Soumya Reddy, Ron Prussick, Paul Yamauchi, Michael Lewitt, Jennifer Soung, Jeffery Weinberg, Mark Lebwohl, Brad Glick, Leon Kircik, Seemal Desai, Steven R. Feldman, Mallory L. Zaino
Journal: Journal of the American Academy of Dermatology (2024)
The Origin and Evolution of Sex Peptide and Sex Peptide Receptor Interactions
Authors: Junhui Peng, Nicolas Svetec, Henrik Molina, Li Zhao
Journal: Molecular Biology and Evolution (2024)

Post-mating responses play a vital role in successful reproduction across diverse species. In fruit flies, sex peptide binds to the sex peptide receptor, triggering a series of post-mating responses. However, the origin of sex peptide receptor predates the emergence of sex peptide. The evolutionary origins of the interactions between sex peptide and sex peptide receptor and the mechanisms by which they interact remain enigmatic. In this study, we used ancestral sequence reconstruction, AlphaFold2 predictions, and molecular dynamics simulations to study sex peptide-sex peptide receptor interactions and their origination. Using AlphaFold2 and long-time molecular dynamics simulations, we predicted the structure and dynamics of sex peptide-sex peptide receptor interactions. We show that sex peptide potentially binds to the ancestral states of Diptera sex peptide receptor. Notably, we found that only a few amino acid changes in sex peptide receptor are sufficient for the formation of sex peptide-sex peptide receptor interactions. Ancestral sequence reconstruction and molecular dynamics simulations further reveal that sex peptide receptor interacts with sex peptide through residues that are mostly involved in the interaction interface of an ancestral ligand, myoinhibitory peptides. We propose a potential mechanism whereby sex peptide-sex peptide receptor interactions arise from the preexisting myoinhibitory peptides-sex peptide receptor interface as well as early chance events both inside and outside the preexisting interface that created novel sex peptide-specific sex peptide-sex peptide receptor interactions. Our findings provide new insights into the origin and evolution of sex peptide-sex peptide receptor interactions and their relationship with myoinhibitory peptides-sex peptide receptor interactions.
Influence of angiotensin II on the gut microbiome: modest effects in comparison to experimental factors
Authors: Rikeish R Muralitharan, Michael E Nakai, Matthew Snelson, Tenghao Zheng, Evany Dinakis, Liang Xie, Hamdi Jama, Madeleine Paterson, Waled Shihata, Flavia Wassef, Antony Vinh, Grant R Drummond, David M Kaye, Charles R Mackay, Francine Z Marques
Journal: Cardiovascular Research (2024)

Abstract Aims Animal models are regularly used to test the role of the gut microbiome in hypertension. Small-scale pre-clinical studies have investigated changes to the gut microbiome in the angiotensin II hypertensive model. However, the gut microbiome is influenced by internal and external experimental factors, which are not regularly considered in the study design. Once these factors are accounted for, it is unclear if microbiome signatures are reproduceable. We aimed to determine the influence of angiotensin II treatment on the gut microbiome using a large and diverse cohort of mice and to quantify the magnitude by which other factors contribute to microbiome variations. Methods and results We conducted a retrospective study to establish a diverse mouse cohort resembling large human studies. We sequenced the V4 region of the 16S rRNA gene from 538 samples across the gastrointestinal tract of 303 male and female C57BL/6J mice randomized into sham or angiotensin II treatment from different genotypes, diets, animal facilities, and age groups. Analysing over 17 million sequencing reads, we observed that angiotensin II treatment influenced α-diversity (P = 0.0137) and β-diversity (i.e. composition of the microbiome, P &amp;lt; 0.001). Bacterial abundance analysis revealed patterns consistent with a reduction in short-chain fatty acid producers, microbial metabolites that lower blood pressure. Furthermore, animal facility, genotype, diet, age, sex, intestinal sampling site, and sequencing batch had significant effects on both α- and β-diversity (all P &amp;lt; 0.001). Sampling site (6.8%) and diet (6%) had the largest impact on the microbiome, while angiotensin II and sex had the smallest effect (each 0.4%). Conclusion Our large-scale data confirmed findings from small-scale studies that angiotensin II impacted the gut microbiome. However, this effect was modest relative to most of the other factors studied. Accounting for these factors in future pre-clinical hypertensive studies will increase the likelihood that microbiome findings are replicable and translatable.
The epidemiology, transmission, diagnosis, and management of drug-resistant tuberculosis—lessons from the South African experience
Authors: Kogieleum Naidoo, Rubeshan Perumal, Helen Cox, Barun Mathema, Marian Loveday, Nazir Ismail, Shaheed Vally Omar, Sophia B Georghiou, Amrita Daftary, Max O'Donnell, Norbert Ndjeka
Journal: The Lancet Infectious Diseases (2024)
A Global Tuberculosis Dictionary: unified terms and definitions for the field of tuberculosis
Authors: Alberto L Garcia-Basteiro, Joanna Ehrlich, Maryline Bonnet, Marianne Calnan, Stephen M Graham, Sabine Hermans, Adriana Jarrett, Rhoda Lewa, Anna Mandalakas, Leonardo Martinez, Giovanni Battista Migliori, Catherine W M Ong, Larissa Otero, Molebogeng Xheedha Rangaka, Mario C B Raviglione, Barbara Seaworth, Willy Ssengooba, Grant Theron, Anete Trajman, Marcel A Behr
Journal: The Lancet Global Health (2024)
Characteristics of anticancer activity of CBP/p300 inhibitors – Features of their classes, intracellular targets and future perspectives of their application in cancer treatment
Authors: Magdalena Strachowska, Agnieszka Robaszkiewicz
Journal: Pharmacology & Therapeutics (2024)

Due to the contribution of highly homologous acetyltransferases CBP and p300 to transcription elevation of oncogenes and other cancer promoting factors, these enzymes emerge as possible epigenetic targets of anticancer therapy. Extensive efforts in search for small molecule inhibitors led to development of compounds targeting histone acetyltransferase catalytic domain or chromatin-interacting bromodomain of CBP/p300, as well as dual BET and CBP/p300 inhibitors. The promising anticancer efficacy in in vitro and mice models led CCS1477 and NEO2734 to clinical trials. However, none of the described inhibitors is perfectly specific to CBP/p300 since they share similarity of a key functional domains with other enzymes, which are critically associated with cancer progression and their antagonists demonstrate remarkable clinical efficacy in cancer therapy. Therefore, we revise the possible and clinically relevant off-targets of CBP/p300 inhibitors that can be blocked simultaneously with CBP/p300 thereby improving the anticancer potential of CBP/p300 inhibitors and pharmacokinetic predicting data such as absorption, distribution, metabolism, excretion (ADME) and toxicity.
When I use a word . . . Naming medicines—mixtures and co-names
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

A medicine can have up to four types of names: Name 1—what the <i>medicine</i> is, as indicated by its full chemical name; Name 2—what the <i>medicine's name</i> is, i.e. its generic name, such as that assigned by the World Health Organization, its International Nonproprietary Name (INN); Name 3—what the <i>medicine's name is called</i>, i.e. any brand names assigned by a pharmaceutical company; Name 4—what the <i>medicine itself is called</i>, i.e. colloquial names given to it by the general public, such as street names for recreational drugs and drugs of abuse. The INN is the most important of these. It establishes for each individual medicine a single name that can be used and recognised globally. Each INN is constructed with, among other things, patient safety in mind. Mixtures of medicines in a single formulation are not given INNs. However, since 1971 in the UK 26 single names have been given to mixtures of drugs, usually two compounds, by combining the prefix co- with syllables taken from the drugs in the mixture. For example, co-amoxiclav contains a mixture of amoxicillin and clavulanic acid. This has sometimes led to serious prescribing errors, when, for example, co-amoxiclav was given to people with penicillin allergy. When using a formulation that is labelled with a co-name, prescribers should ensure that they know what the contents of the mixture are. Conversely, when the label on a package specifies the ingredients of a mixture by listing each name, but does not specify the co-name, it is important that prescribers know what the corresponding co-name was.
Correction: Clinical outcomes in a primary-level non-communicable disease programme for Syrian refugees and the host population in Jordan: A cohort analysis using routine data
Authors: Éimhín Ansbro, Tobias Homan, David Prieto Merino, Kiran Jobanputra, Jamil Qasem, Shoaib Muhammad, Taissir Fardous, Pablo Perel
Journal: PLoS Medicine (2024)

[This corrects the article DOI: 10.1371/journal.pmed.1003279.].
The IL-7R antagonist lusvertikimab reduces leukemic burden in xenograft ALL via antibody-dependent cellular phagocytosis
Authors: Lennart Lenk, Irène Baccelli, Anna Laqua, Julia Heymann, Claas Reimer, Anna Dietterle, Dorothee Winterberg, Caroline Mary, Frédérique Corallo, Julien Taurelle, Emma Narbeburu, Stéphanie Neyton, Mylène Déramé, Sabrina Pengam, Fotini Vogiatzi, Beat Bornhauser, Jean-Pierre Bourquin, Simon Raffel, Vladyslava Dovhan, Thomas Schüler, Gabriele Escherich, Monique L. den Boer, Judith M. Boer, Wiebke Wessels, Matthias Peipp, Julia Alten, Željko Antić, Anke K. Bergmann, Martin Schrappe, Gunnar Cario, Monika Brüggemann, Nicolas Poirier, Denis M. Schewe
Journal: Blood (2024)
Rectal Sparing Approach after preoperative Radio- and/or Chemo-therapy (ReSARCh): a prospective, multicenter, observational study
Authors: Gaya Spolverato, Quoc Riccardo Bao, Paolo Delrio, Mario Guerrieri, Monica Ortenzi, Nicola Cillara, Angelo Restivo, Simona Deidda, Antonino Spinelli, Carmela Romano, Francesco Bianco, Giacomo Sarzo, Emilio Morpurgo, Claudio Belluco, Elisa Palazzari, Giuditta Chiloiro, Elisa Meldolesi, Claudio Coco, Donato Paolo Pafundi, Cosimo Feleppa, Carlo Aschele, Michele Bonomo, Andrea Muratore, Alfredo Mellano, Germana Chiaulon, Filippo Crimì, Isacco Maretto, Alessandro Perin, Emanuele Damiano Luca Urso, Marco Scarpa, Mariasole Bigon, Federico Scognamiglio, Francesca Bergamo, Paola Del Bianco, Maria Antonietta Gambacorta, Daniela Rega, Salvatore Pucciarelli
Journal: International Journal of Surgery (2024)

Rectal-sparing approaches for patients with rectal cancer who achieved a complete or major response following neoadjuvant therapy constitute a paradigm of a potential shift in the management of patients with rectal cancer; however, their role remains controversial. The aim of this study was to investigate the feasibility of rectal-sparing approaches to preserve the rectum without impairing the outcomes.
Neoadjuvant immunotherapy based on PD-1/L1 inhibitors for gastrointestinal tumors: a review of the rationale and clinical advances
Authors: Dong-Xu Wang, Hui Liu, Jin-Cheng Tian, Dao-Lin Zhang, Lun-Jie Yan, Zi-Niu Ding, Han Li, Yu-Chuan Yan, Zhao-Ru Dong, Tao Li
Journal: International Journal of Surgery (2024)

The landscape of current tumor treatment has been revolutionized by the advent of immunotherapy based on PD-1/PD-L1 inhibitors. Leveraging its capacity to mobilize systemic anti-tumor immunity, which is primarily mediated by T cells, there is growing exploration and expansion of its potential value in various stages of clinical tumor treatment. Neoadjuvant immunotherapy induces a robust immune response against tumors prior to surgery, effectively facilitating tumor volume reduction, early eradication or suppression of tumor cell activity, and control of potential metastatic spread, to improve curative surgical resection rates and prevent tumor recurrence. This review delineates the theoretical basis of neoadjuvant immunotherapy from preclinical research evidence, discusses specific challenges in clinical application, and provides a comprehensive overview of clinical research progress in neoadjuvant immunotherapy for gastrointestinal tumors. These findings suggest that neoadjuvant immunotherapy has the potential to ameliorate immunosuppressive states and enhance cytotoxic T cell function while preserving lymphatic drainage in the preoperative period. However, further investigations are needed on specific treatment regimens, suitable patient populations, and measurable endpoints. Despite numerous studies demonstrating the promising efficacy and manageable adverse events of neoadjuvant immunotherapy in gastrointestinal tumors, the availability of high-quality randomized controlled trials is limited, which highlights the necessity for further research.
Could nerve transplantation be the future of this field: a bibliometric analysis about lumbosacral plexus injury
Authors: Sheng Wang, Demeng Xia, Danyan Song, Nan Lu, Aimin Chen
Journal: International Journal of Surgery (2024)

Background: Lumbosacral plexus injury is a highly distressing clinical issue with profound implications for patients’ quality of life. Since the publication of the first relevant study in 1953, there has been very limited progress in basic research and clinical treatment in this field, and the developmental trajectory and research priorities in this field have not been systematically summarized using scientific methods, leaving the future direction of this research to be explored. Methods: Utilizing publications from the Web of Science (WoS) database, our research employed bibliometric methodology to analyze the fundamental components of publications, synthesize research trends, and forecast future directions. Results: A total of 150 publications were included in our study, and the impressive advancement of research heat in this field can be attributed to the continuous increase in the number of papers, ranging from 14 papers in 2000 to 34 papers in 2023 over five years. Regarding the country, a central position in both quantity (H-index=125) and quality of publications (65 publications) is occupied by the United States, and close collaborations with other countries are observed. In terms of publication institutions, the highest number of publications (9 publications) is held by the Second Military Medical University. The journal with the most publications (5 publications) is the Journal of Trauma-Injury Infection and Critical Care. A pivotal role has been played by basic medical research in the development of this field. Concerning hotspots, the focus of the research core can be divided into three clusters (etiology, diagnosis and treatment; molecular, cells and mechanisms; physiology and pathology). Conclusion: This marks the inaugural bibliometric analysis of lumbosacral plexus injuries, offering a comprehensive overview of current publications. Our findings illuminate future research directions, international collaborations, and interdisciplinary relationships. Future research will emphasize clinical treatment and mechanism research, with a focus on sacral nerve stimulation and nerve transplantation.