tbuckley/cabot-search huggingface dataset:
Multiple-wave admixture and adaptive evolution of the Pamirian Wakhi people
Authors: Wanxing Xu, Jiaojiao Liu, Xiaoxi Zhang, Jia Wen, Qidi Feng, Yang Gao, Yuwen Pan, Yan Lu, Asifullah Khan, Shuhua Xu
Journal: Molecular Biology and Evolution (2024)

While whole-genome sequencing has been applied extensively to investigate the genetic diversity of global populations, ethnic minority groups in Pakistan are generally underrepresented. In particular, little is known about the genetic origin and highland adaptation of the Pamirian Wakhi people. According to Chinese historical records, the geographical location and language usage of Wakhi may be closely related to Xinjiang Tajiks. In this study, based on high-coverage (∼30×) whole-genome sequencing of eight Wakhi and 25 Xinjiang Tajik individuals, we performed data analyses together with worldwide populations to gain insights into their genetic composition, demography, and adaptive evolution to the highland environment. The Wakhi derived more than 85% of their ancestry from West Eurasian populations (European ∼44.5%, South Asian ∼42.2%) and 10% from East Eurasian populations (Siberian ∼6.0%, East Asian ∼4.3%). Modeling the admixture history of the Wakhi indicated that the early West-East admixture occurred ∼3,875 to 2,250 years ago and that the recent admixture occurred ∼750 to 375 years ago. We identified selection signatures across EGLN3, in particular, a distinctive evolutionary signature was observed, and a certain underlying selected haplotype showed higher frequency (87.5%) in the Wakhi than in nearby Xinjiang Tajiks and other highlanders. Interestingly, we found high-frequency archaic sequences in the Wakhi genome, which overlapped with several genes related to cellular signaling transduction, including MAGI2, previously associated with high-altitude adaptation. Our analysis indicates that the Wakhi are distinct from the Xinjiang Tajiks and Tajikistan Tajiks and sheds light on the Wakhi's ancestral origin and genetic basis of high-altitude adaptation.
Lipid sensing by PPARα: Role in controlling hepatocyte gene regulatory networks and the metabolic response to fasting
Authors: Anne Fougerat, Justine Bruse, Arnaud Polizzi, Alexandra Montagner, Hervé Guillou, Walter Wahli
Journal: Progress in Lipid Research (2024)

Peroxisome proliferator-activated receptors (PPARs) constitute a small family of three nuclear receptors that act as lipid sensors, and thereby regulate the transcription of genes having key roles in hepatic and whole-body energy homeostasis, and in other processes (e.g., inflammation), which have far-reaching health consequences. Peroxisome proliferator-activated receptor isotype α (PPARα) is expressed in oxidative tissues, particularly in the liver, carrying out critical functions during the adaptive fasting response. Advanced omics technologies have provided insight into the vast complexity of the regulation of PPAR expression and activity, as well as their downstream effects on the physiology of the liver and its associated metabolic organs. Here, we provide an overview of the gene regulatory networks controlled by PPARα in the liver in response to fasting. We discuss impacts on liver metabolism, the systemic repercussions and benefits of PPARα-regulated ketogenesis and production of fibroblast growth factor 21 (FGF21), a fasting- and stress-inducible metabolic hormone. We also highlight current challenges in using novel methods to further improve our knowledge of PPARα in health and disease.
Targeting of the IL-5 pathway in severe asthma reduces mast cell progenitors
Authors: P Abigail Alvarado-Vazquez, Erika Mendez-Enriquez, Maya Salomonsson, Peter Kopac, Ana Koren, Urska Bidovec-Stojkovic, Sabina Škrgat, Oscar E Simonson, Valentyna Yasinska, Sven-Erik Dahlén, Gunnar Pejler, Christer Janson, Peter Korosec, Andrei Malinovschi, Jenny Hallgren
Journal: Journal of Allergy and Clinical Immunology (2024)
Effect of Mepolizumab in airway’s remodelling in patients with late-onset severe asthma with an eosinophilic phenotype
Authors: Kalliopi Domvri, Ioanna Tsiouprou, Petros Bakakos, Paschalis Steiropoulos, Konstantinos Katsoulis, Konstantinos Kostikas, Katerina M. Antoniou, Andriana I. Papaioannou, Nikoletta Rovina, Paraskevi Katsaounou, Theodora Papamitsou, Nicoleta Pastelli, Stavros Tryfon, Evangelia Fouka, Despoina Papakosta, Stelios Loukides, Konstantinos Porpodis
Journal: Journal of Allergy and Clinical Immunology (2024)
Variability in non-tumor areas of colorectal cancer patients as revealed by endoscopic intestinal step biopsies
Authors: Shoko Ikuta, Yutaka Saito, So Takata, Yoichiro Nakatani, Izumi Nagatomo, Satoshi Shiba, Yoshito Takeda, Yasushi Totoki, Sayaka Mizutani, Hironori Sunakawa, Hiroaki Ikematsu, Hiroyuki Takamaru, Atsushi Kumanogoh, Shinichi Yachida
Journal: Molecular Cancer (2024)

A comprehensive endoscopic small and large intestinal untargeted step biopsy procedure was conducted to compare gene expression between the normal intestinal mucosa of healthy individuals and that of patients with colorectal tumors. From 78 participants (healthy individuals [n = 17], patients with colorectal conventional adenomas [n = 6], patients with Tis-T1 colorectal cancer [n = 41], patients with T2-4 colorectal cancer [n = 14]), biopsies of normal mucosa of the terminal ileum, right-sided colon (cecum and ascending colon), and left-sided colorectum (descending colon, sigmoid colon, and rectum) were obtained using a lower gastrointestinal endoscope. RNA was extracted from all samples, and total transcriptome sequencing was performed. Transcriptome data from 388 samples was analyzed. DNA was also extracted from tumor biopsy tissues and analyzed for whole-exome sequencing. In healthy individuals, gene expression differed significantly among the terminal ileum, right-sided colon, and left-sided colorectum, presumably linked to embryological factors. There were differences in gene expression in the normal mucosa in colorectal cancer patients, compared to healthy controls. Patients with tumors, especially T2-4 colorectal cancer, showed considerable variation in gene expression in non-tumor tissues, even in the terminal ileum distant from the tumor site. Based on endoscopic biopsies, the results imply cancer-predisposing conditions in seemingly normal tissues. The present study points to the importance of small intestine and cancer-predisposing conditions in the colon of colorectal cancer patients, with possible implications for developing novel immunotherapy and other therapeutic modalities.
Integrative epidemiology and immuno-transcriptomics uncover a risk and potential mechanism for cutaneous lymphoma unmasking or progression with dupilumab therapy
Authors: Javier S Cabrera-Perez, Vincent J Carey, Oreofe O Odejide, Sonal Singh, Thomas S Kupper, Shiv S Pillai, Scott T Weiss, Ayobami Akenroye
Journal: Journal of Allergy and Clinical Immunology (2024)

There have been multiple reports of the anti-IL-4Rα agent, dupilumab, being associated with the onset and/or progression of cutaneous T-cell lymphoma (CTCL).
Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease
Authors: Svit Ferjančič Benetik, Damijan Knez, Aleš Obreza, Urban Košak, Stanislav Gobec
Journal: Pharmacology & Therapeutics (2024)

The simultaneous targeting of neuroinflammation and cholinergic hypofunction, the key pathological changes in Alzheimer's disease (AD), is not addressed by drugs currently in clinical trials, highlighting a critical therapeutic gap. We propose that dual-acting small molecules that inhibit butyrylcholinesterase (BChE) and mitogen-activated protein kinase p38α (p38α MAPK) represent a novel strategy to combat AD. This hypothesis is supported by cellular and animal studies as well as in silico modelling showing that it is possible to act simultaneously on both enzymes. Amyloid beta (Aβ) plaques trigger a pro-inflammatory microglial response that overactivates p38α MAPK, leading to increased Aβ synthesis, tau hyperphosphorylation, and altered synaptic plasticity. Overactivated microglia exacerbate neuroinflammation and cholinergic degeneration, ultimately leading to cognitive impairment. Structural similarities between the binding sites of BChE and p38α MAPK provide a promising basis for the development of dual inhibitors that could alleviate AD symptoms and address the underlying pathology.
Association between Diet-Related Greenhouse Gas Emissions and Mortality among Japanese Adults: The Japan Collaborative Cohort Study
Authors: Daiki Watanabe, Kotatsu Maruyama, Akiko Tamakoshi, Isao Muraki
Journal: Environmental Health Perspectives (2024)

Planetary and human health are highly intertwined; our current food system is associated with high greenhouse gas emissions (GHGE) and burden of disease.
68Ga-MY6349 PET/CT imaging to assess Trop2 expression in multiple types of cancer
Authors: Haojun Chen, Liang Zhao, Yizhen Pang, Jiyun Shi, Hannan Gao, Yining Sun, Jianhao Chen, Hao Fu, Jiayu Cai, Lingyu Yu, Ru Zeng, Long Sun, Hua Wu, Zhanxiang Wang, Fan Wang
Journal: Journal of Clinical Investigation (2024)

Background Considering trophoblast cell surface antigen 2 (Trop2) is overexpressed in a wide range of human epithelial cancers, it presents an attractive target for the diagnosis and treatment of multiple types of cancer. Herein, we have developed a Trop2-specific radiotracer, 68Ga-MY6349, and present a prospective, investigator-initiated trial to explore the clinical values of 68Ga-MY6349 PET/CT. Methods In this translational study, 90 patients with 15 types of cancer, who underwent 68Ga-MY6349 PET/CT, were enrolled prospectively. Among them, 78 patients underwent paired 68Ga-MY6349 and 18F-FDG PET/CT, and 12 patients with prostate cancer underwent paired 68Ga-MY6349 and 68Ga-PSMA-11 PET/CT. Results Among the 90 patients across 15 types of cancer, 68Ga-MY6349 uptake in tumors was generally high but heterogeneous, varying among lesions, patients, and cancer types. Trop2 expression level determined by immunohistochemistry was highly correlated with 68Ga-MY6349 uptake at primary and metastatic tumor sites. 68Ga-MY6349 PET/CT showed higher tumor uptake (quantified by SUVmax) than 18F-FDG PET/CT in certain types of cancer, including breast (7.2 vs. 5.4, P < 0.001), prostate (9.2 vs. 3.0, P < 0.001), and thyroid cancers (8.5 vs. 3.7, P < 0.001). When compared with 68Ga-PSMA-11, 68Ga-MY6349 PET/CT exhibited comparable lesion uptake (12.2 vs. 12.5, P = 0.223) but a better tumor-to-background contrast (15.8 vs. 12.2, P < 0.001) for primary and metastatic prostate cancer, allowing visualization of more metastatic lesions. Conclusion 68Ga-MY6349 PET/CT is a non-invasive method for comprehensively assessing Trop2 expression in tumors, which can improve the diagnosis and staging for cancer patients, and aid in the decision-making for Trop2-targeted therapies and advancing personalized treatment.
Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized-trial
Authors: Edilmar Alvarado-Tapias, Anna Brujats, Angela Puente, Alba Ardevol, Ainhoa Rodriguez-Arias, Javier Fajardo, Oanna Pavel, Marta Garcia-Guix, Carles Aracil, Maria Poca, Berta Cuyàs, Elisabet Cantó, Rosa Montañés, Alvaro Garcia-Osuna, Àngels Escorsell, Xavier Torras, Càndid Villanueva
Journal: Hepatology (2024)

Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal-hypertension and suboptimal response to traditional-NSBBs.
Letter to the Editor: Enhancing automated speech analysis for hepatic encephalopathy detection
Authors: Sheng Li, Zhou Wu
Journal: Hepatology (2024)

Department of Anorectal Surgery, Ningbo No.2 Hospital, Ningbo, Zhejiang, China Correspondence Zhou Wu, No. 41, Northwest Street, Haishu District, Ningbo, Zhejiang, China. Email: [email protected]
Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis via extracellular vesicles
Authors: Tsai-Ling Liao, Der-Yuan Chen, Shie-Liang Hsieh, Ying-Ying Yang, Yi-Ming Chen, Kuo-Tung Tang, Chung-Hsin Chang, Sheng-Shun Yang
Journal: Hepatology (2024)

Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear.
A single-cell transcriptomic map of the murine and human multiple myeloma immune microenvironment across disease stages
Authors: Emma Verheye, Daliya Kancheva, Hatice Satilmis, Niels Vandewalle, Rong Fan, Pauline M. R. Bardet, Emile J. Clappaert, Kevin Verstaen, Ann De Becker, Karin Vanderkerken, Kim De Veirman, Damya Laoui
Journal: Journal of Hematology & Oncology (2024)

The long-term effectiveness of immunotherapies against Multiple Myeloma (MM) remains elusive, demonstrated by the inevitable relapse in patients. This underscores the urgent need for an in-depth analysis of the MM tumor-immune microenvironment (TME). Hereto, a representative immunocompetent MM mouse model can offer a valuable approach to study the dynamic changes within the MM-TME and to uncover potential resistance mechanisms hampering effective and durable therapeutic strategies in MM. We generated a comprehensive single-cell RNA-sequencing atlas of the MM-TME in bone marrow and spleen encompassing different stages of disease, using the immunocompetent 5T33MM mouse model. Through comparative analysis, we correlated our murine dataset with the pathogenesis in MM patients by reanalyzing publicly available datasets of human bone marrow samples across various disease stages. Using flow cytometry, we validated the dynamic changes upon disease progression in the 5T33MM model. Furthermore, interesting target populations, as well as the immune-boosting anti-CD40 agonist (αCD40) therapy were tested ex vivo on murine and human primary samples and in vivo using the 5T33MM model. In this study, we identified the heterogenous and dynamic changes within the TME of murine and human MM. We found that the MM-TME was characterized by an increase in T cells, accompanied with an exhausted phenotype. Although neutrophils appeared to be rather innocuous at early disease stages, they acquired a pro-tumorigenic phenotype during MM progression. Moreover, conventional dendritic cells (cDCs) showed a less activated phenotype in MM, underscoring the potential of immune-boosting therapies such as αCD40 therapy. Importantly, we provided the first pre-clinical evaluation of αCD40 therapy and demonstrated successful induction of cDC- and T-cell activation, accompanied by a significant short-term anti-tumor response. This resource provides a comprehensive and detailed immune atlas of the evolution in human and murine MM disease progression. Our findings can contribute to immune-based patient stratification and facilitate the development of novel and durable (immune) therapeutic strategies in MM.
Nodal Burden and Oncologic Outcomes in Patients With Residual Isolated Tumor Cells After Neoadjuvant Chemotherapy (ypN0i+): The OPBC-05/ICARO Study
Authors: Giacomo Montagna, Alison Laws, Massimo Ferrucci, Mary M. Mrdutt, Susie X. Sun, Suleyman Bademler, Hakan Balbaloglu, Nora Balint-Lahat, Maggie Banys-Paluchowski, Andrea V. Barrio, John Benson, Nuran Bese, Judy C. Boughey, Marissa K. Boyle, Emilia J. Diego, Claire Eden, Ruth Eller, Maite Goldschmidt, Callie Hlavin, Martin Heidinger, Justyna Jelinska, Güldeniz Karadeniz Cakmak, Susan B. Kesmodel, Tari A. King, Henry M. Kuerer, Julie Loesch, Francesco Milardi, Dawid Murawa, Tracy-Ann Moo, Tehillah S. Menes, Daniele Passeri, Jessica M. Pastoriza, Andraz Perhavec, Nina Pislar, Natália Polidorio, Avina Rami, Jai Min Ryu, Alexandra Schulz, Varadan Sevilimedu, M. Umit Ugurlu, Cihan Uras, Annemiek van Hemert, Stephanie M. Wong, Tae-Kyung Robyn Yoo, Jennifer Q. Zhang, Hasan Karanlik, Neslihan Cabioğlu, Marie-Jeanne Vrancken Peeters, Monica Morrow, Walter P. Weber, Sung Gwe Ahn, Mariacarla Andreozzi, Daniel Meirelles Barbalho, Jean François Boileau, Edi Brogi, Flavia Vidal Cabero, Daniela Cocco, Fabio Corsi, Angelena Crown, Eelco de Bree, Maria del Mar Vernet-Tomas, Christine Deutschmann, Nina Ditsch, Emanuela Esposito, Oluwadamilola M. Fayanju, Franziska Fick, Florian Fitzal, Meghan R. Flanagan, Damiano Gentile, Oreste D. Gentilini, Anne Grabenstetter, Mehmet Ali Gulcelik, Jörg Heil, Johannes Holtschmidt, Natalia Krawczyk, Thorsten Kühn, Sherko Kümmel, Cornelia Leo, Mahmut Muslumanoglu, Valentina Nekljudova, Lisa A. Newman, Melissa L. Pilewskie, Fiorita Poulakaki, Fabian Riedel, Nicola Rocco, Freya R. Schnabel, Christopher Schwartz, Emily L. Siegel, Colin Simonson, Christian Singer, Leonardo Ribeiro Soares, Ekaterini Christina Tampaki, Athanasios Tampakis, Marios Konstantinos Tasoulis, Christoph Tausch, Cicero Urban, Astrid Botty Van den Bruele, Glenn Vergauwen, Denise Vorburger, Fredrik Wärnberg, Anna Weiss, Austin D. Williams, Kerstin Wimmer, Steven G. Woodward, Firdos M. Ziauddin
Journal: Journal of Clinical Oncology (2024)

The nodal burden of patients with residual isolated tumor cells (ITCs) in the sentinel lymph nodes (SLNs) after neoadjuvant chemotherapy (NAC) (ypN0i+) is unknown, and axillary management is not standardized. We investigated rates of additional positive lymph nodes (LNs) at axillary lymph node dissection (ALND) and oncologic outcomes in patients with ypN0i+ treated with and without ALND.
Impact of JN.1 booster vaccination on neutralisation of SARS-CoV-2 variants KP.3.1.1 and XEC
Authors: Prerna Arora, Christine Happle, Amy Kempf, Inga Nehlmeier, Metodi V Stankov, Alexandra Dopfer-Jablonka, Georg M N Behrens, Stefan Pöhlmann, Markus Hoffmann
Journal: The Lancet Infectious Diseases (2024)
Feasibility of modified double-layered suturing for a large mucosal defect after duodenal endoscopic submucosal dissection (Origami method)
Authors: Teppei Masunaga, Motoki Sasaki, Shoma Murata, Yuri Imura, Daisuke Minezaki, Anna Tojo, Hinako Sakurai, Kentaro Iwata, Kurato Miyazaki, Mari Mizutani, Michiko Nishikawa, Teppei Akimoto, Yusaku Takatori, Shintaro Kawasaki, Noriko Matsuura, Hideomi Tomida, Atsushi Nakayama, Tomohisa Sujino, Kaoru Takabayashi, Naohisa Yahagi, Motohiko Kato
Journal: Endoscopy (2024)

Modified double-layered suturing (Origami method; OGM), which can achieve robust closure even for large mucosal defects by folding the muscle layer using only through-the-scope clips. This study aimed to evaluate the feasibility of this OGM in duodenal ESD.
A needed (r)evolution to improve colorectal cancer screening: binding patient-centered/shared decision-making medicine with large language models in an emerging knowledge society
Authors: Santiago Camacho
Journal: Endoscopy (2024)

Performing procedures in healthy but high risk population is a major challenge for traditional cancer screening methods [1]. One of the most difficult procedures to accept is colonoscopy, which is nevertheless the best way of identifying and eventually removing early colorectal cancer (CRC) lesions. The lack of clarity about why it should be performed is however very worrying, as even first-degree relatives of patients with CRC have reservations about giving their consent (only 15.4% have had a colonoscopy in the previous 5 years) [2]. These types of reservations, which would be greater in patients with no family history of CRC, could result in an inadequate procedure that should be rescheduled or even cancelled with all the associated underlying costs [3]. In addition, the increase in CRC among younger patients requires new, more effective communication strategies. Although phone calls, text messages, and social networks, have been used successfully, the use of large language models (LLMs) has not been adequately evaluated in CRC screening in open populations and health professionals.
Cuproptosis-related lncRNA JPX regulates malignant cell behavior and epithelial-immune interaction in head and neck squamous cell carcinoma via miR-193b-3p/PLAU axis
Authors: Mouyuan Sun, Ning Zhan, Zhan Yang, Xiaoting Zhang, Jingyu Zhang, Lianjie Peng, Yaxian Luo, Lining Lin, Yiting Lou, Dongqi You, Tao Qiu, Zhichao Liu, Qianting Wang, Yu Liu, Ping Sun, Mengfei Yu, Huiming Wang
Journal: International Journal of Oral Science (2024)

The development, progression, and curative efficacy of head and neck squamous cell carcinoma (HNSCC) are influenced by complex interactions between epithelial and immune cells. Nevertheless, the specific changes in the nature of these interactions and their underlying molecular mechanisms in HNSCC are not yet fully understood. Cuproptosis, a form of programmed cell death that is dependent on copper, has been implicated in cancer pathogenesis. However, the understanding of cuproptosis in the context of HNSCC remains limited. In this study, we have discovered that cuproptosis-related long non-coding RNAs (CRLs) known as JPX play a role in promoting the expression of the oncogene urokinase-type plasminogen activator (PLAU) by competitively binding to miR-193b-3p in HNSCC. The increased activity of the JPX/miR-193b-3p/PLAU axis in malignant epithelial cells leads to enhanced cell proliferation, migration, and invasion in HNSCC. Moreover, the overexpression of PLAU in tumor epithelial cells facilitates its interaction with the receptor PLAUR, predominantly expressed on macrophages, thereby influencing the abnormal epithelial-immune interactome in HNSCC. Notably, the JPX inhibitor Axitinib and the PLAU inhibitor Palbociclib may not only exert their effects on the JPX/miR-193b-3p/PLAU axis that impacts the malignant tumor behaviors and the epithelial-immune cell interactions but also exhibit synergistic effects in terms of suppressing tumor cell growth and arresting cell cycle by targeting epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK4/6) for the treatment of HNSCC.
β-Ketoenamine covalent organic framework nanoplatform combined with immune checkpoint blockade via photodynamic immunotherapy inhibit glioblastoma progression
Authors: Tengfeng Yan, Qiuye Liao, Zhihao Chen, Yang Xu, Wenping Zhu, Ping Hu, Si Zhang, Yanze Wu, Lei Shu, Junzhe Liu, Min Luo, Hongxin Shu, Yilei Sheng, Li Wang, Chun Xu, Chang Lei, Hongming Wang, Qingsong Ye, Li Yang, Xingen Zhu
Journal: Bioactive Materials (2024)
Innovative spiral nerve conduits: Addressing nutrient transport and cellular activity for critical-sized nerve defects
Authors: Allen Zennifer, S K Praveenn Kumar, Shambhavi Bagewadi, Swathi Unnamalai, Davidraj Chellappan, Sama Abdulmalik, Xiaojun Yu, Swaminathan Sethuraman, Dhakshinamoorthy Sundaramurthi, Sangamesh G Kumbar
Journal: Bioactive Materials (2024)