tbuckley/cabot-search huggingface dataset:
When I use a word . . . . Medical blue plaques—penicillin
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

English Heritage has only this year announced that it will start putting up blue plaques in areas of the country outside London. The first such plaque, at 2 Crossbeck Road in Ilkley, West Yorkshire, on what used to be St Winifred's Hospital, commemorates the work of the midwife Daphne Steele (1927–2004), the first black nursing matron in the NHS. It supplements a previous plaque to her that was put up on St James's Hospital in Balham, South London, where she trained as a nurse after coming to the UK from Guyana in 1951. However, other organisations have been putting up plaques outside London for many years. In Oxford, for example, there are several plaques celebrating different aspects of the development of penicillin, mostly put up by the Oxfordshire Blue Plaques Board. These include: a blue plaque on the Sir William Dunn School of Pathology in Saint Cross Road, Oxford, commemorating the isolation and purification of penicillin by Howard Florey, Ernst Chain, and Norman Heatley in 1938–41; a plaque to Heatley on his house in Old Marston; two plaques in the Old Radcliffe Infirmary in Woodstock Road, commemorating the first systemic clinical use of penicillin in treating infection; and two plaques to Dorothy Hodgkin, who elucidated the chemical structure of penicillin, one at the front of the Inorganic Chemistry Department in Oxford University and one on the front of her house in Woodstock Road.
<i>PNPLA3</i>fatty liver allele was fixed in Neanderthals and segregates neutrally in humans
Authors: Andreas Geier, Jonas Trost, Ke Wang, Clemens Schmid, Marcin Krawczyk, Stephan Schiffels
Journal: Gut (2024)

Objective Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date. Design Here we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for PNPLA3 p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed. Results We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3 risk allele, whereas allele frequencies in modern human populations range from very low in Africa to &gt;50% in Mesoamerica. Over the last 15 000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10 000 years. Conclusion Archaic human individuals exclusively carried a fixed PNPLA3 allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of PNPLA3 p.I148M.
Function of mast cell and bile-cholangiocarcinoma interplay in cholangiocarcinoma microenvironment
Authors: Anda Shi, Zengli Liu, Zhongqi Fan, Kangshuai Li, Xingkai Liu, Yongchang Tang, Jiaming Hu, Xingyong Li, Lizhuang Shu, Liming Zhao, Lingling Huang, Zhiyue Zhang, Guoyue Lv, Zongli Zhang, Yunfei Xu
Journal: Gut (2024)

Objective The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites. Design Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9. Results Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gaq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferation by activating HRH1-Gaq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gas signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and SLC22A3 deletion resulted in HA accumulation. Conclusion Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.
Recovery Dynamics and Prognosis After Dialysis for Acute Kidney Injury
Authors: Heng-Chih Pan, Hsing-Yu Chen, Nai-Chi Teng, Fang-Yu Yeh, Tao-Min Huang, Chun Yin See, Chiao-Yin Sun, Yung-Chang Chen, Likwang Chen, Vin-Cent Wu
Journal: JAMA Network Open (2024)

Importance The interplay among baseline kidney function, severity of acute kidney disease (AKD), and post-AKD kidney function has significant associations with patient outcomes. However, a comprehensive understanding of how these factors are collectively associated with mortality, major adverse cardiac events (MACEs), and end-stage kidney disease (ESKD) in patients with dialysis-requiring acute kidney injury (AKI-D) is yet to be fully explored. Objective To investigate the associations of baseline kidney function, AKD severity, and post-AKD kidney function with mortality, MACEs, and ESKD in patients with AKI-D. Design, Setting, and Participants This nationwide, population-based cohort study of patients with AKI-D was conducted between January 1, 2015, and December 31, 2018, using data from various health care settings included in the Taiwan nationwide population-based cohort database. Data analysis was conducted from April 28, 2022, to June 30, 2023. Exposure Exposure to severe AKI and baseline and post-AKD kidney function. Main Outcomes and Measures The primary outcomes were all-cause mortality and incident MACEs, and secondary outcomes were risks of permanent dialysis and readmission. Results A total of 6703 of 22 232 patients (mean [SD] age, 68.0 [14.7] years; 3846 [57.4%] male) with AKI-D with post-AKD kidney function follow-up and AKD stage data were enrolled. During a mean (SD) 1.2 (0.9) years of follow-up, the all-cause mortality rate was 28.3% (n = 1899), while the incidence rates of MACEs and ESKD were 11.1% (n = 746) and 16.7% (n = 1119), respectively. After adjusting for known covariates, both post-AKD kidney function and baseline kidney function, but not AKD severity, were independently associated with all-cause mortality, MACEs, ESKD, and readmission. Moreover, worse post-AKD kidney function correlated with progressive and significant increases in the risk of adverse outcomes. Conclusions and Relevance In this cohort study of patients with AKI-D, more than one-quarter of patients died after 1.2 years of follow-up. Baseline and post-AKD kidney functions serve as important factors associated with the long-term prognosis of patients with AKI-D. Therefore, concerted efforts to understand the transition from post-AKD to chronic kidney disease are crucial.
How common are side effects of treatment to prevent gout flares when starting allopurinol?
Authors: Helen Saul, Brendan Deeney, Laura Swaithes, Edward Roddy
Journal: BMJ (2024)

The study Roddy E, Bajpai R, Forrester H, et al. Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink. Ann Rheum Dis 2023;82:1618-25. To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/how-common-are-side-effects-of-treatment-to-prevent-gout-flares-when-starting-allopurinol/
PRMT1 promotes pancreatic cancer development and resistance to chemotherapy
Authors: Bomin Ku, David Eisenbarth, Seonguk Baek, Tae-Keun Jeong, Ju-Gyeong Kang, Daehee Hwang, Myung-Giun Noh, Chan Choi, Sungwoo Choi, Taejun Seol, Hail Kim, Yun-Hee Kim, Sang Myung Woo, Sun-Young Kong, Dae-Sik Lim
Journal: Cell Reports Medicine (2024)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of and potential as a therapeutic target for PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.
Access to abortion: a constitutional right
Authors: None The Lancet Public Health
Journal: The Lancet Public Health (2024)

On March 4, 2024, French lawmakers gathered in Congress, in Versailles Palace, and voted by an overwhelming 780-72 vote to enshrine access to abortion in the constitution, giving women a guaranteed freedom to voluntarily terminate a pregnancy. With globally 6 in 10 unintended pregnancies for women aged 15–49 years ending in abortion, access to abortion is a crucial health service for women but remains inaccessible for many women. France is the first country to guarantee access to an abortion in their constitution.
Revealing the grammar of small RNA secretion using interpretable machine learning
Authors: Bahar Zirak, Mohsen Naghipourfar, Ali Saberi, Delaram Pouyabahar, Amirhossein Zarezadeh, Lixi Luo, Lisa Fish, Doowon Huh, Albertas Navickas, Ali Sharifi-Zarchi, Hani Goodarzi
Journal: Cell Genomics (2024)

Small non-coding RNAs can be secreted through a variety of mechanisms, including exosomal sorting, in small extracellular vesicles, and within lipoprotein complexes. However, the mechanisms that govern their sorting and secretion are not well understood. Here, we present ExoGRU, a machine learning model that predicts small RNA secretion probabilities from primary RNA sequences. We experimentally validated the performance of this model through ExoGRU-guided mutagenesis and synthetic RNA sequence analysis. Additionally, we used ExoGRU to reveal cis and trans factors that underlie small RNA secretion, including known and novel RNA-binding proteins (RBPs), e.g., YBX1, HNRNPA2B1, and RBM24. We also developed a novel technique called exoCLIP, which reveals the RNA interactome of RBPs within the cell-free space. Together, our results demonstrate the power of machine learning in revealing novel biological mechanisms. In addition to providing deeper insight into small RNA secretion, this knowledge can be leveraged in therapeutic and synthetic biology applications.
Restoring SRSF3 in Kupffer cells attenuates obesity-related insulin resistance
Authors: Hong Gao, Karina C. E. Rocha, Zhongmou Jin, Deepak Kumar, Dinghong Zhang, Ke Wang, Manasi Das, Andrea Farrell, Tyler Truong, Yasemin Tekin, Hyun Suh Jung, Julia Kempf, Nicholas J. G. Webster, Wei Ying
Journal: Hepatology (2024)

Background and Aims: In obesity, depletion of KCs expressing CRIg (complement receptor of the Ig superfamily) leads to microbial DNA accumulation, which subsequently triggers tissue inflammation and insulin resistance. However, the mechanism underlying obesity-mediated changes in KC complement immune functions is largely unknown. Approach and Results: Using KC-specific deactivated Cas9 transgenic mice treated with guide RNA, we assessed the effects of restoring CRIg or the serine/arginine-rich splicing factor 3 (SRSF3) abundance on KC functions and metabolic phenotypes in obese mice. The impacts of weight loss on KC responses were evaluated in a diet switch mouse model. The role of SRSF3 in regulating KC functions was also evaluated using KC-specific SRSF3 knockout mice. Here, we report that overexpression of CRIg in KCs of obese mice protects against bacterial DNA accumulation in metabolic tissues. Mechanistically, SRSF3 regulates CRIg expression, which is essential for maintaining the CRIg+ KC population. During obesity, SRSF3 expression decreases, but it is restored with weight loss through a diet switch, normalizing CRIg+ KCs. KC SRSF3 is also repressed in obese human livers. Lack of SRSF3 in KCs in lean and obese mice decreases their CRIg+ population, impairing metabolic parameters. During the diet switch, the benefits of weight loss are compromised due to SRSF3 deficiency. Conversely, SRSF3 overexpression in obese mice preserves CRIg+ KCs and improves metabolic responses. Conclusions: Restoring SRSF3 abundance in KCs offers a strategy against obesity-associated tissue inflammation and insulin resistance by preventing bacterial DNA accumulation.
Letter to the Editor: Is right heart assessment vital for evaluating terlipressin-related outcomes in hepatorenal syndrome-acute kidney injury?
Authors: Qirui Guo, Jie Wang, Guangjian Wang, Xiaoting Wang
Journal: Hepatology (2024)

Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China Letter to the Editor: Is right heart assessment vital for evaluating Terlipressin-related outcomes in Hepatorenal Syndrome-AKI ? Contribution:Carefully analyzed the details of the research, identified and proposed innovative points, and took full responsibility for drafting the letter. Email: [email protected] Contribution:Engaged in in-depth discussions on the innovative points, offering constructive ideas for the letter, and collaboratively explored relevant perspectives. Email: [email protected] Contribution:Engaged in in-depth discussions on the innovative points, offering constructive ideas for the letter, and collaboratively explored relevant perspectives. Email: [email protected] Contribution:Thoroughly reviewed the manuscript, provided valuable academic guidance, ensuring the scholarly rigor and quality of the document. Email: [email protected] Abbreviations list:AKI, Acute Kidney Injury; ICU, Intensive Care Unit; NSBB, Non-Selective Beta-Blocker. Correspondence Xiaoting Wang, Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, #1 Shuaifuyuan, Dongcheng District, Beijing 100730, China. Email: [email protected] This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
Regulation of rheumatoid arthritis microenvironment via a self-healing injectable hydrogel for improved inflammation elimination and bone repair
Authors: Wenbo Geng, Jie Zhao, Bailong Tao, Yulu Yang, Qiaojian Duan, Pengfei Gao, Tingting He, Shaopeng Liu, Qian Feng, Peng Zhao, Kaiyong Cai
Journal: Bioactive Materials (2024)

The rheumatoid arthritis (RA) microenvironment is often followed by a vicious circle of high inflammation, endogenous gas levels imbalance, and poor treatment. To break the circle, we develop a dual-gas-mediated injectable hydrogel for modulating the immune microenvironment of RA and simultaneously releasing therapeutic drugs. The hydrogel (DNRS gel) could be broken down on-demand by consuming excessive nitric oxide (NO) and releasing therapeutic hydrogen sulfide (H
Feeder-free differentiation of human iPSCs into natural killer cells with cytotoxic potential against malignant brain rhabdoid tumor cells
Authors: Sonia Kiran, Yu Xue, Drishty B. Sarker, Yan Li, Qing-Xiang Amy Sang
Journal: Bioactive Materials (2024)

Natural killer (NK) cells are cytotoxic immune cells that can eliminate target cells without prior stimulation. Human induced pluripotent stem cells (iPSCs) provide a robust source of NK cells for safe and effective cell-based immunotherapy against aggressive cancers. In this
Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors
Authors: Ryan B. Corcoran, Khanh T. Do, Jeong E. Kim, James M. Cleary, Aparna R. Parikh, Oladapo O. Yeku, Niya Xiong, Colin D. Weekes, Jennifer Veneris, Leanne G. Ahronian, Gianluca Mauri, Jun Tian, Bryanna L. Norden, Alexa G. Michel, Emily E. Van Seventer, Giulia Siravegna, Kyle Camphausen, Gary Chi, Isobel J. Fetter, Joan S. Brugge, Helen Chen, Naoko Takebe, Richard T. Penson, Dejan Juric, Keith T. Flaherty, Ryan J. Sullivan, Jeffrey W. Clark, Rebecca S. Heist, Ursula A. Matulonis, Joyce F. Liu, Geoffrey I. Shapiro
Journal: Clinical Cancer Research (2024)

Abstract Purpose: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. Patients and Methods: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non–small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. Results: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. Conclusions: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.
Mast Cell Sarcoma Mimicking Lymphoma or Metastatic Disease on 18F-FDG PET/CT
Authors: Florian Rosar, Samer Ezziddin, Jörg Thomas Bittenbring, Konstantinos Christofyllakis, Caroline Burgard
Journal: Clinical Nuclear Medicine (2024)

Abstract We report an 18 F-FDG PET/CT scan of a 47-year-old man diagnosed with diffuse mast cell sarcoma with lymph node, bone, liver, spleen, and lung involvement. This interesting image should remind colleagues to consider mast cell sarcoma as a rare differential diagnosis in patients with multiple, intensely hypermetabolic lesions in various organs and lymph nodes.
Targeting the innate immune system in pediatric and adult AML
Authors: Alicia Perzolli, Joost B Koedijk, C Michel Zwaan, Olaf Heidenreich
Journal: Leukemia (2024)

Abstract While the introduction of T cell-based immunotherapies has improved outcomes in many cancer types, the development of immunotherapies for both adult and pediatric AML has been relatively slow and limited. In addition to the need to identify suitable target antigens, a better understanding of the immunosuppressive tumor microenvironment is necessary for the design of novel immunotherapy approaches. To date, most immune characterization studies in AML have focused on T cells, while innate immune lineages such as monocytes, granulocytes and natural killer (NK) cells, received less attention. In solid cancers, studies have shown that innate immune cells, such as macrophages, myeloid-derived suppressor cells and neutrophils are highly plastic and may differentiate into immunosuppressive cells depending on signals received in their microenvironment, while NK cells appear to be functionally impaired. Hence, an in-depth characterization of the innate immune compartment in the TME is urgently needed to guide the development of immunotherapeutic interventions for AML. In this review, we summarize the current knowledge on the innate immune compartment in AML, and we discuss how targeting its components may enhance T cell-based- and other immunotherapeutic approaches.
SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits
Authors: Alberto Preda, Fabrizio Montecucco, Federico Carbone, Giovanni G Camici, Thomas F Lüscher, Simon Kraler, Luca Liberale
Journal: Cardiovascular Research (2024)

Abstract An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins’ role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.