tbuckley/cabot-search huggingface dataset:
Tumor cell–intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance
Authors: Naijun Miao, Dongqing Cao, Jingsi Jin, Guizhi Ma, Haihui Yu, Junwen Qu, Guiping Li, Caixia Gao, Dong Dong, Fan Xia, Wenwen Li
Journal: The Journal of Experimental Medicine (2024)

Changes in mechanosensitive ion channels following radiation have seldom been linked to therapeutic sensitivity or specific factors involved in antitumor immunity. Here, in this study, we found that the mechanical force sensor, Piezo2, was significantly upregulated in tumor cells after radiation, and Piezo2 knockout in tumor cells enhanced tumor growth suppression by radiotherapy. Specifically, loss of Piezo2 in tumor cells induced their IL-15 expression via unleashing JAK2/STAT1/IRF-1 axis after radiation. This increase in IL-15 activates IL-15Rα on tumor-infiltrating CD8+ T cells, thereby leading to their augmented effector and stem cell–like properties, along with reduced terminal exhausted feature. Importantly, Piezo2 expression was negatively correlated with CD8 infiltration, as well as with radiosensitivity of patients with rectum adenocarcinoma receiving radiotherapy treatment. Together, our findings reveal that tumor cell–intrinsic Piezo2 induces radioresistance by dampening the IRF-1/IL-15 axis, thus leading to impaired CD8+ T cell–dependent antitumor responses, providing insights into the further development of combination strategies to treat radioresistant cancers.
Why Was the Azithromycin “for Life” Trial Necessary?
Authors: Kathryn Maitland, A Sarah Walker
Journal: New England Journal of Medicine (2024)

In 2009, a cluster-randomized trial showed a 49% reduction in all-cause mortality among Ethiopian children 1 to 9 years of age in the year after mass distribution of a single dose of azithromycin for trachoma prevention — a reduction that was sustained over the following 26 months.1 This remarkable finding led to further multinational cluster-randomized trials examining mass distribution of azithromycin for children 1 to 59 months of age in trachoma-endemic areas of Niger, Tanzania, and Malawi (the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance [MORDOR] trial)2 and such distribution combined with seasonal malaria prophylaxis . . .
Epigenetic Therapy in a Rare Ovarian Cancer — A Double-Edged Sword
Authors: Charles Hsu, Jason A Konner, Mrinal M Gounder
Journal: New England Journal of Medicine (2024)

A woman with a rare ovarian tumor driven by EZH2 activity responded to tazemetostat, an EZH2 inhibitor, but T-cell acute lymphoblastic leukemia later developed.
A Mixed Methods Approach to Understanding the Public Health Impact of a School-Based Citizen Science Program to Reduce Arsenic in Private Well Water
Authors: Ashley Taylor, Alexis Garretson, Karen H. Bieluch, Kate L. Buckman, Hannah Lust, Cait Bailey, Anna E. Farrell, Brian P. Jackson, Rebecca Lincoln, Erin Arneson, Sarah R. Hall, Bruce A. Stanton, Jane E. Disney
Journal: Environmental Health Perspectives (2024)

Exposure to arsenic (As) in well water is a well-documented public health issue for Maine and New Hampshire, as well as for other states in the United States and abroad. Arsenic contamination of well water in these locations is primarily attributed to metasedimentary bedrock that leaches As into groundwater. However, As can also enter groundwater reserves from soils contaminated by the historical use of arsenical pesticides. Approximately half of the households in Maine and New Hampshire rely on private wells, many of which have elevated As. Arsenic exposure has been associated with an increased risk of cancer, cardiovascular disease, reduced infection resistance, and lower intelligence quotient in children. Despite these known health impacts, well water testing and treatment are not universal.
Azithromycin to Reduce Mortality — An Adaptive Cluster-Randomized Trial
Authors: Kieran S O'Brien, Ahmed M Arzika, Abdou Amza, Ramatou Maliki, Bawa Aichatou, Ismael Mamane Bello, Diallo Beidi, Nasser Galo, Naser Harouna, Alio M Karamba, Sani Mahamadou, Moustapha Abarchi, Almou Ibrahim, Elodie Lebas, Brittany Peterson, Zijun Liu, Victoria Le, Emily Colby, Thuy Doan, Jeremy D Keenan, Catherine E Oldenburg, Travis C Porco, Benjamin F Arnold, Thomas M Lietman
Journal: New England Journal of Medicine (2024)

BackgroundTwice-yearly mass distribution of azithromycin to children is a promising intervention to reduce childhood mortality in sub-Saharan Africa. The World Health Organization recommended restricting distribution to infants 1 to 11 months of age to mitigate antimicrobial resistance, although this more limited treatment had not yet been tested.MethodsWe randomly assigned rural communities in Niger to four twice-yearly distributions of azithromycin for children 1 to 59 months of age (child azithromycin group), four twice-yearly distributions of azithromycin for infants 1 to 11 months of age and placebo for children 12 to 59 months of age (infant azithromycin group), or placebo for children 1 to 59 months of age. Census workers who were not aware of the group assignments monitored mortality twice yearly over the course of 2 years. We assessed three primary community-level mortality outcomes (deaths per 1000 person-years), each examining a different age group and pairwise group comparison.Download a PDF of the Plain Language Summary.ResultsA total of 1273 communities were randomly assigned to the child azithromycin group (1229 were included in the analysis), 773 to the infant azithromycin group (751 included in the analysis), and 954 to the placebo group (929 included in the analysis). Among 382,586 children, 419,440 person-years and 5503 deaths were recorded. Lower mortality among children 1 to 59 months of age was observed in the child azithromycin group (11.9 deaths per 1000 person-years; 95% confidence interval [CI], 11.3 to 12.6) than in the placebo group (13.9 deaths per 1000 person-years; 95% CI, 13.0 to 14.8) (representing 14% lower mortality with azithromycin; 95% CI, 7 to 22; P<0.001). Mortality among infants 1 to 11 months of age was not significantly lower in the infant azithromycin group (22.3 deaths per 1000 person-years; 95% CI, 20.0 to 24.7) than in the placebo group (23.9 deaths per 1000 person-years; 95% CI, 21.6 to 26.2) (representing 6% lower mortality with azithromycin; 95% CI, −8 to 19). Five serious adverse events were reported: three in the placebo group, one in the infant azithromycin group, and one in the child azithromycin group.ConclusionsAzithromycin distributions to children 1 to 59 months of age significantly reduced mortality and was more effective than treatment of infants 1 to 11 months of age. Antimicrobial resistance must be monitored. (Funded by the Bill and Melinda Gates Foundation; AVENIR ClinicalTrials.gov number, NCT04224987.) Quick Take Azithromycin to Reduce Childhood Mortality in Niger 2m 45s
Determining a robust prognostic biomarker for 804 patients with pancreatic cancer using a machine learning computational framework
Authors: Qihang Yuan, Jiaao Sun, Zhijun Hong, Dong Shang
Journal: International Journal of Surgery (2024)

First Affiliated Hospital of Dalian Medical University, Dalian, China Qihang Yuan and Jiaao Sun contributed to this study equally. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. *Corresponding authors. Address: . E-mail: [email protected] (D. Shang); First Affiliated Hospital of Dalian Medical University, CHINA. E-mail: [email protected] (Z Hong). Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/international-journal-of-surgery. Published online ■ ■ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-nc-sa/4.0/
A novel surgical risk predictor combining frailty and hypoalbuminemia – A cohort study of 9.8m patients from the ACS-NSQIP database
Authors: Adriana C. Panayi, Samuel Knoedler, Jasmin Rühl, Sarah Friedrich, Valentin Haug, Ulrich Kneser, Dennis P. Orgill, Gabriel Hundeshagen
Journal: International Journal of Surgery (2024)

Introduction: The functional decline seen in frail patients is associated with significant morbidity and mortality. The modified frailty index 5 (mFI-5) score is an accepted risk predictor score in surgery. Hypoalbuminemia has been correlated with poor postoperative outcomes. There exists, however, a gap in the literature regarding the combined assessment of frailty and hypoalbuminemia and the predictive power of this combined assessment. This retrospective cohort study aimed to investigate the association of preoperative albumin and frailty, as assessed with the mFI-5 score, and its ability to predict surgical outcomes. Methods: We queried the ACS-NSQIP database (2008–2021) to identify all surgical patients. Perioperative data, including demographics and preoperative laboratory values, including albumin, were collected. The predictive power of the mFI-5 and hypoalbuminemia (Alb) independently and in combination (mFI-5+Alb), was assessed using multivariable linear and logistic regression models 30-day outcomes were assessed including mortality, length of hospital stay, reoperation, medical and surgical complications, and discharge destination. Results: A total of 9 782 973 patients were identified, of whom 4 927 520 (50.4%) were nonfrail (mFI=0), 3 266 636 had a frailty score of 1 (33.4%), 1 373 968 a score of 2 (14.0%), 188 821 a score of 3 (1.9%), and 26 006 a score greater or equal to 4 (0.3%). Albumin levels were available for 4 570 473 patients (46.7%), of whom 848 315 (18.6%) had hypoalbuminemia. The combined assessment (mFI-5+Alb) was found to be a more accurate risk predictor than each factor independently for all outcomes. A weak negative correlation between serum albumin levels and mFI scores was established (Spearman R : −0.2; &lt;0.0001). Conclusions: Combined assessment of frailty and albumin was the strongest risk predictor. Therefore, for patients undergoing surgery, we recommend consideration of both serum albumin and frailty in order to optimally determine perioperative planning, including multidisciplinary care mobilization and prehabilitation and posthabilitation.
Brain-computer interfaces: The innovative key to unlocking neurological conditions
Authors: Hongyu Zhang, Le Jiao, Songxiang Yang, Haopeng Li, Xinzhan Jiang, Jing Feng, Shuhuai Zou, Qiang Xu, Jianheng Gu, Xuefeng Wang, Baojian Wei
Journal: International Journal of Surgery (2024)

Neurological disorders such as Parkinson’s disease, stroke, and spinal cord injury can pose significant threats to human mortality, morbidity, and functional independence. Brain–Computer Interface (BCI) technology, which facilitates direct communication between the brain and external devices, emerges as an innovative key to unlocking neurological conditions, demonstrating significant promise in this context. This comprehensive review uniquely synthesizes the latest advancements in BCI research across multiple neurological disorders, offering an interdisciplinary perspective on both clinical applications and emerging technologies. We explore the progress in BCI research and its applications in addressing various neurological conditions, with a particular focus on recent clinical studies and prospective developments. Initially, the review provides an up-to-date overview of BCI technology, encompassing its classification, operational principles, and prevalent paradigms. It then critically examines specific BCI applications in movement disorders, disorders of consciousness, cognitive and mental disorders, as well as sensory disorders, highlighting novel approaches and their potential impact on patient care. This review reveals emerging trends in BCI applications, such as the integration of artificial intelligence and the development of closed-loop systems, which represent significant advancements over previous technologies. The review concludes by discussing the prospects and directions of BCI technology, underscoring the need for interdisciplinary collaboration and ethical considerations. It emphasizes the importance of prioritizing bidirectional and high-performance BCIs, areas that have been underexplored in previous reviews. Additionally, we identify crucial gaps in current research, particularly in long-term clinical efficacy and the need for standardized protocols. The role of neurosurgery in spearheading the clinical translation of BCI research is highlighted. Our comprehensive analysis presents BCI technology as an innovative key to unlocking neurological disorders, offering a transformative approach to diagnosing, treating, and rehabilitating neurological conditions, with substantial potential to enhance patients’ quality of life and advance the field of neurotechnology.
Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension
Authors: Jason Hong, Lejla Medzikovic, Wasila Sun, Brenda Wong, Grégoire Ruffenach, Christopher J. Rhodes, Adam Brownstein, Lloyd L. Liang, Laila Aryan, Min Li, Arjun Vadgama, Zeyneb Kurt, Tae-Hwi Schwantes-An, Elizabeth A. Mickler, Stefan Gräf, Mélanie Eyries, Katie A. Lutz, Michael W. Pauciulo, Richard C. Trembath, Frédéric Perros, David Montani, Nicholas W. Morrell, Florent Soubrier, Martin R. Wilkins, William C. Nichols, Micheala A. Aldred, Ankit A. Desai, David-Alexandre Trégouët, Soban Umar, Rajan Saggar, Richard Channick, Rubin M. Tuder, Mark W. Geraci, Robert S. Stearman, Xia Yang, Mansoureh Eghbali
Journal: Circulation (2024)

BACKGROUND: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare. METHODS: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics. RESULTS: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN , coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor–β/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH. CONCLUSIONS: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.
Can CA-125/CEA ratio be used for the differential diagnosis between ovarian and non-ovarian cancers? A research letter
Authors: Jeferson R. Zanon, Elisa B. Simioni, Flávia F. Barbin, Priscila G. Pedrão, Carlos E.M.C. Andrade, Diocésio A.P. de Andrade, João P. Bilibio, José H.T.G. Fregnani, Ricardo dos Reis
Journal: International Journal of Surgery (2024)

Zanon, Jeferson R MD, MSc; Simioni, Elisa B MD; Barbin, Flávia F MD, MSc; Pedrão, Priscila G MSc; Andrade, Carlos E M C MD, MSc; de Andrade, Diocésio A P MD, PhD; Bilibio, João P MD, PhD; Fregnani, José Humberto T G MD, PhD; dos Reis, Ricardo MD, PhD Author Information
Amino Acid Infusion to Protect Kidney Function after Cardiac Surgery
Authors: Marlies Ostermann, Andrew D Shaw
Journal: New England Journal of Medicine (2024)

Cardiac surgery–associated acute kidney injury (AKI) is linked to adverse outcomes including an increased risk of death, postoperative complications, and higher rates of incident or progressive chronic kidney disease.1,2 The cause of cardiac surgery–associated AKI is multifactorial. It is also well recognized that hemodynamic alterations can result in "functional" AKI, in which the glomerular filtration rate (GFR) decreases acutely without clinically significant tubular cell injury. In this latter context, the risk of adverse outcomes is lower. In 1983, the administration of a protein load was shown to increase GFR. This finding introduced the concept of renal functional reserve,3 which is . . .
Determinants of clinical response to injection laryngoplasty in unilateral vocal fold paralysis: a systematic review and meta-analysis
Authors: Alaa Safia, Uday Abd Elhadi, Mohamad Roch, Kenan Kassem, Rabia Safiya, Ahmed Zubeidat, Nader Nofal, Anwar Heib, Shlomo Merchavy, Taiser Bishara
Journal: International Journal of Surgery (2024)

Unilateral vocal fold paralysis (UVFP) significantly impairs vocal function, affecting patients' quality of life. Injection laryngoplasty, a primary treatment modality for UVFP, varies in effectiveness based on the material used, injection volume, and procedural nuances. This study aims to systematically analyze how these factors influence treatment outcomes to optimize intervention strategies.
Targeting<i>Gsk3a</i>reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma
Authors: Xin Zheng, Luyu Yang, Xiaotian Shen, Junjie Pan, Yiran Chen, Jixuan Chen, Hao Wang, Jiaqi Meng, Zhenchao Chen, Sunzhe Xie, Yitong Li, Bolun Zhu, Wenwei Zhu, Lunxiu Qin, Lu Lu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy. Methods We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored. Results Gsk3a , as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody. Conclusions We identified a potential HCC immune evasion target, Gsk3a , through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.
John Launer: How to be a chronicologist
Authors: John Launer
Journal: BMJ (2024)

Although nearly all my clinical career has been in primary care, my work these days brings me into quite a lot of contact with hospital consultants.I'm involved in teaching them the skills for supervising juniors on complex cases, and so I sometimes have conversations with the consultants about such cases.I usually have only a fraction of the specialist knowledge the consultants do, but I can draw on my experience as a GP in managing uncertainty, dealing with the social, psychological, and ethical aspects of medicine,
Systemic assessment of manual circular stapler versus powered circular stapler for anastomosis in rectal cancer: A large-scale Chinese multicenter prospective cohort study
Authors: Yikuan Chen, Ruijia Zhang, Juan Fan, Dakui Luo, Weijin Gu, Fangqi Liu, Wei Zhang, Guole Lin, Quan Wang, Xinxiang Li
Journal: International Journal of Surgery (2024)

Mechanical anastomosis in rectal cancer surgery offers several advantages but is plagued by complications like leaks and strictures. Variations in surgeons’ experiences affect outcomes, but powered circular anastomosis has emerged as a promising solution, ensuring uniform staple formation and reducing manual manipulation. This multicenter, randomized, parallel-controlled study in China compared IntoCare™‘s powered circular staplers (ICS) with manual circular staplers (MCS) in 382 patients (195 ICS, 187 MCS). Both groups had comparable anastomotic leakage rates. ICS significantly reduced anastomosis time while maintaining similar safety profiles. Postoperative recovery and complication rates were closely matched. The use of ICS in rectal cancer surgeries effectively reduces anastomosis time without compromising safety, offering a promising innovation to enhance the efficacy of rectal cancer surgeries while maintaining patient safety.
Abdominal perfusion pressure is critical for survival analysis in patients with intra-abdominal hypertension: mortality prediction using incomplete data
Authors: Liang Xu, Weijie Zhao, Jiao He, Siyu Hou, Jialin He, Yan Zhuang, Ying Wang, Hua Yang, Jingjing Xiao, Yuan Qiu
Journal: International Journal of Surgery (2024)

Background: Abdominal perfusion pressure (APP) is a salient feature in the design of a prognostic model for patients with intra-abdominal hypertension (IAH). However, incomplete data significantly limits the size of the beneficiary patient population in clinical practice. Using advanced artificial intelligence methods, we developed a robust mortality prediction model with APP from incomplete data. Methods: We retrospectively evaluated the patients with IAH from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Incomplete data were filled in using generative adversarial imputation nets (GAIN). Lastly, demographic, clinical, and laboratory findings were combined to build a 7-day mortality prediction model. Results: We included 1354 patients in this study, of which 63 features were extracted. Data imputation with GAIN achieved the best performance. Patients with an APP&lt; 60 mmHg had significantly higher all-cause mortality within 7 to 90 days. The difference remained significant in long-term survival even after propensity score matching (PSM) eliminated other mortality risks between groups. Lastly, the built machine learning model for 7-day modality prediction achieved the best results with an AUC of 0.80 in patients with confirmed IAH outperforming the other four traditional clinical scoring systems. Conclusions: APP reduction is an important survival predictor affecting the survival prognosis of patients with IAH. We constructed a robust model to predict the 7-day mortality probability of patients with IAH, which is superior to the commonly used clinical scoring systems.
Rediscovering the human thymus through cutting-edge technologies
Authors: Francesca Pala, Luigi D. Notarangelo, Marita Bosticardo
Journal: The Journal of Experimental Medicine (2024)

Recent technological advances have transformed our understanding of the human thymus. Innovations such as high-resolution imaging, single-cell omics, and organoid cultures, including thymic epithelial cell (TEC) differentiation and culture, and improvements in biomaterials, have further elucidated the thymus architecture, cellular dynamics, and molecular mechanisms underlying T cell development, and have unraveled previously unrecognized levels of stromal cell heterogeneity. These advancements offer unprecedented insights into thymic biology and hold promise for the development of novel therapeutic strategies for immune-related disorders.