tbuckley/cabot-search huggingface dataset:
Comparative long-term outcomes of natural orifice specimen extraction surgery and conventional laparoscopic colectomy for left-sided colorectal cancer: a propensity score-matched analysis
Authors: Shu-Zhen Xu, Zhen-Fa Wang, Zhi-Jie Ding, Shi-Feng Zhang, Si-Bo Yuan, Feng Yan, Guo-Yan Liu, Jian-Chun Cai
Journal: International Journal of Surgery (2024)

Natural orifice specimen extraction surgery (NOSES) is currently widely used in left-sided colorectal cancer. Some clinical comparative studies have been conducted, providing evidence of its safety and oncological benefits. However, these studies are typically characterized by small sample sizes and short postoperative follow-up periods. Consequently, in this research, the authors adopt the propensity score matching method to undertake a large-scale retrospective comparative study on NOSES colectomy for left-sided colorectal cancer, with the goal of further augmenting the body of evidence-based medical support for NOSES.
“On/off”-switchable crosslinked PTX-nanoformulation with improved precise delivery for NSCLC brain metastases and restrained adverse reaction over nab-PTX
Authors: Shuaijun Li, Caiting Meng, Qian Hao, Ruina Zhou, Luyao Dai, Yucheng Guo, Sitong Zhao, Xin Zhou, Chunju Lou, Ji Xu, Peng Xu, Jinfan Yang, Yifan Ding, Yanni Lv, Shengli Han, Shuai Li, Jing Li, Huafeng Kang, Zhengtao Xiao, Mingqian Tan, Xiaobin Ma, Hao Wu
Journal: Biomaterials (2024)
Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis
Authors: Jaleh Fallah, Jianjin Xu, Chana Weinstock, Xin Gao, Brian L. Heiss, William F. Maguire, Elaine Chang, Sundeep Agrawal, Shenghui Tang, Laleh Amiri-Kordestani, Richard Pazdur, Paul G. Kluetz, Daniel L. Suzman
Journal: Journal of Clinical Oncology (2024)

We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene.
Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With Peritoneal Carcinomatosis: The Need for Clear Answers Through Proper Questions
Authors: Francesca Salani, Caterina Vivaldi, Erion Rreka, Virginia Genovesi, Gianluca Masi, Piero Vincenzo Lippolis, Lorenzo Fornaro
Journal: Journal of Clinical Oncology (2024)
Behind the Mask of Intensive Care Unit Healthcare Workers
Authors: Hannah Wozniak, Ghislaine Douflé, Mika Hamilton, Erminio Santangelo, Martin Urner, Matteo Parotto, Margaret Herridge, Laura Dragoi
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Behind the Mask of Intensive Care Unit Healthcare Workers." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Prognostic and Predictive Value of Immunoscore in Stage III Colorectal Cancer: Pooled Analysis of Cases From the SCOT and IDEA-HORG Studies
Authors: Enric Domingo, Caroline Kelly, Jennifer Hay, Owen Sansom, Noori Maka, Karin Oien, Tim Iveson, Mark Saunders, Rachel Kerr, Ian Tomlinson, Joanne Edwards, Andrea Harkin, Marta Nowak, Viktor Koelzer, Alistair Easton, Ioannis Boukovinas, Eleni Moustou, Ippokratis Messaritakis, Maria Chondrozoumaki, Michaela Karagianni, Franck Pagès, Fanny Arnoux, Christelle Lautard, Yoann Lovera, Isabelle Boquet, Aurélie Catteau, Jérôme Galon, Ioannis Souglakos, David N. Church, David Church, Enric Domingo, Joanne Edwards, Bengt Glimelius, Ismail Gogenur, Andrea Harkin, Jen Hay, Timothy Iveson, Emma Jaeger, Caroline Kelly, Rachel Kerr, Noori Maka, Hannah Morgan, Karin Oien, Clare Orange, Claire Palles, Campbell Roxburgh, Owen Sansom, Mark Saunders, Ian Tomlinson
Journal: Journal of Clinical Oncology (2024)

PURPOSE Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 v 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials. METHODS Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing. Predefined cutoffs (IS-Low and IS-High) were used to classify cases into two groups for analysis of disease-free survival (3-year DFS) and multivariable-adjusted hazard ratios (mvHRs) by Cox regression. RESULTS IS was determined in 2,608 (99.5%) eligible cases, with 877 (33.7%) samples classified as IS-Low. IS-Low tumors were more commonly high-risk (T4 and/or N2; 52.9% IS-Low v 42.2% IS-High; P &lt; .001) and in younger patients ( P = .024). Patients with IS-Low tumors had significantly shorter DFS in the CAPOX, FOLFOX, and combined cohorts (mvHR, 1.52 [95% CI, 1.28 to 1.82]; mvHR, 1.58 [95% CI, 1.22 to 2.04]; and mvHR, 1.55 [95% CI, 1.34 to 1.79], respectively; P &lt; .001 all comparisons), regardless of sex, BMI, clinical risk group, tumor location, treatment duration, or chemotherapy regimen. IS prognostic value was greater in younger (≤65 years) than older (&gt;65 years) patients in the CAPOX cohort (mvHR, 1.92 [95% CI, 1.50 to 2.46] v 1.28 [95% CI, 1.01 to 1.63], P INTERACTION = .026), and in DNA mismatch repair proficient than deficient mismatch repair disease (mvHR, 1.68 [95% CI, 1.41 to 2.00] v 0.67 [95% CI, 0.30 to 1.49], P INTERACTION = .03), although these exploratory analyses were uncorrected for multiple testing. Adding IS to a model containing all clinical variables significantly improved prediction of DFS (likelihood ratio test, P &lt; .001) regardless of MMR status. CONCLUSION IS is prognostic in stage III CRC treated with FOLFOX or CAPOX, including within clinically relevant tumor subgroups. Possible variation in IS prognostic value by age and MMR status, and prediction of benefit from extended adjuvant therapy merit validation.
Airway Occlusion Pressure (P0.1) and Dyspnea During Mechanical Ventilation: Giving Words to the Pleas of the Respiratory Centers
Authors: Joaquin Pérez, Irene Telias
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Airway Occlusion Pressure (P0.1) and Dyspnea During Mechanical Ventilation: Giving Words to the Pleas of the Respiratory Centers ." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
How Can Radiopharmaceutical Therapies Reach Their Full Potential? Improving Dose Reporting and Phase I Clinical Trial Design
Authors: Ana P. Kiess, Joseph O'Donoghue, Carlos Uribe, Lisa Bodei, Robert F. Hobbs, Jacob Hesterman, Adam L. Kesner, George Sgouros, Tom Bäck, Manuel Bardies, Alessandro Bartolini, Sören Bentzen, Peter Bernhardt, Ingrid Bloise, Lisa Bodei, Wesley Bolch, Patrik Brodin, Julia Brosch-Lenz, Jacek Capala, Carlo Chiesa, Patricia E. Cole, Marta Cremonesi, Emmanuel Deshayes, Yuni Dewaraja, Roberto Formento-Cavaier, Gerhard Glatting, Harwig Hennekes, Jacob Hesterman, Rob Hobbs, Vicki Jardine, Jessica Jensen, Adam Kesner, Ana P. Kiess, Mark W. Konijnenberg, Clemens Kratochwil, Phillip H. Kuo, Roberto Maass-Moreno, Michael Morris, Quyen Nguyen, Joseph O'Donoghue, Stig Palm, Neeta Pandit-Taskar, Laurens Raes, Hendrik Rathke, Babak Saboury, Nicola Salem, Lore Santoro, Oliver Sartor, Mike Sathekge, George Sgouros, Eileen Sneeden, Lidia Strigari, Scott Tagawa, Carlos Uribe, Amanda Walker, Wolfgang Weber, Fred Wilson, Tahir Yusufaly, Sabine Zitzmann-Kolbe
Journal: Journal of Clinical Oncology (2024)
Doctors’ industrial action: in search of an endgame
Authors: Kamran Abbasi
Journal: BMJ (2024)

To those, like me, who lived through the miners' strike in South Yorkshire in the 1980s, it's clear that the then prime minister Margaret Thatcher was driven by hard ideology and harder economics rather than, as retrospectively claimed, that she championed climate action.The end of the slave trade was driven by hard economics more than the principle of ending slavery.Indeed, slavery continued for decades afterwards.The lesson here is that, apart from exceptional cases, the political world of power and privilege invariably dances to an economic tune.
The Role of Inflammation and Fibrosis in ILD Treatment Decisions
Authors: Juergen Behr, Margaret L. Salisbury, Simon L. F. Walsh, Anna J. Podolanczuk, Lida P. Hariri, Gary M. Hunninghake, Martin Kolb, Christopher J. Ryerson, Vincent Cottin, Mary B. Beasley, Tamera Corte, Allan R. Glanville, Ayodeji Adegunsoye, Cory Hogaboam, Wim A. Wuyts, Imre Noth, Justin M. Oldham, Luca Richeldi, Ganesh Raghu, Athol U. Wells
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"The Role of Inflammation and Fibrosis in ILD Treatment Decisions." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma
Authors: James K. Godfrey, Lei Gao, Geoffrey Shouse, Joo Y. Song, Stacy Pak, Brian Lee, Bihong T. Chen, Avyakta Kallam, John H. Baird, Guido Marcucci, Lucy Y. Ghoda, Stephanie Vauleon, Alexey V Danilov, Alex F. Herrera, Larry W Kwak, Lihua E Budde
Journal: Blood (2024)
Just a spoonful of metformin helps the medicine go down
Authors: Theophilos Tzaridis, Robert J Wechsler-Reya
Journal: Journal of Clinical Investigation (2024)

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors.
Lymphatic malformations: mechanistic insights and evolving therapeutic frontiers
Authors: Milena Petkova, Ingvar Ferby, Taija Mäkinen
Journal: Journal of Clinical Investigation (2024)

The lymphatic vascular system is gaining recognition for its multifaceted role and broad pathological significance. Once perceived as a mere conduit for interstitial fluid and immune cell transport, recent research has unveiled its active involvement in critical physiological processes and common diseases, including inflammation, autoimmune diseases, and atherosclerosis. Consequently, abnormal development or functionality of lymphatic vessels can result in serious health complications. Here, we discuss lymphatic malformations (LMs), which are localized lesions that manifest as fluid-filled cysts or extensive infiltrative lymphatic vessel overgrowth, often associated with debilitating, even life-threatening, consequences. Genetic causes of LMs have been uncovered, and several promising drug-based therapies are currently under investigation and will be discussed.
Circadian Influences on Myocardial Ischemia-Reperfusion Injury and Heart Failure
Authors: Tobias Eckle, Júlia Bertazzo, Tarak Nath Khatua, Seyed Reza Fatemi Tabatabaei, Naghmeh Moori Bakhtiari, Lori A. Walker, Tami A. Martino
Journal: Circulation Research (2024)

The impact of circadian rhythms on cardiovascular function and disease development is well established, with numerous studies in genetically modified animals emphasizing the circadian molecular clock's significance in the pathogenesis and pathophysiology of myocardial ischemia and heart failure progression. However, translational preclinical studies targeting the heart's circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine. In this review, we explore circadian molecular mechanisms and novel therapies, including (1) intense light, (2) small molecules modulating the circadian mechanism, and (3) chronotherapies such as cardiovascular drugs and meal timings. These promise significant clinical translation in circadian medicine for cardiovascular disease. (4) Additionally, we address the differential functioning of the circadian mechanism in males versus females, emphasizing the consideration of biological sex, gender, and aging in circadian therapies for cardiovascular disease.
Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery
Authors: Mari Kim, Richard F. Keep, Shirley L. Zhang
Journal: Circulation Research (2024)

The blood-brain barrier (BBB) is a critical interface separating the central nervous system from the peripheral circulation, ensuring brain homeostasis and function. Recent research has unveiled a profound connection between the BBB and circadian rhythms, the endogenous oscillations synchronizing biological processes with the 24-hour light-dark cycle. This review explores the significance of circadian rhythms in the context of BBB functions, with an emphasis on substrate passage through the BBB. Our discussion includes efflux transporters and the molecular timing mechanisms that regulate their activities. A significant focus of this review is the potential implications of chronotherapy, leveraging our knowledge of circadian rhythms for improving drug delivery to the brain. Understanding the temporal changes in BBB can lead to optimized timing of drug administration, to enhance therapeutic efficacy for neurological disorders while reducing side effects. By elucidating the interplay between circadian rhythms and drug transport across the BBB, this review offers insights into innovative therapeutic interventions.
Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis
Authors: Dennis G. Moledina, Wassim Obeid, Rex N. Smith, Ivy Rosales, Meghan E. Sise, Gilbert Moeckel, Michael Kashgarian, Michael Kuperman, Kirk N. Campbell, Sean Lefferts, Kristin Meliambro, Markus Bitzer, Mark A. Perazella, Randy L. Luciano, Jordan S. Pober, Lloyd G. Cantley, Robert B. Colvin, F. Perry Wilson, Chirag R. Parikh
Journal: Journal of Clinical Investigation (2024)
Circadian Rhythms in Cardiovascular Metabolism
Authors: Hind Lal, Suresh Kumar Verma, Yajing Wang, Min Xie, Martin E. Young
Journal: Circulation Research (2024)

Energetic demand and nutrient supply fluctuate as a function of time-of-day, in alignment with sleep-wake and fasting-feeding cycles. These daily rhythms are mirrored by 24-hour oscillations in numerous cardiovascular functional parameters, including blood pressure, heart rate, and myocardial contractility. It is, therefore, not surprising that metabolic processes also fluctuate over the course of the day, to ensure temporal needs for ATP, building blocks, and metabolism-based signaling molecules are met. What has become increasingly clear is that in addition to classic signal-response coupling (termed reactionary mechanisms), cardiovascular-relevant cells use autonomous circadian clocks to temporally orchestrate metabolic pathways in preparation for predicted stimuli/stresses (termed anticipatory mechanisms). Here, we review current knowledge regarding circadian regulation of metabolism, how metabolic rhythms are synchronized with cardiovascular function, and whether circadian misalignment/disruption of metabolic processes contribute toward the pathogenesis of cardiovascular disease.
Circadian Regulation of Cardiac Arrhythmias and Electrophysiology
Authors: Brian P. Delisle, Abhilash Prabhat, Don E. Burgess, Makoto Ono, Karyn A. Esser, Elizabeth A. Schroder
Journal: Circulation Research (2024)

Circadian rhythms in physiology and behavior are ≈24-hour biological cycles regulated by internal biological clocks (ie, circadian clocks) that optimize organismal homeostasis in response to predictable environmental changes. These clocks are present in virtually all cells in the body, including cardiomyocytes. Many decades ago, clinicians and researchers became interested in studying daily patterns of triggers for sudden cardiac death, the incidence of sudden cardiac death, and cardiac arrhythmias. This review highlights historical and contemporary studies examining the role of day/night rhythms in the timing of cardiovascular events, delves into changes in the timing of these events over the last few decades, and discusses cardiovascular disease-specific differences in the timing of cardiovascular events. The current understanding of the environmental, behavioral, and circadian mechanisms that regulate cardiac electrophysiology is examined with a focus on the circadian regulation of cardiac ion channels and ion channel regulatory genes. Understanding the contribution of environmental, behavioral, and circadian rhythms on arrhythmia susceptibility and the incidence of sudden cardiac death will be essential in developing future chronotherapies.
Contralateral versus ipsilateral vaccine boosting for COVID-19: considering the broader scientific landscape
Authors: Paul Goepfert
Journal: Journal of Clinical Investigation (2024)

In the relentless battle against the COVID-19 pandemic, the deployment of mRNA vaccines has stood out as a beacon of hope. The successes of Pfizer-BioNTech NT162b2 and Moderna mRNA-1273 vaccines have been remarkable, marking a revolutionary advancement in the field of vaccinology. Despite their rapid development and impressive efficacy, challenges have emerged, particularly concerning the waning immune response over time and the evolving landscape of SARS-CoV-2 variants. The study published in this issue of JCI by Fazli et al. introduces an approach to potentially enhancing the immune responses generated by COVID-19 mRNA vaccines. The study meticulously examines the outcomes of nearly 1,000 participants who received one or two booster doses with the Pfizer-BioNTech NT162b2 vaccine either ipsilaterally or contralaterally in relation to the initial vaccine dose. Intriguingly, those who received the booster contralaterally exhibited a heightened antibody response that was particularly noteworthy in the later time points after boost.
ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis through activation of NRF2
Authors: Maowu Luo, Lei Bao, Yuanyuan Xue, Ming Zhu, Ashwani Kumar, Chao Xing, Jennifer E. Wang, Yingfei Wang, Weibo Luo
Journal: Journal of Clinical Investigation (2024)

Breast cancer stem cells (BCSCs) mitigate oxidative stress to maintain their viability and plasticity. However, the regulatory mechanism of oxidative stress in BCSCs remains unclear. We recently found that the histone reader ZMYND8 was upregulated in BCSCs. Here, we showed that ZMYND8 reduced ROS and iron to inhibit ferroptosis in aldehyde dehydrogenase–high (ALDHhi) BCSCs, leading to BCSC expansion and tumor initiation in mice. The underlying mechanism involved a two-fold posttranslational regulation of nuclear factor erythroid 2–related factor 2 (NRF2). ZMYND8 increased stability of NRF2 protein through KEAP1 silencing. On the other hand, ZMYND8 interacted with and recruited NRF2 to the promoters of antioxidant genes to enhance gene transcription in mammospheres. NRF2 phenocopied ZMYND8 to enhance BCSC stemness and tumor initiation by inhibiting ROS and ferroptosis. Loss of NRF2 counteracted ZMYND8's effects on antioxidant genes and ROS in mammospheres. Interestingly, ZMYND8 expression was directly controlled by NRF2 in mammospheres. Collectively, these findings uncover a positive feedback loop that amplifies the antioxidant defense mechanism sustaining BCSC survival and stemness.
The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling
Authors: Babita Madan, Shawn R. Wadia, Siddhi Patnaik, Nathan Harmston, Emile Tan, Iain Bee Huat Tan, W. David Nes, Enrico Petretto, David M. Virshup
Journal: Journal of Clinical Investigation (2024)

Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here, we report that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulated the abundance of the specific C4-methyl sterols lophenol and dihydro-T-MAS. Highlighting its clinical relevance, FAXDC2 was repressed in Wnt/β-catenin–high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulated in the cancerous tissues and not in adjacent normal tissues. FAXDC2 linked Wnts to RTK/MAPK signaling. Wnt inhibition drove increased recycling of RTKs and activation of the MAPK pathway, and this required FAXDC2. Blocking Wnt signaling in Wnt-high cancers caused both differentiation and senescence; and this was prevented by knockout of FAXDC2. Our data show the integration of 3 ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation.
Circadian Effects on Vascular Immunopathologies
Authors: Qun Zeng, Valeria Maria Oliva, María Ángeles Moro, Christoph Scheiermann
Journal: Circulation Research (2024)

Circadian rhythms exert a profound impact on most aspects of mammalian physiology, including the immune and cardiovascular systems. Leukocytes engage in time-of-day–dependent interactions with the vasculature, facilitating the emigration to and the immune surveillance of tissues. This review provides an overview of circadian control of immune-vascular interactions in both the steady state and cardiovascular diseases such as atherosclerosis and infarction. Circadian rhythms impact both the immune and vascular facets of these interactions, primarily through the regulation of chemoattractant and adhesion molecules on immune and endothelial cells. Misaligned light conditions disrupt this rhythm, generally exacerbating atherosclerosis and infarction. In cardiovascular diseases, distinct circadian clock genes, while functioning as part of an integrated circadian system, can have proinflammatory or anti-inflammatory effects on these immune-vascular interactions. Here, we discuss the mechanisms and relevance of circadian rhythms in vascular immunopathologies.
Circadian Clock and Hypoxia
Authors: Francesca Sartor, Borja Ferrero-Bordera, Jeffrey Haspel, Markus Sperandio, Paul M. Holloway, Martha Merrow
Journal: Circulation Research (2024)

The timing of life on Earth is remarkable: between individuals of the same species, a highly similar temporal pattern is observed, with shared periods of activity and inactivity each day. At the individual level, this means that over the course of a single day, a person alternates between two states. They are either upright, active, and communicative or they lie down in a state of (un)consciousness called sleep where even the characteristic of neuronal signals in the brain shows distinctive properties. The circadian clock governs both of these time stamps-activity and (apparent) inactivity-making them come and go consistently at the same approximate time each day. This behavior thus represents the meeting of two pervasive systems: the circadian clock and metabolism. In this article, we will describe what is known about how the circadian clock anticipates daily changes in oxygen usage, how circadian clock regulation may relate to normal physiology, and to hypoxia and ischemia that can result from pathologies such as myocardial infarction and stroke.