tbuckley/cabot-search huggingface dataset:
Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD–positive AML
Authors: Jorge Cortes
Journal: Journal of Hematology & Oncology (2024)

Mutations in FMS-related receptor tyrosine kinase 3 (FLT3) are among the most common alterations in acute myeloid leukemia (AML), present in ≈30% of newly diagnosed AML cases. Internal tandem duplications (ITD) in FLT3 (FLT3-ITD) occur in ≈25% of newly diagnosed AML cases and are associated with unfavorable outcomes. Quizartinib (formerly AC220) is a novel, second-generation, highly potent, and selective type II FLT3 inhibitor. Quizartinib is approved in Japan as monotherapy for the treatment of adult patients with FLT3-ITD–positive relapsed/refractory (R/R) AML. Quizartinib is also approved in the United States, Japan, Europe, and United Kingdom in combination with chemotherapy during induction and consolidation, and as maintenance monotherapy (but, in the United States, not after allogeneic hematopoietic cell transplantation [allo-HCT]), for the treatment of adult patients with newly diagnosed FLT3-ITD–positive AML. In this review, we summarize preclinical studies that established quizartinib as a potent and selective type II FLT3 inhibitor as well as early and pivotal phase 3 clinical studies (QuANTUM-R and QuANTUM-First) that led to the approvals of quizartinib. We also summarize mechanisms of resistance to quizartinib along with its safety profile. Furthermore, we review the ongoing post hoc analyses of the QuANTUM-First data elucidating the impact of allo-HCT, the presence of measurable residual disease, and number and length of ITD on the clinical outcomes of quizartinib. We also describe the impact of quizartinib on patient-reported outcomes. Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD–positive AML, patients with FLT3-ITD–negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD–negative AML.
The protozoan commensal <i>Tritrichomonas musculis</i> is a natural adjuvant for mucosal IgA
Authors: Eric Yixiao Cao, Kyle Burrows, Pailin Chiaranunt, Ana Popovic, Xueyang Zhou, Cong Xie, Ayushi Thakur, Graham Britton, Matthew Spindler, Louis Ngai, Siu Ling Tai, Dragos Cristian Dasoveanu, Albert Nguyen, Jeremiah J. Faith, John Parkinson, Jennifer L. Gommerman, Arthur Mortha
Journal: The Journal of Experimental Medicine (2024)

Immunoglobulin (Ig) A supports mucosal immune homeostasis and host–microbiota interactions. While commensal bacteria are known for their ability to promote IgA, the role of non-bacterial commensal microbes in the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T cell–dependent, IgA class-switch recombination, and intestinal accumulation of IgA-secreting plasma cells (PC). T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells is central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, T.mu further improves the induction of IgA-secreting PC specific to orally ingested antigens and their peripheral dissemination, identifying T.mu as a “natural adjuvant” for IgA. Collectively, these findings propose a protozoa-driven mode of IgA induction to support intestinal immune homeostasis.
Going the Distance—Whether the Outcome Is Worth the Travel
Authors: Ngoc-Quynh Chu, Daniela Molena
Journal: JAMA Surgery (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast JAMA+ AI Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Travel to High-Volume Centers and Survival After Esophagectomy for Cancer
Authors: Sara Sakowitz, Syed Shahyan Bakhtiyar, Saad Mallick, Jane Yanagawa, Peyman Benharash
Journal: JAMA Surgery (2024)

Ongoing efforts have encouraged the regionalization of esophageal adenocarcinoma treatment to high-volume centers (HVCs). Yet such centralization has been linked with increased patient travel burden and reduced postoperative continuity of care.
Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease
Authors: Saborni Chakraborty, Bowie Yik-Ling Cheng, Desmond L Edwards, Joseph C Gonzalez, David Kung-Chun Chiu, Hong Zheng, Courtney Scallan, Xinrong Guo, Gene S Tan, Greg P Coffey, Pamela B Conley, Patrick S Hume, William J Janssen, Derek E Byers, Philip A Mudd, Jeffery Taubenberger, Matthew Memoli, Mark M Davis, Katrin F Chua, Michael S Diamond, Evangelos Andreakos, Purvesh Khatri, Taia T Wang
Journal: Immunity (2024)

While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor κB (NF-κB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains.
White matter aging and its impact on brain function
Authors: Janos Groh, Mikael Simons
Journal: Neuron (2024)

Aging has a detrimental impact on white matter, resulting in reduced volume, compromised structural integrity of myelinated axons, and an increase in white matter hyperintensities. These changes are closely linked to cognitive decline and neurological disabilities. The deterioration of myelin and its diminished ability to regenerate as we age further contribute to the progression of neurodegenerative disorders. Understanding these changes is crucial for devising effective disease prevention strategies. Here, we will discuss the structural alterations in white matter that occur with aging and examine the cellular and molecular mechanisms driving these aging-related transformations. We highlight how the progressive disruption of white matter may initiate a self-perpetuating cycle of inflammation and neural damage.
An AI-driven preoperative radiomic subtype for predicting the prognosis and treatment response of patients with papillary thyroid carcinoma
Authors: Qiang Li, Weituo Zhang, Tian Liao, Yi Gao, Yanzhi Zhang, Anqi Jin, Ben Ma, Ning Qu, Huan Zhang, Xiangqian Zheng, Dapeng Li, Xinwei Yun, Jingzhu Zhao, Herbert Yu, Ming Gao, Yu Wang, Biyun Qian
Journal: Clinical Cancer Research (2024)

From 8% to 28% of patients with papillary thyroid carcinoma (PTC) experience recurrence, complicating risk stratification and treatment. We previously identified an inflammatory molecular subtype of PTC associated with poor prognosis. Based on this subtype, we aimed to develop and validate a noninvasive radiomic signature to predict prognosis and treatment response in patients with PTC.
Imaging in Diagnosis and Active Surveillance for Prostate Cancer
Authors: Thomas Li, Sunny Nalavenkata, Jonathan Fainberg
Journal: JAMA Surgery (2024)

Importance Active surveillance (AS) has become an increasingly important option for managing low-risk and select intermediate-risk prostate cancer. Although imaging, particularly multiparametric magnetic resonance imaging (mpMRI), has emerged in the prebiopsy pathway for the diagnosis of prostate cancer, the role of mpMRI in patient selection for AS and the necessity of prostate biopsies during AS remain poorly defined. Despite well-founded biopsy schedules, there has been substantial investigation into whether imaging may supplant the need for prostate biopsies during AS. This review aimed to summarize the contemporary role of imaging in the diagnosis and surveillance of prostate cancer. Observations Multiparametric MRI is the most established form of imaging in prostate cancer, with routine prebiopsy use being shown to help urologists distinguish between clinically significant and clinically insignificant disease. The visibility of these lesions on mpMRI closely correlates with their behavior, with visible disease portending a worse prognosis. Combined with other clinical data, risk calculators may better delineate patients with higher-risk disease and exclude them from undergoing AS. While current evidence suggests that mpMRI cannot replace the need for prostate biopsy during AS due to the possibility of missing higher-risk disease, the addition of prostate biomarkers may help to reduce the frequency of these biopsies. The role of prostate-specific antigen positron emission tomography/computed tomography is still emerging but has shown promising early results as an adjunct to mpMRI in initial diagnosis. Conclusions and Relevance Imaging in prostate cancer helps to better select patients appropriate for AS, and future studies may strengthen the predictive capabilities of risk calculators. Multiparametric MRI has been shown to be imperative to rationalizing biopsies for patients enrolled in AS. However, heterogeneity in the evidence of mpMRI during AS has suggested that further prospective studies and randomized clinical trials, particularly in homogenizing reporting standards, may reveal a more defined role in monitoring disease progression.
Benefits of Different Balanced Resuscitation Ratios for Thoracic vs Abdominopelvic Traumatic Hemorrhage
Authors: Danielle Brabender, Kazuhide Matsushima, Morgan Schellenberg, Kenji Inaba, Charles Wade, John B. Holcomb, Matthew Martin
Journal: JAMA Surgery (2024)

This comparative effectiveness research uses data from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial to compare benefits with balanced resuscitation for thoracic vs abdominopelvic traumatic hemorrhage.
Vagus Nerve Preservation for Early Distal Gastric Cancer With Monitoring and Indocyanine Green Labeling
Authors: Zhibo Yan, Meng Wei, Tongchao Zhang, Jinghao Guo, Ao Yu, Yize Liang, Yadi Huang, Xiaohan Cui, Honglei Wang, Kuiquan Zhou, Zikun Dong, Wenbin Yu
Journal: JAMA Surgery (2024)

Radical gastric cancer surgery can cause functional and physiological disorders due to the resection of perigastric vagus nerves. Few studies have used intraoperative neurophysiological monitoring and indocyanine green (ICG) labeling to preserve the perigastric vagus nerve and to evaluate the corresponding effects.
Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn’s disease
Authors: Jinjie Wu, Wanyi Zeng, Hongyu Xie, Mujia Cao, Jingyi Yang, Yanchun Xie, Zhanhao Luo, Zongjin Zhang, Haoyang Xu, Weidong Huang, Tingyue Zhou, Jinyu Tan, Xiaomin Wu, Zihuan Yang, Shu Zhu, Ren Mao, Zhen He, Ping Lan
Journal: Cell Host & Microbe (2024)

Hyperplasia of mesenteric tissues in Crohn's disease, called creeping fat (CrF), is associated with surgical recurrence. Although microbiota translocation and colonization have been found in CrF, convincing mouse phenotypes and the underlying mechanisms of CrF formation remain unclear. Utilizing single-nucleus RNA (snRNA) sequencing of CrF and different mouse models, we demonstrate that the commensal Achromobacter pulmonis induces mesenteric adipogenesis through macrophage alteration. Targeted metabolome analysis reveals that L-kynurenine is the most enriched metabolite in CrF. Upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) enhances kynurenine metabolism and drives mesenteric adipogenesis. Leveraging single-cell RNA (scRNA) sequencing of mouse mesenteric tissues and macrophage-specific IDO1 knockout mice, we verify the role of macrophage-sourced L-kynurenine in mesenteric adipogenesis. Mechanistically, L-kynurenine-induced adipogenesis is mediated by the aryl hydrocarbon receptors in adipocytes. Administration of an IDO1 inhibitor or bacteria engineered to degrade L-kynurenine alleviates mesenteric adipogenesis in mice. Collectively, our study demonstrates that microbiota-induced modulation of macrophage metabolism potentiates CrF formation.
Is It Just Component Separation That Improves Reoperation Rates?
Authors: Wendy A. Brown, Yit Leang, Kaleb R. Lourensz
Journal: JAMA Surgery (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast JAMA+ AI Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Demographics and Immunotherapy Efficacy for Advanced Hepatocellular carcinoma: A Systematic Review and Meta-Analysis of Phase III Clinical Trials
Authors: Yu-Yun Shao, Andrei R. Akhmetzhanov
Journal: Liver Cancer (2024)

Introduction: Immune checkpoint inhibitors (ICIs) are fundamental in treating advanced hepatocellular carcinoma (HCC). Considering previous reports implied varied responses among patient subgroups, such as patients with different hepatitis etiologies, we planned this meta-analysis to identify specific populations that might derive greater survival benefits from ICIs as a first-line treatment. Methods: We conducted a comprehensive search in PubMed and the Cochrane Library for phase III clinical trials comparing ICIs and multikinase inhibitors (MKIs) as first-line therapies for advanced HCC. We extracted and synthesized hazard ratios (HRs) for overall survival (OS) across different patient subgroups mainly using the random effect model. Results: Our analysis included nine phase III trials involving ICIs, either alone or in combination with other treatments, compared with MKIs. The synthesized HRs for patients with hepatitis B virus, hepatitis C virus, and nonviral etiologies were 0.74, 0.77, and 0.86, respectively, showing no significant differences (p = 0.13). Such finding remained when we only analyzed clinical trials with positive results. HRs consistently favored ICIs across various demographics such as age, sex, geographic region, performance status, alpha-fetoprotein levels, and disease stage or extent. Notably, patients with extrahepatic spread showed a trend towards better outcomes (HR 0.73) compared to those without (HR 0.85, p = 0.07). Conclusion: The efficacy of ICIs as a first-line treatment for advanced HCC was consistent across diverse patient subgroups, regardless of hepatitis etiology or other demographic factors. These findings do not support using these characteristics to determine the use of ICI therapy in advanced HCC.
Abstract IA026: Methods for tumor subtype classification using cell-free DNA
Authors: Gavin Ha
Journal: Clinical Cancer Research (2024)

Abstract Accurately diagnosing the tumor histological subtype is crucial for clinical care. Changes in subtype can emerge during treatment resistance. However, obtaining a biopsy to determine the tumor histology presents challenges for patients with advanced cancers. Circulating tumor DNA (ctDNA) is a non-invasive 'liquid biopsy' solution that overcomes this limitation of tissue accessibility. Current ctDNA approaches primarily focuses on detecting genetic mutations, but these alterations alone may not fully delineate tumor histological subtypes or explain treatment resistance. Recent advancements highlight the value of epigenetic information obtained from profiling nucleosome positioning and accessibility in ctDNA. I will discuss how we applied these concepts to develop computational methods for predicting transcriptional activity and classifying tumor subtypes and phenotypes in breast, prostate, and lung cancers. These tools have applications in monitoring treatment-induced phenotype changes and expand on the utility of ctDNA for precision oncology. Citation Format: Gavin Ha. Methods for tumor subtype classification using cell-free DNA [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA026.
Abstract PR001: The CTC RPL/RPS gene signature: Targeting translation and the cell cycle inversely affects CTC metabolism but not metastasis
Authors: Dario Marchetti
Journal: Clinical Cancer Research (2024)

Abstract Melanoma brain metastasis (MBM) is the most devastating consequence of melanoma, is increasing in frequency, and is linked to poor prognosis and dismal survival. By employing an unbiased, multipronged approach, we discovered a CTC gene signature for ribosomal protein large/small subunits (RPL/RPS) which associated with MBM onset and progression. Experimental strategies involved capturing, transcriptional profiling, and interrogating CTCs, either directly isolated from blood of melanoma patients at distinct stages of progression, from CTC-driven MBM in experimental animals, or by developing/applying the first MRI CTC- derived MBM xenograft model (MRI-MBM CDX) to discriminate MBM spatial and temporal growth, thus faithfully recreating its clinical presentation. Accordingly, we hypothesized that targeting CTC ribogenesis can prevent melanoma metastasis in general, MBM in particular. We treated CDX cohorts with FDA-approved protein translation inhibitor omacetaxine in the presence or absence of CDK4/CDK6 inhibitor palbociclib, and monitored metastatic development and cell proliferation. Necropsies and IVIS imaging showed decreased MBM/extracranial metastasis in drug-treated mice, and RNA-Seq on mouse-blood-derived CTCs revealed downregulation of four RPL/RPS genes of the CTC signature. Notably, by performing the first-ever functional metabolic characterization of circulating neoplastic cells/CTCs in real- time, coupled with confirmatory RT-qPCR, we found that omacetaxine and palbociclib inversely affected glycolytic metabolism, and demonstrated that dual targeting of cell translation and proliferation is critical to suppress plasticity in metastasis-competent CTCs. This study identifies the relevance of targeting the CTC RPL/RPS signature to suppress melanoma metastasis, and set forward notions for novel therapies to affect metastasis by the deregulation of translation controlling CTC states. Studies involving structural and mechanistic analyses of CTC dormant vs active ribosomes by cryogenic electron microscopy are in progress. Citation Format: Dario Marchetti. The CTC RPL/RPS gene signature: Targeting translation and the cell cycle inversely affects CTC metabolism but not metastasis [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR001.