tbuckley/cabot-search huggingface dataset:
Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma
Authors: Katherine M. Jackson, Peter C. Jones, Laura M. Fluke, Trevan D. Fischer, John F. Thompson, Alistair J. Cochran, Stacey L. Stern, Mark B. Faries, Dave S. B. Hoon, Leland J. Foshag
Journal: JAMA Network Open (2024)

Importance While smoking is associated with a decreased incidence of cutaneous melanoma, the association of smoking with melanoma progression and death is not well defined. Objective To determine the association of smoking with survival in patients with early-stage primary cutaneous melanoma. Design, Setting, and Participants This cohort study performed a post hoc analysis of data derived from the randomized, multinational first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II). Participants were accrued for MSLT-I from January 20, 1994, to March 29, 2002; MSLT-II, from December 21, 2004, to March 31, 2014. Median follow-up was 110.0 (IQR, 53.4-120.0) months for MSLT-I and 67.6 (IQR, 25.8-110.2) months for MSLT-II. Patients aged 18 to 75 years with clinical stages I or II melanoma with a Breslow thickness of 1.00 mm or greater or Clark level IV to V and available standard prognostic and smoking data were included. Analyses were performed from October 4, 2022, to March 31, 2023. Exposure Current, former, and never smoking. Main Outcomes and Measures Melanoma-specific survival of patients with current, former, and never smoking status was assessed for the entire cohort and for nodal observation and among subgroups with sentinel lymph node biopsy (SLNB)–negative and SLNB-positive findings. Results Of 6279 included patients, 3635 (57.9%) were men, and mean (SD) age was 52.7 (13.4) years. The most common tumor location was an extremity (2743 [43.7%]), and mean (SD) Breslow thickness was 2.44 (2.06) mm. Smoking status included 1077 (17.2%) current, 1694 (27.0%) former, and 3508 (55.9%) never. Median follow-up was 78.4 (IQR, 30.5-119.6) months. Current smoking was associated with male sex, younger age, trunk site, thicker tumors, tumor ulceration, and SLNB positivity. Current smoking was associated with a greater risk of melanoma-associated death by multivariable analysis for the entire study (hazard ratio [HR], 1.48 [95% CI, 1.26-1.75]; P &amp;amp;lt; .001). Former smoking was not. The increased risk of melanoma-specific mortality associated with current smoking was greatest for patients with SLNB-negative melanoma (HR, 1.85 [95% CI, 1.35-2.52]; P &amp;amp;lt; .001), but also present for patients with SLNB-positive melanoma (HR, 1.29 [95% CI, 1.04-1.59]; P = .02) and nodal observation (HR, 1.68 [95% CI, 1.09-2.61]; P = .02). Smoking at least 20 cigarettes/d doubled the risk of death due to melanoma for patients with SLNB-negative disease (HR, 2.06 [95% CI, 1.36-3.13]; P &amp;amp;lt; .001). Conclusions and Relevance The findings of this cohort study suggest that patients with clinical stage I and II melanoma who smoked had a significantly increased risk of death due to melanoma. Smoking status should be assessed at time of melanoma diagnosis and may be considered a risk factor for disease progression.
METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2
Authors: Weicheng Lu, Xiaohua Yang, Weiqiang Zhong, Guojun Chen, Xinqi Guo, Qingqing Ye, Yixin Xu, Zhenhua Qi, Yaqi Ye, Jingyun Zhang, Yuge Wang, Xintong Wang, Shu Wang, Qiyue Zhao, Weian Zeng, Junting Huang, Huijie Ma, Jingdun Xie
Journal: Journal of Clinical Investigation (2024)

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4–L6 DRG neurons in the CINP in a DBP/METT14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment.
CDC Laboratory Recommendations for Syphilis Testing, United States, 2024
Authors: John R. Papp, Ina U. Park, Yetunde Fakile, Lara Pereira, Allan Pillay, Gail A. Bolan
Journal: MMWR Recommendations and Reports (2024)

This report provides new CDC recommendations for tests that can support a diagnosis of syphilis, including serologic testing and methods for the identification of the causative agent Treponema pallidum. These comprehensive recommendations are the first published by CDC on laboratory testing for syphilis, which has traditionally been based on serologic algorithms to detect a humoral immune response to T. pallidum. These tests can be divided into nontreponemal and treponemal tests depending on whether they detect antibodies that are broadly reactive to lipoidal antigens shared by both host and T. pallidum or antibodies specific to T. pallidum, respectively. Both types of tests must be used in conjunction to help distinguish between an untreated infection or a past infection that has been successfully treated. Newer serologic tests allow for laboratory automation but must be used in an algorithm, which also can involve older manual serologic tests. Direct detection of T. pallidum continues to evolve from microscopic examination of material from lesions for visualization of T. pallidum to molecular detection of the organism. Limited point-of-care tests for syphilis are available in the United States; increased availability of point-of-care tests that are sensitive and specific could facilitate expansion of screening programs and reduce the time from test result to treatment. These recommendations are intended for use by clinical laboratory directors, laboratory staff, clinicians, and disease control personnel who must choose among the multiple available testing methods, establish standard operating procedures for collecting and processing specimens, interpret test results for laboratory reporting, and counsel and treat patients. Future revisions to these recommendations will be based on new research or technologic advancements for syphilis clinical laboratory science.
Prothrombin Complex Concentrate vs Conservative Management in ICH Associated With Direct Oral Anticoagulants
Authors: Bonaventure Ip, Sangqi Pan, Zhong Yuan, Trista Hung, Ho Ko, Xinyi Leng, Yuying Liu, Shuang Li, Sing Yau Lee, Cyrus Cheng, Howard Chan, Vincent Mok, Yannie Soo, Xiaoli Wu, Leong Ting Lui, Rosa Chan, Jill Abrigo, Qi Dou, David Seiffge, Thomas Leung
Journal: JAMA Network Open (2024)

Importance Intracerebral hemorrhage (ICH) associated with direct oral anticoagulant (DOAC) use carries extremely high morbidity and mortality. The clinical effectiveness of hemostatic therapy is unclear. Objective To compare the clinical and radiological outcomes of DOAC-associated ICH treated with prothrombin complex concentrate (PCC) vs conservative management. Design, Setting, and Participants In this population-based, propensity score–weighted retrospective cohort study, patients who developed DOAC-associated ICH from January 1, 2016, to December 31, 2021, in Hong Kong were identified. The outcomes of patients who received 25 to 50 IU/kg PCC with those who received no hemostatic agents were compared. Data were analyzed from May 1, 2022, to June 30, 2023. Main Outcomes and Measures The primary outcome was modified Rankin scale of 0 to 3 or returning to baseline functional status at 3 months. Secondary outcomes were mortality at 90 days, in-hospital mortality, and hematoma expansion. Weighted logistic regression was performed to evaluate the association of PCC with study outcomes. In unweighted logistic regression models, factors associated with good neurological outcome and hematoma expansion in DOAC-associated ICH were identified. Results A total of 232 patients with DOAC-associated ICH, with a mean (SD) age of 77.2 (9.3) years and 101 (44%) female patients, were included. Among these, 116 (50%) received conservative treatment and 102 (44%) received PCC. Overall, 74 patients (31%) patients had good neurological recovery and 92 (39%) died within 90 days. Median (IQR) baseline hematoma volume was 21.7 mL (3.6-66.1 mL). Compared with conservative management, PCC was not associated with improved neurological recovery (adjusted odds ratio [aOR], 0.62; 95% CI, 0.33-1.16; P = .14), mortality at 90 days (aOR, 1.03; 95% CI, 0.70-1.53; P = .88), in-hospital mortality (aOR, 1.11; 95% CI, 0.69-1.79; P = .66), or reduced hematoma expansion (aOR, 0.94; 95% CI, 0.38-2.31; P = .90). Higher baseline hematoma volume, lower Glasgow coma scale, and intraventricular hemorrhage were associated with lower odds of good neurological outcome but not hematoma expansion. Conclusions and Relevance In this cohort study, Chinese patients with DOAC-associated ICH had large baseline hematoma volumes and high rates of mortality and functional disability. PCC treatment was not associated with improved functional outcome, hematoma expansion, or mortality. Further studies on novel hemostatic agents as well as neurosurgical and adjunctive medical therapies are needed to identify the best management algorithm for DOAC-associated ICH.
The Mutographs biorepository: A unique genomic resource to study cancer around the world
Authors: Sandra Perdomo, Behnoush Abedi-Ardekani, Ana Carolina de Carvalho, Aida Ferreiro-Iglesias, Valérie Gaborieau, Thomas Cattiaux, Hélène Renard, Priscilia Chopard, Christine Carreira, Andreea Spanu, Arash Nikmanesh, Ricardo Cortez Cardoso Penha, Samuel O. Antwi, Patricia Ashton-Prolla, Cristina Canova, Taned Chitapanarux, Riley Cox, Maria Paula Curado, José Carlos de Oliveira, Charles Dzamalala, Elenora Fabianova, Lorenzo Ferri, Rebecca Fitzgerald, Lenka Foretova, Steven Gallinger, Alisa M. Goldstein, Ivana Holcatova, Antonio Huertas, Vladimir Janout, Sonata Jarmalaite, Radka Kaneva, Luiz Paulo Kowalski, Tomislav Kulis, Pagona Lagiou, Jolanta Lissowska, Reza Malekzadeh, Dana Mates, Valerie McCorrmack, Diana Menya, Sharayu Mhatre, Blandina Theophil Mmbaga, André de Moricz, Péter Nyirády, Miodrag Ognjanovic, Kyriaki Papadopoulou, Jerry Polesel, Mark P. Purdue, Stefan Rascu, Lidia Maria Rebolho Batista, Rui Manuel Reis, Luis Felipe Ribeiro Pinto, Paula A. Rodríguez-Urrego, Surasak Sangkhathat, Suleeporn Sangrajrang, Tatsuhiro Shibata, Eduard Stakhovsky, Beata Świątkowska, Carlos Vaccaro, Jose Roberto Vasconcelos de Podesta, Naveen S. Vasudev, Marta Vilensky, Jonathan Yeung, David Zaridze, Kazem Zendehdel, Ghislaine Scelo, Estelle Chanudet, Jingwei Wang, Stephen Fitzgerald, Calli Latimer, Sarah Moody, Laura Humphreys, Ludmil B. Alexandrov, Michael R. Stratton, Paul Brennan
Journal: Cell Genomics (2024)

Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites. Genomic, exposure, and clinical data will be publicly available through the International Cancer Genome Consortium Accelerating Research in Genomic Oncology platform. The Mutographs sample and metadata biorepository constitutes a legacy resource for new projects and collaborations aiming to increase our current research efforts in cancer genomic epidemiology globally.
Region-specific transcriptomic responses to obesity and diabetes in macaque hypothalamus
Authors: Ying Lei, Xian Liang, Yunong Sun, Ting Yao, Hongyu Gong, Zhenhua Chen, Yuanqing Gao, Hui Wang, Ru Wang, Yunqi Huang, Tao Yang, Miao Yu, Longqi Liu, Chun-Xia Yi, Qing-Feng Wu, Xingxing Kong, Xun Xu, Shiping Liu, Zhi Zhang, Tiemin Liu
Journal: Cell Metabolism (2024)

The hypothalamus plays a crucial role in the progression of obesity and diabetes; however, its structural complexity and cellular heterogeneity impede targeted treatments. Here, we profiled the single-cell and spatial transcriptome of the hypothalamus in obese and sporadic type 2 diabetic macaques, revealing primate-specific distributions of clusters and genes as well as spatial region, cell-type-, and gene-feature-specific changes. The infundibular (INF) and paraventricular nuclei (PVN) are most susceptible to metabolic disruption, with the PVN being more sensitive to diabetes. In the INF, obesity results in reduced synaptic plasticity and energy sensing capability, whereas diabetes involves molecular reprogramming associated with impaired tanycytic barriers, activated microglia, and neuronal inflammatory response. In the PVN, cellular metabolism and neural activity are suppressed in diabetic macaques. Spatial transcriptomic data reveal microglia's preference for the parenchyma over the third ventricle in diabetes. Our findings provide a comprehensive view of molecular changes associated with obesity and diabetes.
Smoking and Melanoma Outcomes—Another Reason to Quit
Authors: Mary S. Brady
Journal: JAMA Network Open (2024)

Katherine M. Jackson, MD; Peter C. Jones, MD; Laura M. Fluke, DO; Trevan D. Fischer, MD; John F. Thompson, MD; Alistair J. Cochran, MD; Stacey L. Stern, MS; Mark B. Faries, MD; Dave S. B. Hoon, PhD; Leland J. Foshag, MD
Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner
Authors: Jianqing She, Gulinigaer Tuerhongjiang, Manyun Guo, Junhui Liu, Xiang Hao, Liangan Guo, Nairong Liu, Wen Xi, Tao Zheng, Bin Du, Bowen Lou, Xiyu Gao, Xiao Yuan, Yue Yu, Yi Zhang, Fan Gao, Xiaozhen Zhuo, Ying Xiong, Xiang Zhang, Jun Yu, Zuyi Yuan, Yue Wu
Journal: Cell Metabolism (2024)
GDF15 is a major determinant of ketogenic diet-induced weight loss
Authors: Jun Feng Lu, Meng Qing Zhu, Bo Xia, Na Na Zhang, Xiao Peng Liu, Huan Liu, Rui Xin Zhang, Jun Ying Xiao, Hui Yang, Ying Qi Zhang, Xiao Miao Li, Jiang Wei Wu
Journal: Cell Metabolism (2024)

(Cell Metabolism 35, 2165–2182.e1–e7; December 5, 2023) In the preparation of this manuscript, the GTT and ITT data shown in Figures 6M and 6N were inadvertently duplicated from Figures 4H and 4K. In the new version of Figure 6, the authors provide the correct data. This error has now been corrected online. The error does not affect any conclusions in the paper. The authors sincerely apologize for the mistakes and any resulting confusion they may have caused. GDF15 is a major determinant of ketogenic diet-induced weight lossLu et al.Cell MetabolismDecember 05, 2023In BriefApplication of a ketogenic diet (KD) for obesity management has been widely promoted, yet its underlying mechanism remains elusive. Here Lu et al. reveal a major role for GDF15 in this process. Their findings uncover a liver PPARγ-GDF15-dependent mechanism underlying KD-mediated obesity management, advancing the understanding of KD’s metabolic actions. Full-Text PDF
Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors
Authors: Solange Peters, Eric Angevin, Teresa Alonso-Gordoa, Kristoffer Rohrberg, Ignacio Melero, Begoña Mellado, Jose-Luis Perez-Gracia, Josep Tabernero, Celine Adessi, Christophe Boetsch, Carl Watson, Joseph Dal Porto, David Dejardin, Christopher Del Nagro, Valeria Nicolini, Stefan Evers, Christian Klein, Barbara Leutgeb, Pavel Pisa, Eva Rossmann, José Saro, Pablo Umana, Jehad Charo, Volker Teichgräber, Neeltje Steeghs
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The immunocytokine cergutuzumab amunaleukin (CEA-IL2v) showed manageable safety and favorable pharmacodynamics in phase I/Ib trials in patients with advanced/metastatic carcinoembryonic antigen-positive (CEA+) solid tumors, but this was accompanied by a high incidence of anti-drug antibodies (ADA). We examined B-cell depletion with obinutuzumab as a potential mitigation strategy. Experimental Design: Preclinical data comparing B-cell depletion with rituximab versus obinutuzumab are summarized. Substudies of phase I/Ib trials investigated the effect of obinutuzumab pretreatment on ADA development, safety, pharmacodynamics, and antitumor activity of CEA-IL2v ± atezolizumab in patients with advanced/metastatic or unresectable CEA+ solid tumors who had progressed on standard of care. Results: Preclinical data showed superior B-cell depletion with obinutuzumab versus rituximab. In clinical studies, patients received CEA-IL2v monotherapy with (n = 16) or without (n = 6) obinutuzumab pretreatment (monotherapy study), or CEA-IL2v + atezolizumab + obinutuzumab pretreatment (n = 5; combination study). In the monotherapy study, after four cycles (every 2 weeks treatment), 0/15 evaluable patients administered obinutuzumab pretreatment had ADAs versus 4/6 patients without obinutuzumab. Obinutuzumab pretreatment with CEA-IL2v monotherapy showed no new safety signals and pharmacodynamic data suggested minimal impact on T cells and natural killer cells. Conversely, increased liver toxicity was observed in the combination study (CEA-IL2v + atezolizumab + obinutuzumab pretreatment). Conclusions: These preliminary findings suggest that obinutuzumab pretreatment before CEA-IL2v administration in patients with CEA+ solid tumors may be a feasible and potent ADA mitigation strategy, with an acceptable safety profile, supporting broader investigation of obinutuzumab pretreatment for ADA mitigation in other settings.
TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS
Authors: Jing Yan, Yu Meng Wang, Andrea Hellwig, Hilmar Bading
Journal: Cell Reports Medicine (2024)

Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1G93A ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy. FP802 also effectively blocks NMDA-induced death of neurons in ALS patient-derived forebrain organoids. These results establish eNMDAR toxicity as a key player in ALS pathogenesis. TI inhibitors may provide an effective treatment option for ALS patients.
Updated recommendations for the Cochrane rapid review methods guidance for rapid reviews of effectiveness
Authors: Chantelle Garritty, Candyce Hamel, Marialena Trivella, Gerald Gartlehner, Barbara Nussbaumer-Streit, Declan Devane, Chris Kamel, Ursula Griebler, Valerie J King
Journal: BMJ (2024)

This article provides updated guidance on methods for conducting rapid reviews of effectiveness, targeted at Cochrane and other stakeholders interested in the methodology of rapid reviews. The guidance, developed by the Cochrane Rapid Reviews Methods Group, builds upon previous interim guidance, and incorporates changes based on an evaluation of its application, a scope of the literature on rapid review methodology, and input from a diverse group of experts in rapid review methods. The guidance consists of 24 specific recommendations supporting the conduct of rapid reviews, applicable both within and outside Cochrane. It underscores the importance of considering the appropriateness of undertaking rapid reviews and advocates for a tailored, iterative approach to each review. Key defining features of rapid reviews, such as restricted methods, how the dimension of timelines factors into rapid reviews, and the involvement of knowledge users (eg, patient and public partners, healthcare providers, policy makers), are outlined. The paper presents a definition of a Cochrane rapid review and additional considerations for rapid reviews of effectiveness to enhance the efficiency of the review process. In conclusion, the Cochrane Rapid Review Methods Group's updated guidance, complemented by examples, seeks to guide methodological decisions in the design and conduct of rapid reviews, facilitating timely decision making in healthcare.
An alternative splicing signature defines the basal-like phenotype and predicts worse clinical outcome in pancreatic cancer
Authors: Veronica Ruta, Chiara Naro, Marco Pieraccioli, Adriana Leccese, Livia Archibugi, Eleonora Cesari, Valentina Panzeri, Chantal Allgöwer, Paolo Giorgio Arcidiacono, Massimo Falconi, Carmine Carbone, Giampaolo Tortora, Federica Borrelli, Fabia Attili, Cristiano Spada, Giuseppe Quero, Sergio Alfieri, Claudio Doglioni, Alexander Kleger, Gabriele Capurso, Claudio Sette
Journal: Cell Reports Medicine (2024)

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. PDAC presents with molecularly distinct subtypes, with the basal-like one being associated with enhanced chemoresistance. Splicing dysregulation contributes to PDAC; however, its involvement in subtype specification remains elusive. Herein, we uncover a subtype-specific splicing signature associated with prognosis in PDAC and the splicing factor Quaking (QKI) as a determinant of the basal-like signature. Single-cell sequencing analyses highlight QKI as a marker of the basal-like phenotype. QKI represses splicing events associated with the classical subtype while promoting basal-like events associated with shorter survival. QKI favors a plastic, quasi-mesenchymal phenotype that supports migration and chemoresistance in PDAC organoids and cell lines, and its expression is elevated in high-grade primary tumors and metastatic lesions. These studies identify a splicing signature that defines PDAC subtypes and indicate that QKI promotes an undifferentiated, plastic phenotype, which renders PDAC cells chemoresistant and adaptable to environmental changes.