tbuckley/cabot-search huggingface dataset:
Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis
Authors: Kevin Kleffman, Grace Levinson, Indigo V.L. Rose, Lili M. Blumenberg, Sorin A.A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von Itter, Alfredo Floristán, Gillian Baptiste, Nicole M. Eskow, James A. Tranos, Jenny Chen, Eleazar C. Vega y Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue-Ming Li, Paul Mathews, Ronald B. DeMattos, Beatrix Ueberheide, Kelly V. Ruggles, Shane A. Liddelow, Robert J. Schneider, Eva Hernando
Journal: Cancer Discovery (2022)

Abstract Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared with those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Aβ) for growth and survival in the brain parenchyma. Melanoma-secreted Aβ activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacologic inhibition of Aβ decreases brain metastatic burden. Significance: Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer's disease, two previously unrelated pathologies; establish Aβ as a promising therapeutic target for brain metastasis; and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma. This article is highlighted in the In This Issue feature, p. 1171
Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial
Authors: Ahmed J Yousuf, Seid Mohammed, Liesl Carr, Mohammadali Yavari Ramsheh, Claudia Micieli, Vijay Mistry, Kairobi Haldar, Adam Wright, Petr Novotny, Sarah Parker, Sarah Glover, Joanne Finch, Niamh Quann, Cassandra L Brookes, Rachel Hobson, Wadah Ibrahim, Richard J Russell, Catherine John, Michele A Grimbaldeston, David F Choy, Dorothy Cheung, Michael Steiner, Neil J Greening, Christopher E Brightling
Journal: The Lancet Respiratory Medicine (2022)
Quality standards for the management of non-alcoholic fatty liver disease (NAFLD): consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group
Authors: Stuart McPherson, Matthew J Armstrong, Jeremy F Cobbold, Lynsey Corless, Quentin M Anstee, Richard J Aspinall, Stephen T Barclay, Paul N Brennan, Tessa M Cacciottolo, Robert D Goldin, Kate Hallsworth, Vanessa Hebditch, Kathryn Jack, Helen Jarvis, Jill Johnson, Wenhao Li, Dina Mansour, Mary McCallum, Ashis Mukhopadhya, Richard Parker, Valerie Ross, Ian A Rowe, Ankur Srivastava, Prarthana Thiagarajan, Alexandra I Thompson, Jeremy Tomlinson, Emmanuel A Tsochatzis, Andrew Yeoman, William Alazawi
Journal: The Lancet. Gastroenterology & hepatology (2022)
Molecular architecture determines brain delivery of a transferrin receptor–targeted lysosomal enzyme
Authors: Annie Arguello, Cathal S. Mahon, Meredith E.K. Calvert, Darren Chan, Jason C. Dugas, Michelle E. Pizzo, Elliot R. Thomsen, Roni Chau, Lorna A. Damo, Joseph Duque, Meng Fang, Tina Giese, Do Jin Kim, Nicholas Liang, Hoang N. Nguyen, Hilda Solanoy, Buyankhishig Tsogtbaatar, Julie C. Ullman, Junhua Wang, Mark S. Dennis, Dolores Diaz, Kannan Gunasekaran, Kirk R. Henne, Joseph W. Lewcock, Pascal E. Sanchez, Matthew D. Troyer, Jeffrey M. Harris, Kimberly Scearce-Levie, Lu Shan, Ryan J. Watts, Robert G. Thorne, Anastasia G. Henry, Mihalis S. Kariolis
Journal: The Journal of Experimental Medicine (2022)

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR-binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases.
Genetic Polymorphisms and Correlation with Treatment-Induced Cardiotoxicity and Prognosis in Patients with Breast Cancer
Authors: Parvin F. Peddi, Peter A. Fasching, Duan Liu, Emmanuel Quinaux, Nicholas J. Robert, Vicente Valero, John Crown, Carla Falkson, Adam Brufsky, Julie M. Cunningham, Richard M. Weinshilboum, Tadeusz Pienkowski, Wolfgang Eiermann, Miguel Martín, Valerie Bee, Xiaoyan Wang, Liewei Wang, Eric Yang, Dennis J. Slamon, Sara A. Hurvitz
Journal: Clinical Cancer Research (2022)

Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. HER2 codon 655 and SLC28A3 gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported.Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in HER2 codon 655 and SLC28A3. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes.Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in HER2 (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the SLC28A3 gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non-trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy.In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.
Anticoagulant Therapy for 6 Weeks vs 3 Months and Recurrence and Bleeding in Patients Younger Than 21 Years With Provoked Venous Thromboembolism—Reply
Authors: Neil A. Goldenberg, Leonardo R. Brandão, Christoph Male
Journal: JAMA (2022)

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 HomeNew OnlineCurrent IssueFor Authors Publications 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 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 journal
Regional vs General Anesthesia and Incidence of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery
Authors: Chika Edward Uzoigwe, Frederick Campbell-Jones
Journal: JAMA (2022)

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 HomeNew OnlineCurrent IssueFor Authors Publications 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 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 journal
Provisional Mortality Data — United States, 2021
Authors: Farida B. Ahmad, Jodi A. Cisewski, Robert N. Anderson
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

The CDC National Center for Health Statistics' (NCHS) National Vital Statistics System (NVSS) collects and reports annual mortality statistics using U.S. death certificate data. Because of the time needed to investigate certain causes of death and to process and review death data, final annual mortality data for a given year are typically released 11 months after the end of the calendar year. Provisional data, which are based on death certificate data received but not fully reviewed by NCHS, provide an early estimate of deaths before the release of final data. NVSS routinely releases provisional mortality data for all causes of death and for deaths involving COVID-19.* This report presents an overview of provisional U.S. mortality data for 2021, including a comparison of death rates for 2020 and 2021. In 2021, approximately 3,458,697 deaths† occurred in the United States. From 2020 to 2021, the age-adjusted death rate (AADR) increased by 0.7%, from 835.4 to 841.6 per 100,000 standard population. COVID-19 was reported as the underlying cause or a contributing cause in an estimated 460,513 (13.3%) of those deaths (111.4 deaths per 100,000). The highest overall death rates by age occurred among persons aged ≥85 years, and the highest overall AADRs by sex and race and ethnicity occurred among males and non-Hispanic American Indian or Alaska Native (AI/AN) and non-Hispanic Black or African American (Black) populations. COVID-19 death rates were highest among persons aged ≥85 years, non-Hispanic Native Hawaiian or other Pacific Islander (NH/OPI) and AI/AN populations, and males. For a second year, the top three leading causes of death by underlying cause were heart disease, cancer, and COVID-19. Provisional death estimates provide an early indication of shifts in mortality trends and can guide public health policies and interventions aimed at reducing mortality directly or indirectly associated with the pandemic and among persons most affected, including persons who are older, male, or from certain race and ethnic minority groups.
In adults with overweight or obesity, adding weight-lowering drugs to lifestyle modification improves weight loss
Authors: Shohinee Sarma, Lorraine Lipscombe
Journal: Annals of Internal Medicine (2022)

Source Citation Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. Lancet. 2022;399:259-69. 34895470
Dietary<i>Lactobacillus</i>-Derived Exopolysaccharide Enhances Immune-Checkpoint Blockade Therapy
Authors: Hirotaka Kawanabe-Matsuda, Kazuyoshi Takeda, Marie Nakamura, Seiya Makino, Takahiro Karasaki, Kazuhiro Kakimi, Megumi Nishimukai, Tatsukuni Ohno, Jumpei Omi, Kuniyuki Kano, Akiharu Uwamizu, Hideo Yagita, Ivo Gomperts Boneca, Gérard Eberl, Junken Aoki, Mark J. Smyth, Ko Okumura
Journal: Cancer Discovery (2022)

Microbes and their byproducts have been reported to regulate host health and immune functions. Here we demonstrated that microbial exopolysaccharide produced by Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 (EPS-R1) induced CCR6+ CD8+ T cells of mice and humans. In mice, ingestion of EPS-R1 augmented antitumor effects of anti-CTLA-4 or anti-PD-1 monoclonal antibody against CCL20-expressing tumors, in which infiltrating CCR6+ CD8+ T cells were increased and produced IFNγ accompanied by a substantial immune response gene expression signature maintaining T-cell functions. Of note, the antitumor adjuvant effect of EPS-R1 was also observed in germ-free mice. Furthermore, the induction of CCR6 expression was mediated through the phosphorylated structure in EPS-R1 and a lysophosphatidic acid receptor on CD8+ T cells. Overall, we find that dietary EPS-R1 consumption induces CCR6+ CD8+ T cells in Peyer's patches, favoring a tumor microenvironment that augments the therapeutic effect of immune-checkpoint blockade depending on CCL20 production by tumors. Gut microbiota- and probiotic-derived metabolites are attractive agents to augment the efficacy of immunotherapies. Here we demonstrated that dietary consumption of Lactobacillus-derived exopolysaccharide induced CCR6+ CD8+ T cells in Peyer's patches and improved the tumor microenvironment to augment the therapeutic effects of immune-checkpoint blockade against CCL20-producing tumors. See related commentary by Di Luccia and Colonna, p. 1189. This article is highlighted in the In This Issue feature, p. 1171.
Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2–Deficient Hearts
Authors: Chantal J.M. van Opbergen, Navratan Bagwan, Svetlana R. Maurya, Joon-Chul Kim, Abigail N. Smith, Daniel J. Blackwell, Jeffrey N. Johnston, Björn C. Knollmann, Marina Cerrone,, Alicia Lundby, Mario Delmar
Journal: Circulation (2022)

Exercise training, and catecholaminergic stimulation, increase the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy correlated with plakophilin-2 (PKP2) mutations. Separate data show that reduced abundance of PKP2 leads to dysregulation of intracellular Ca
Advancing the inclusion of underrepresented women in clinical research
Authors: Barbara E Bierer, Laura G Meloney, Hayat R Ahmed, Sarah A White
Journal: Cell Reports Medicine (2022)

Women, and specifically women of color, are underrepresented in clinical trials, limiting biological understanding and contributing to health inequities and social injustice. Analyses of barriers to inclusion suggest practical interventions that together create a roadmap of specific and actionable steps to increase diverse representation in research and sustainable change.
Prevalence of nasopharyngeal Streptococcus pneumoniae carriage and resistance to macrolides in the setting of azithromycin mass drug administration: analysis from a cluster-randomised controlled trial in Malawi, 2015–17
Authors: John D Hart, Lyson Samikwa, Harry Meleke, Sarah E Burr, Jen Cornick, Khumbo Kalua, Robin L Bailey
Journal: The Lancet Microbe (2022)

Azithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study.In the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1-59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015-17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to culture Streptococcus pneumoniae. The primary outcome was the proportion of S pneumoniae isolates exhibiting macrolide resistance at 12 months and 24 months, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02048007.At baseline, 3467 (76%) of 4541 eligible children in the azithromycin group and 3107 (72%) of 4308 eligible children in the placebo group were treated. 564 nasopharyngeal swabs were taken from the azithromycin group and 563 from the placebo group, with similar numbers of swabs taken at 12 months and 24 months. In both groups at baseline, carriage of S pneumoniae was greater than 85% and the proportion of strains resistant to macrolides was 28%. At the 12-month follow-up, macrolide resistance was higher in the azithromycin group (36·9%, 95% CI 32·5-41·2) than in the placebo group (21·6%, 17·7-25·4; OR 2·26, 95% CI 1·46-3·49; p=0·0002). At 24 months, macrolide resistance remained higher in the azithromycin group (43·9%, 39·2-48·5) compared with placebo (32·8%, 28·5-37·1; OR 1·66, 1·15-2·40; p=0·0069).These findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality.Bill & Melinda Gates Foundation.
Tumor Immune Microenvironment of Brain Metastases: Toward Unlocking Antitumor Immunity
Authors: Matthew R. Strickland, Christopher Alvarez-Breckenridge, Justin F. Gainor, Priscilla K. Brastianos
Journal: Cancer Discovery (2022)

Brain metastasis (BrM) is a devastating complication of solid tumors associated with poor outcomes. Immune-checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, but determinants of response are incompletely understood. Given the rising incidence of BrM, improved understanding of immunobiologic principles unique to the central nervous system (CNS) and dissection of those that govern the activity of ICIs are paramount toward unlocking BrM-specific antitumor immunity. In this review, we seek to discuss the current clinical landscape of ICI activity in the CNS and CNS immunobiology, and we focus, in particular, on the role of glial cells in the CNS immune response to BrM. There is an urgent need to improve patient selection for and clinical activity of ICIs in patients with cancer with concomitant BrM. Increased understanding of the unique immunobiologic principles that govern response to ICIs in the CNS is critical toward identifying targets in the tumor microenvironment that may potentiate antitumor immunity.
Intracellular infection and immune system cues rewire adipocytes to acquire immune function
Authors: George Caputa, Mai Matsushita, David E. Sanin, Agnieszka M. Kabat, Joy Edwards-Hicks, Katarzyna M. Grzes, Roland Pohlmeyer, Michal A. Stanczak, Angela Castoldi, Jovana Cupovic, Aaron J. Forde, Petya Apostolova, Maximilian Seidl, Nikki van Teijlingen Bakker, Matteo Villa, Francesc Baixauli, Andrea Quintana, Alexandra Hackl, Lea Flachsmann, Fabian Hässler, Jonathan D. Curtis, Annette E. Patterson, Philipp Henneke, Erika L. Pearce, Edward J. Pearce
Journal: Cell Metabolism (2022)
Lumbar Spinal Stenosis
Authors: Kristin L. Walter, John E. O’Toole
Journal: JAMA (2022)

Lumbar Spinal StenosisLumbar spinal stenosis involves narrowing of the spinal canal, which extends through the center of the spinal vertebrae, in the lower back area.Lumbar spinal stenosis may cause pressure on the nerve roots that branch out from the spinal cord, which can result in pain, tingling, numbness, muscle fatigue, and, if severe, weakness in the legs.
Multiomic Analysis Reveals Comprehensive Tumor Heterogeneity and Distinct Immune Subtypes in Multifocal Intrahepatic Cholangiocarcinoma
Authors: Shuling Chen, Yubin Xie, Yuhong Cai, Huanjing Hu, Minghui He, Lijuan Liu, Changyi Liao, Yuanqi Wang, Jianping Wang, Xiaoxue Ren, Qianwen Zeng, Hong Peng, Shunli Shen, Shaoqiang Li, Dongming Li, Jiaming Lai, Baogang Peng, Jian Ren, Ming Kuang, Sui Peng
Journal: Clinical Cancer Research (2021)

Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making.We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed.Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor-immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression.There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.