tbuckley/cabot-search huggingface dataset:
APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis
Authors: Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson
Journal: Molecular Neurodegeneration (2021)

Abstract Background Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. Methods Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. Results Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13 C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. Conclusions Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a ‘Warburg like’ endophenotype that is observable in young females decades prior to clinically manifest AD.
Engineered exosomes: desirable target-tracking characteristics for cerebrovascular and neurodegenerative disease therapies
Authors: Meng Xu, Tao Feng, Bowen Liu, Fen Qiu, Youhua Xu, Yonghua Zhao, Ying Zheng
Journal: Theranostics (2021)

As extracellular vesicles secreted by cells, exosomes are intercellular signalosomes for cell communication and pharmacological effectors. Because of their special properties, including low toxicity and immunogenicity, biodegradability, ability to encapsulate endogenous biologically active molecules and cross the blood-brain barrier (BBB), exosomes have great therapeutic potential in cerebrovascular and neurodegenerative diseases. However, the poor targeting ability of natural exosomes greatly reduces the therapeutic effect. Using engineering technology, exosomes can obtain active targeting ability to accumulate in specific cell types and tissues by attaching targeting units to the membrane surface or loading them into cavities. In this review, we outline the improved targeting functions of bioengineered exosomes, tracing and imaging techniques, administration methods, internalization in the BBB, and therapeutic effects of exosomes in cerebrovascular and neurodegenerative diseases and further evaluate the clinical opportunities and challenges in this research field.
Transpapillary removal of migrated magnets after magnetic compression biliary anastomosis
Authors: Andrea Tringali, Vincenzo Perri, Ivo Boškoski, Alessandro Cina, Guido Costamagna
Journal: Endoscopy (2021)

A 59-year-old man underwent orthotopic liver transplantation; liver re-transplantation was needed 24 hours later owing to primary liver failure. A large incisional hernia was repaired 5 years later.
Regulation of protein abundance in genetically diverse mouse populations
Authors: Gregory R. Keele, Tian Zhang, Duy T. Pham, Matthew Vincent, Timothy A. Bell, Pablo Hock, Ginger D. Shaw, Joao A. Paulo, Steven C. Munger, Fernando Pardo-Manuel de Villena, Martin T. Ferris, Steven P. Gygi, Gary A. Churchill
Journal: Cell Genomics (2021)

Genetically diverse mouse populations are powerful tools for characterizing the regulation of the proteome and its relationship to whole-organism phenotypes. We used mass spectrometry to profile and quantify the abundance of 6,798 proteins in liver tissue from mice of both sexes across 58 Collaborative Cross (CC) inbred strains. We previously collected liver proteomics data from the related Diversity Outbred (DO) mice and their founder strains. We show concordance across the proteomics datasets despite being generated from separate experiments, allowing comparative analysis. We map protein abundance quantitative trait loci (pQTLs), identifying 1,087 local and 285 distal in the CC mice and 1,706 local and 414 distal in the DO mice. We find that regulatory effects on individual proteins are conserved across the mouse populations, in particular for local genetic variation and sex differences. In comparison, proteins that form complexes are often co-regulated, displaying varying genetic architectures, and overall show lower heritability and map fewer pQTLs. We have made this resource publicly available to enable quantitative analyses of the regulation of the proteome.
Somatic<i>PIK3CA</i>Mutations in Sporadic Cerebral Cavernous Malformations
Authors: Matthieu Peyre, Danielle Miyagishima, Franck Bielle, Françoise Chapon, Michael Sierant, Quitterie Venot, Julie Lerond, Pauline Marijon, Samiya Abi-Jaoude, Tuan Le Van, Karim Labreche, Richard Houlston, Maxime Faisant, Stéphane Clémenceau, Anne-Laure Boch, Aurelien Nouet, Alexandre Carpentier, Julien Boetto, Angeliki Louvi, Michel Kalamarides
Journal: New England Journal of Medicine (2021)

Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood.We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis.We found that in mice expressing one of two common genetic drivers of meningioma - Pik3caH1047R or AKT1E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3caH1074R and AKT1E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin.In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).
Abstract 16528: Structural Instability, the Potential Cause for Current BVS Scaffold’s Failure
Authors: Yuying Bi, Tim Wu, Xuejun Jiang, Edward Kislauskis, Roger Laham
Journal: Circulation (2018)

Introduction and Hypothesis: The major reason for current Bioresorbable Scaffold (BRS) failure is due primarily to their lower radial force which leading to larger strut thickness, higher recoil ra...
Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction
Authors: Ambarish Pandey, Sanjiv J. Shah, Javed Butler, Dean L. Kellogg, Gregory D. Lewis, Daniel E. Forman, Robert J. Mentz, Barry A. Borlaug, Marc A. Simon, Julio A. Chirinos, Roger A. Fielding, Elena Volpi, Anthony J.A. Molina, Mark J. Haykowsky, Flora Sam, Bret H. Goodpaster, Alain G. Bertoni, Jamie N. Justice, James P. White, Jingzhone Ding, Scott L. Hummel, Nathan K. LeBrasseur, George E. Taffet, Iraklis I. Pipinos, Dalane Kitzman
Journal: Journal of the American College of Cardiology (2021)
PD-1 blockade and vaccination provide therapeutic benefit against SIV by inducing broad and functional CD8 <sup>+</sup> T cells in lymphoid tissue
Authors: Sheikh Abdul Rahman, Bhrugu Yagnik, Alexander P. Bally, Kristen N. Morrow, Shelly Wang, Thomas H. Vanderford, Gordon J. Freeman, Rafi Ahmed, Rama Rao Amara
Journal: Science Immunology (2021)

PD-1 blockade combined with vaccination induced anti-SIV immunity and reduced SIV viral reservoirs in lymphoid tissue.
Myosin Modulation in Hypertrophic Cardiomyopathy and Systolic Heart Failure: Getting Inside the Engine
Authors: Matthew J. Daniels, Luca Fusi, Christopher Semsarian, Srihari S. Naidu
Journal: Circulation (2021)

he palpable heartbeat requires synchronous activation, and inactivation, of trillions of motors, compartmentalized in billions of cardiomyocytes, in a fraction of a second.To bring the biophysical concepts of myocardial contraction in health and disease closer to the practicing cardiologist, we draw parallels with motor vehicles to discuss both recent advances describing how the heart modulates itself and a new era of myocardial therapeutics.Contraction requires 2 proteins: myosin and actin.MYH7 (myosin) is the molecular engine of the heart, converting the chemical energy of adenosine triphosphate (ATP) into movement.Force production at the level of the cardiomyocyte occurs when millions of myosin engines combine, pulling each of ≈50 sarcomeres per heart cell ≈10% of their resting length closer (Figure [A]).Mechanical work changes rapidly and reversibly.This is most obvious within a heartbeat, between systole (contraction) and diastole (relaxation).The Frank-Starling mechanism adjusts performance beat to beat in response to changing preload and afterload.Cardiac adaptation to pregnancy, exercise, or injury develops over longer periods.Here, we simplify what happens under the hood and explain how this applies to patients.The way myosin works dictates how the heart regulates force production.Myosin takes fixed steps (≈10 nm) that generate small amounts of force (picoNewton range), using an ATP hydrolysis mechanism that is slow (10 s -1 ).Flexibility requires variable recruitment of myosin motors.Therein lies the challenge of regulation. MYOFILAMENT-BASED REGULATION OF CARDIAC CONTRACTILITYThe molecular accelerator/brake that underpins the Frank-Starling mechanism is housed in myosin itself.
Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases
Authors: Yana Vinogradova, Tom Dening, Julia Hippisley-Cox, Lauren Taylor, Michael Moore, Carol Coupland
Journal: BMJ (2021)

Abstract Objective To assess the risks of developing dementia associated with different types and durations of menopausal hormone therapy. Design Two nested case-control studies. Setting UK general practices contributing to QResearch or the Clinical Practice Research Datalink (CPRD), using all links to hospital, mortality, and social deprivation data. Participants 118 501 women aged 55 and older with a primary diagnosis of dementia between 1998 and 2020, matched by age, general practice, and index date to 497 416 female controls. Main outcome measures Dementia diagnoses from general practice, mortality, and hospital records; odds ratios for menopausal hormone treatments adjusted for demographics, smoking status, alcohol consumption, comorbidities, family history, and other prescribed drugs. Results Overall, 16 291 (14%) women with a diagnosis of dementia and 68 726 (14%) controls had used menopausal hormone therapy more than three years before the index date. Overall, no increased risks of developing dementia associated with menopausal hormone therapy were observed. A decreased global risk of dementia was found among cases and controls younger than 80 years who had been taking oestrogen-only therapy for 10 years or more (adjusted odds ratio 0.85, 95% confidence interval 0.76 to 0.94). Increased risks of developing specifically Alzheimer’s disease were found among women who had used oestrogen-progestogen therapy for between five and nine years (1.11, 1.04 to 1.20) and for 10 years or more (1.19, 1.06 to 1.33). This was equivalent to, respectively, five and seven extra cases per 10 000 woman years. Detailed risk associations for the specific progestogens studied are also provided. Conclusion This study gives estimates for risks of developing dementia and Alzheimer’s disease in women exposed to different types of menopausal hormone therapy for different durations and has shown no increased risks of developing dementia overall. It has shown a slightly increased risk of developing Alzheimer’s disease among long term users of oestrogen-progestogen therapies.
Different Risks and Benefits Leading to Similar Costs After Sleeve Gastrectomy and Roux-en-Y Gastric Bypass
Authors: David Arterburn, Kristina H. Lewis
Journal: JAMA Network Open (2021)

Jean-Eric Tarride, MA, PhD; Aristithes G. Doumouras, MD, MPH; Dennis Hong, MD, MSc; J. Michael Paterson, MSc; Semra Tibebu, MPH; Francis Nguyen, MPH; Richard Perez, MSc; Valerie H. Taylor, MD, PhD; Feng Xie, PhD; Vanessa Boudreau, MD; Eleanor Pullenayegum, MA, PhD; David R. Urbach, MSc, MD; Mehran Anvari, MB BS, PhD
Comparison of SARS-CoV-2 Antibody Response Following Vaccination With BNT162b2 and mRNA-1273
Authors: Deborah Steensels, Noella Pierlet, Joris Penders, Dieter Mesotten, Line Heylen
Journal: JAMA (2021)

Deborah Steensels, PharmD, PhD; Els Oris, MD; Laura Coninx, MSc, PhD; Dieter Nuyens, MD, PhD; Marie-Luce Delforge, MD, PhD; Pieter Vermeersch, MD, PhD; Line Heylen, MD, PhD
急性期再灌流時にNo-Reflowとなり,亜急性期の再PCI時に異なった反応を示した急性心筋梗塞の二例
Authors: 森川修司, 曽根孝仁, 坪井英之, 武川博昭, 森島逸郎, 上杉道伯, 高木健督, 丹羽亨, 泉雄介, 山本寿彦
Journal: Circulation (2007)
What Is the Optimal Treatment for Vulnerable Older Women With Ovarian Cancer?
Authors: Makoto Kosaka, Tomonori Mizutani, Hiroto Ishiki
Journal: JAMA Oncology (2021)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Oncology journal
Extremely short bioavailability and fast pharmacodynamic effects of pMHC-based nanomedicines
Authors: Yang Yang, Kristofor K Ellestad, Santiswarup Singha, Muhammad Myn Uddin, Robert Clarke, Debajyoti Mondal, Nahir Garabatos, Patricia Solé, Cesar Fandos, Pau Serra, Pere Santamaria
Journal: Journal of Controlled Release (2021)

Nanoparticles (NPs) coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHCs) can blunt autoimmune diseases by re-programming cognate effector T-lymphocytes into disease-suppressing regulatory T-cells, followed by massive expansion. Here, a method to quantify the absolute amounts of the active drug product is developed, to understand the relationship between bioavailability and pharmacodynamics. Incubation with plasma results in the formation of a protein corona that stabilizes the directional pMHC coat, shielding it from proteolysis or anti-drug antibody recognition, without any appreciable loss in biological potency. A quantitative method that harnesses these features indicates that the half-life of these compounds in the circulation and organs is an order of magnitude shorter (minutes vs. hours) than that measured using commonly-used semi-quantitative methods. Extensive transmission electron microscopy-based organ scanning and flow cytometry-based enumeration of pMHCII-NP capturing cells confirmed that these compounds are rapidly captured (within 1 min) by liver sinusoidal endothelial cells, Kupffer cells, splenic phagocytes and cognate T-cells, leading to a fast decline in the circulation. Therefore, the powerful pharmacodynamic effects of these compounds are dissociated from long bioavailability, implying a hit-and-run event. Collectively, these data provide a detailed view of the life-cycle of a nanoimmunomedicine, and suggest that the real half-lives of intact nanomedicines may be much shorter than those estimated using indirect approaches.
4-Aminopyridine is a promising treatment option for patients with gain-of-function <i>KCNA2</i> -encephalopathy
Authors: Ulrike B. S. Hedrich, Stephan Lauxmann, Markus Wolff, Matthis Synofzik, Thomas Bast, Adrian Binelli, José M. Serratosa, Pedro Martínez-Ulloa, Nicholas M. Allen, Mary D. King, Kathleen M. Gorman, Bruria Ben Zeev, Michal Tzadok, Lily Wong-Kisiel, Dragan Marjanovic, Guido Rubboli, Sanjay M. Sisodiya, Florian Lutz, Harshad Pannikkaveettil Ashraf, Kirsten Torge, Pu Yan, Christian Bosselmann, Niklas Schwarz, Monika Fudali, Holger Lerche
Journal: Science Translational Medicine (2021)

4-Aminopyridine is a potential therapeutic option for a subgroup of patients with KCNA2 -encephalopathy and gain-of-function variants.
Integrating the genomic and TCR repertoire signatures predicts prognosis in primary epithelial ovarian cancer.
Authors: Yang Xiang, Shan Zhu, Dongyan Cao, Xi-Run Wan, Chunliu Zhang, Junjun Yang, Jiaxin Yang, Mei Yu, Ying Zhang, Tong Ren, Jing Wang, Peiling Li, Guo-Nan Zhang, Jing Bai, Yanfang Guan, Xuefeng Xia
Journal: Journal of Clinical Oncology (2021)

e17547 Background: Epithelial ovarian cancer is one of the common causes of gynecologic cancer death around the world. Histologically, EOC is classified into 5 major sub-types: high-grade serous (HGSOC), low grade serous (LGSOC), clear cell (CCOC), endometrioid (ENOC) and mucinous (MOC). Baseline genomic and immunomicroenvironmental characteristics of treatment-naive patients may offer an insight into recurrent risks. Methods: 101 patients with treatment-naive EOC were enrolled, including 60 HGSOC, 14 LGSOC, 8 ENOC, 14 CCOC, 5 MOC. Tumor tissues and paired peripheral blood samples were collected and performed with target sequencing of 1021 genes and TCR repertoire sequencing. Patients were intensively followed up for at least one year. To explored the molecular characteristic among 5 sub-types, genomic features and TCR repertoire signature were evaluated. Results: The mutation rate of PTEN loss was comparable among 5 sub-types for 53.3% (32/60) in HGSOC, 57.1% (8/14) in LGSOC, 42.9% (6/14) in CCOC, 50% (4/8) in ENOC, 40% (2/5) in MOC. Patients with PTEN loss tended to have lower tumor mutation burden (p = 0.077, Wilcoxon test), especially in HGSOC (p = 0.048, Wilcoxon test). Patients with CCOC and ENOC had significantly higher clonality, which indicates T cell expansion, than SOC tumor (HGSOC, LGSOC) (p = 0.036, Wilcoxon test). Moreover, the proportion of top 10, top 50 and top 100 T cell clones were all significantly higher in CCOC and ENOC than that in SOC(p = 0.0072, 0.0041, 0.0058, Wilcoxon test).In addition, richness and Shannon-index, two metrics for T cell diversity, were significantly higher in SOC comparing with CCOC and ENOC(p = 0.032, 0.0018, Wilcoxon test). After integrated the genomic and TCR features, more favorite disease-free survival (DFS) was found in patients with PTEN loss wild type, higher TMB, higher clonality and lower Shannon-index (p = 0.041, HR = 0.24, Mantel–Cox test). Conclusions: Our results highlight the traits of genomic and TCR repertoire in different subtypes of epithelial ovarian cancer and their prognostic significance. Interestingly, higher T cell clonality in CCOC and ENOC patients were found, which suggested the anti-cancer immune response was better activated. However, our study gets a preliminary result, and further verification work is needed.
PM2.5 Exposure of Mice during Spermatogenesis: A Role of Inhibitor κB Kinase 2 in Pro-Opiomelanocortin Neurons
Authors: Lianglin Qiu, Minjie Chen, Xiaoke Wang, Sufang Chen, Zhekang Ying
Journal: Environmental Health Perspectives (2021)

Background: Epidemiological studies have shown that exposure to ambient fine particulate matter with aerodynamic diameter less than or equal to 2.5 μm (PM2.5) correlates with a decrease in sperm count, but the biological mechanism remains elusive. Objectives: This study tested whether hypothalamic inflammation, an emerging pathophysiological mediator, mediates the development of lower epididymal sperm count due to PM2.5 exposure. Methods: Inhibitor κB kinase 2 (IKK2) was conditionally knocked out either in all neurons or subtypes of hypothalamic neurons of mice. Effects of concentrated ambient PM2.5 (CAP) exposure on hypothalamic inflammation, the hypothalamic–pituitary–gonadal (HPG) axis, and epididymal sperm count of these mouse models were then assessed. Furthermore, to test whether hypothalamic inflammation is sufficient to decrease sperm production, we overexpressed constitutively active IKK2 (IKK2ca) either in all neurons or subtypes of hypothalamic neurons and assessed hypothalamic inflammation, the HPG axis, and sperm production of these overexpression mouse models. Results: CAP-exposed wild-type control mice vs. filtered air (FA)-exposed wild-type control mice had a higher expression of hypothalamic inflammatory markers, lower functional indexes of the HPG axis, and a lower epididymal sperm count. In contrast, all these measurements for CAP- vs. FA-exposed mice deficient of IKK2 in all neurons were comparable. We also found that overexpression of IKK2ca in either all neurons or pro-opiomelanocortin (POMC) neurons only, but not in Agouti-related protein (AgRP) neurons only, resulted in lower functional indexes of the HPG axis and a lower epididymal sperm count. Moreover, we showed that CAP- vs. FA-exposed mice deficient of IKK2 in POMC neurons had a comparable expression of hypothalamic inflammatory markers, comparable functional indexes of the HPG axis, and a comparable epididymal sperm count. Discussion: This mouse model study shows a causal role of IKK2 of POMC neurons in the development of lower epididymal sperm count due to PM2.5 exposure, providing a mechanistic insight into this emerging pathogenesis. https://doi.org/10.1289/EHP8868