tbuckley/cabot-search huggingface dataset:
Use of the PsycheMERGE Network to Investigate the Association Between Depression Polygenic Scores and White Blood Cell Count
Authors: Julia M. Sealock, Younga H. Lee, Arden Moscati, Sanan Venkatesh, Georgios Voloudakis, Peter Straub, Kritika Singh, Yen-Chen A. Feng, Tian Ge, Panos Roussos, Jordan W. Smoller, Guanhua Chen, Lea K. Davis
Journal: JAMA Psychiatry (2021)

Although depression is a common psychiatric disorder, its underlying biological basis remains poorly understood. Pairing depression polygenic scores with the results of clinical laboratory tests can reveal biological processes involved in depression etiology and in the physiological changes resulting from depression.To characterize the association between depression polygenic scores and an inflammatory biomarker, ie, white blood cell count.This genetic association study was conducted from May 19, 2019, to June 5, 2021, using electronic health record data from 382 452 patients across 4 health care systems. Analyses were conducted separately in each health care system and meta-analyzed across all systems. Primary analyses were conducted in Vanderbilt University Medical Center's biobank. Replication analyses were conducted across 3 other PsycheMERGE sites: Icahn School of Medicine at Mount Sinai, Mass General Brigham, and the Million Veteran Program. All patients with available genetic data and recorded white blood cell count measurements were included in the analyses. Primary analyses were conducted in individuals of European descent and then repeated in a population of individuals of African descent.Depression polygenic scores.White blood cell count.Across the 4 PsycheMERGE sites, there were 382 452 total participants of European ancestry (18.7% female; median age, 57.9 years) and 12 383 participants of African ancestry (61.1% female; median age, 39.0 [range, birth-90.0 years]). A laboratory-wide association scan revealed a robust association between depression polygenic scores and white blood cell count (β, 0.03; SE, 0.004; P = 1.07 × 10-17), which was replicated in a meta-analysis across the 4 health care systems (β, 0.03; SE, 0.002; P = 1.03 × 10-136). Mediation analyses suggested a bidirectional association, with white blood cell count accounting for 2.5% of the association of depression polygenic score with depression diagnosis (95% CI, 2.2%-20.8%; P = 2.84 × 10-70) and depression diagnosis accounting for 9.8% of the association of depression polygenic score with white blood cell count (95% CI, 8.4%-11.1%; P = 1.78 × 10-44). Mendelian randomization provided additional support for an association between increased white blood count and depression risk, but depression modeled as the exposure showed no evidence of an influence on white blood cell counts.This genetic association study found that increased depression polygenic scores were associated with increased white blood cell count, and suggests that this association may be bidirectional. These findings highlight the potential importance of the immune system in the etiology of depression and may motivate future development of clinical biomarkers and targeted treatment options for depression.
AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway
Authors: Ram Hari Pokhrel, Suman Acharya, Jae-Hee Ahn, Ye Gu, Mahesh Pandit, Jong-Oh Kim, Yun-Yong Park, Ben Kang, Hyun-Jeong Ko, Jae-Hoon Chang
Journal: Molecular Cancer (2021)

Abstract Background AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor immunity, particularly the function of regulatory T cells (Tregs), is poorly defined. Methods AMPKα1 fl/fl Foxp3 YFP-Cre , Foxp3 YFP-Cre , Rag1 −/− , and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation. Results The deletion of the AMPKα1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3β (GSK-3β), inhibiting the expression of PD-1 in Tregs. Conclusion Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3β signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.
Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab and Remission Induction in ANCA-Associated Vasculitis
Authors: David R. W. Jayne, Peter A. Merkel, Pirow Bekker
Journal: JAMA (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
Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus
Authors: Marcus M. Soliai, Atsushi Kato, Britney A. Helling, Catherine T. Stanhope, James E. Norton, Katherine A. Naughton, Aiko I. Klinger, Emma E. Thompson, Selene M. Clay, Soyeon Kim, Juan C. Celedón, James E. Gern, Daniel J. Jackson, Matthew C. Altman, Robert C. Kern, Bruce K. Tan, Robert P. Schleimer, Dan L. Nicolae, Jayant M. Pinto, Carole Ober
Journal: Genome Medicine (2021)

Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma.Genome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease (n=66) or were healthy participants (n=38). We mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci.Asthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci.This study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.
Wearable Printed Temperature Sensors: Short Review on Latest Advances for Biomedical Applications
Authors: Saleem Khan, Shaukat Ali, Arshad Khan, Amine Bermak
Journal: IEEE Reviews in Biomedical Engineering (2021)

The rapid growth in wearable biosensing devices is driven by the strong desire to monitor the human health data and to predict the symptoms of chronic diseases at an early stage. Different sensors are developed for continuous monitoring of various biomarkers through wearable and implantable sensing patches. Temperature sensor has proved to be an important physiological parameter amongst the various wearable biosensing patches. This paper highlights the recent progresses made in printing of functional nanomaterials for developing wearable temperature sensors on polymeric substrates. A special focus is given to the advanced functional nanomaterials as well as their deposition through printing technologies. The geometric resolutions, shape, physical and electrical characteristics as well as sensing properties using different materials are compared and summarized. Wearability is the main concern of these newly developed sensors, which is summarized by discussing representative examples. Finally, the challenges concerning the stability, repeatability, reliability, sensitivity, linearity, ageing, and large-scale manufacturing are discussed with future outlook of the wearable systems.
Efficacy of a Cell-Culture–Derived Quadrivalent Influenza Vaccine in Children
Authors: Terence Nolan, Alexandre C. Fortanier, Brett Leav, Airi Põder, Lulu C. Bravo, Henryk T. Szymański, Marten Heeringa, Wim Vermeulen, Vince Matassa, Igor Smolenov, Jonathan M. Edelman
Journal: New England Journal of Medicine (2021)

Cell-culture–derived influenza vaccines may enable a closer antigenic match to circulating strains of influenza virus by avoiding egg-adapted mutations.
Characterization of Prescription Patterns and Estimated Costs for Use of Oxygen Concentrators for Home Oxygen Therapy in the US
Authors: Peter A. Kahn, Christopher M. Worsham, Gretchen Berland
Journal: JAMA Network Open (2021)

states, median annual electricity costs ranged from $36 (low-flow 100-watt concentrators) to $751 (high-flow 700-watt concentrators). DiscussionThis study's findings suggest that, depending on the needs of the patient, local electricity prices, and the flow rate of oxygen prescribed, the cost of running electric oxygen concentrators can vary substantially and potentially result in financial hardship or suboptimal use of therapy because of cost concerns.Concentrator prescription patterns were highly variable by state.Factors such as altitude, prevalence of pulmonary disease, air quality, occupational exposures, and average age of beneficiaries likely contribute to prescribed oxygen flow rates and oxygen concentrator use patterns.Limitations of this study include lack of patient-level data, including concentrator use, health outcomes, utility service information, and nonelectricity costs to patients.Further study is needed to better characterize the relationship between durable medical equipment with persistently highly variable costs, such as oxygen concentrators; patient use patterns; and health outcomes.State and federal policy makers should consider the implications of high-cost durable medical equipment and consider policy solutions to offset the cost of these devices.Particular consideration should be given to individuals with fixed or low income who receive these medical devices through Medicare and Medicaid programs.These patients are less likely to possess the resources to use the Table.State-Level Estimated Annual Electricity Costs of Oxygen Concentrators Estimated annual operating cost, median (range) [IQR], US$ a 24 h daily use 12 h daily use 8 h daily use Low-flow concentrators (1-3 LPM) 100-W models 107 (84-284) [97-
Chemotherapy of Gastrointestinal Cancer
Authors: Charles G. Moertel
Journal: New England Journal of Medicine (1978)

IN this country, and, indeed, the world over, gastrointestinal cancer causes more deaths than cancer taking origin in any other organ system. Although management of these diseases has traditionally been considered the realm of the surgeon, there has not been any substantive improvement in surgical treatment since the middle of this century. Overall end results remain dismal, with five-year survival rates of less than 5 per cent for carcinomas of the esophagus, pancreas, liver and biliary tract, and only 12 per cent for carcinomas of the stomach.1 Even in the area of greatest surgical success, large-bowel cancer, well over half . . .
Activation of Raf signalling in NF2-null Schwann cells leads to sustained proliferation; an investigation of a new and inducible model for human schwannoma
Authors: Charlotte Lespade, Liyam Laraba, Evyn Woodhouse, Marie Srotyr, Alison C Lloyd, David B Parkinson
Journal: Neuro-Oncology (2021)

Abstract Aims The NF2 gene encodes the tumour suppressor Merlin, which is deleted in 100% of patients with the familial tumour predisposition syndrome neurofibromatosis type 2 but also in 70% of those who develop sporadic schwannomas. The Raf-TR mouse model uses a tamoxifen-inducible Raf-kinase/ oestrogen receptor fusion protein (Raf-TR) expressed in myelinating Schwann cells to mimic a nerve injury response in Schwann cell by activating Raf/MEK/ERK signalling in the absence of peripheral nerve injury. We will assess whether Raf/MEK/ERK activation on an NF2 null background leads to tumourigenesis within the vestibular nerves and dorsal root ganglia (DRGs), two tumour sites identified in the Periostin-Cre mouse model in which schwannoma formation is spontaneous, with a view to generating an inducible NF2 null schwannoma mouse model. Method Mice with a Schwann cell specific loss of Merlin were crossed with mice carrying a tamoxifen-inducible Raf-TR gene to generate Raf-TR+/-; P0-Cre+/-; NF2fl/fl (Cre+) mice which were NF2 null and compared to Raf-TR+/-; P0-Cre-/-; NF2fl/fl (Cre-) littermate controls. Mice were injected with tamoxifen or vehicle for five consecutive days and their vestibular nerves and dorsal root ganglia (DRGs) were analysed at various timepoints . An EdU proliferation assay was used to quantify the proliferation in the vestibular ganglia, as well as the DRGs. Rates of proliferation were compared to Cre- age-matched littermate controls treated with tamoxifen or vehicle. Results In the Periostin-Cre NF2 null schwannoma model, tumours form spontaneously in the DRGs and vestibular ganglia. In our new model, we see a clear increase in proliferation at 21 d post-injection in the NF2 null (Cre+) tamoxifen-treated mice compared to control (Cre-) tamoxifen-treated controls in both DRGs and vestibular ganglia. Cre- tamoxifen-treated mice do not show increased proliferation compared to Cre- vehicle controls. Taken together, this shows that activation of the Raf/MEK/ERK pathway in Schwann cells only causes a sustained proliferation response on an NF2 null background in the DRGs and vestibular ganglia. We are assessing later timepoints to further characterise tumour development in these mice. Conclusion Combining the Raf-TR mouse model to create a demyelinating phenotype with an NF2 null background leads to vastly increased rates of proliferation at the sites of schwannoma tumourigenesis within the peripheral nervous system: the DRGs and the vestibular ganglia. The high proliferation in the vestibular ganglia in particular is similar to the development of vestibular schwannomas in patients with Neurofibromatosis type 2. The new mouse model used in this study shows potential to be very useful as an inducible schwannoma tumour model, in which we can study the early events of tumour formation.
Impact of excluded studies on medical male circumcision and HIV risk compensation – Authors' reply
Authors: Yanxiao Gao, Yinghui Sun, Weiran Zheng, Huachun Zou
Journal: The Lancet Global Health (2021)

We thank Witness Mapanga and colleagues for their comment on our meta-analysis.1Gao Y Yuan T Zhan Y et al.Association between medical male circumcision and HIV risk compensation among heterosexual men: a systematic review and meta-analysis.Lancet Glob Health. 2021; 9: e932-e941Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar The appendix (pp 1–4) shows a list of the excluded studies and reasons they were excluded, based on the exclusion criteria. Given the many different types of traditional (ritual or religious) circumcision in the world, the heterogeneity of technique and completeness, and their typical use before sexual debut, we excluded studies that reported on the association between traditional circumcision and risk compensation, or studies that did not separate medical male circumcision and traditional circumcision. The study in Zambia that Mapanga and colleagues refer to reported on condom use and the number of sexual partners, and found a tendency towards risk compensation.2Garenne M Matthews A Voluntary medical male circumcision and HIV in Zambia: expectations and observations.J Biosoc Sci. 2020; 52: 560-572Crossref PubMed Scopus (7) Google Scholar Although that study was based on a nationally representative sample, the proportion of men who underwent traditional circumcision was unknown. As a result, that study was excluded. We uphold our exclusion criteria so as to make a concrete conclusion. We declare no competing interests. Download .pdf (.71 MB) Help with pdf files Supplementary appendix Association between medical male circumcision and HIV risk compensation among heterosexual men: a systematic review and meta-analysisThe promotion of circumcision as an HIV preventive measure does not appear to increase higher-risk sexual behaviours in heterosexual men. Ongoing sexual health education should be maintained as a vital component of effective MMC programmes. Full-Text PDF Open AccessImpact of excluded studies on medical male circumcision and HIV risk compensationYanxiao Gao and colleagues (July, 2021)1 present a systematic review and meta-analysis on the important topic of the association between voluntary medical male circumcision and HIV risk compensation among heterosexual men. Their findings indicate that there were no significant associations between medical male circumcision and multiple sex partners or condomless sex, suggesting that medical male circumcision does not increase higher risk sexual behaviours in heterosexual men. Full-Text PDF Open Access
Degenerative adversarial neuroimage nets for brain scan simulations: Application in ageing and dementia
Authors: Daniele Ravi, Stefano B. Blumberg, Silvia Ingala, Frederik Barkhof, Daniel C. Alexander, Neil P. Oxtoby
Journal: Medical Image Analysis (2021)

Accurate and realistic simulation of high-dimensional medical images has become an important research area relevant to many AI-enabled healthcare applications. However, current state-of-the-art approaches lack the ability to produce satisfactory high-resolution and accurate subject-specific images. In this work, we present a deep learning framework, namely 4D-Degenerative Adversarial NeuroImage Net (4D-DANI-Net), to generate high-resolution, longitudinal MRI scans that mimic subject-specific neurodegeneration in ageing and dementia. 4D-DANI-Net is a modular framework based on adversarial training and a set of novel spatiotemporal, biologically-informed constraints. To ensure efficient training and overcome memory limitations affecting such high-dimensional problems, we rely on three key technological advances: i) a new 3D training consistency mechanism called Profile Weight Functions (PWFs), ii) a 3D super-resolution module and iii) a transfer learning strategy to fine-tune the system for a given individual. To evaluate our approach, we trained the framework on 9852 T1-weighted MRI scans from 876 participants in the Alzheimer's Disease Neuroimaging Initiative dataset and held out a separate test set of 1283 MRI scans from 170 participants for quantitative and qualitative assessment of the personalised time series of synthetic images. We performed three evaluations: i) image quality assessment; ii) quantifying the accuracy of regional brain volumes over and above benchmark models; and iii) quantifying visual perception of the synthetic images by medical experts. Overall, both quantitative and qualitative results show that 4D-DANI-Net produces realistic, low-artefact, personalised time series of synthetic T1 MRI that outperforms benchmark models.
AL Amyloidosis: Current Chemotherapy and Immune Therapy Treatment Strategies
Authors: Giada Bianchi, Yifei Zhang, Raymond L. Comenzo
Journal: JACC CardioOncology (2021)

Immunoglobulin light chain (AL) amyloidosis is an incurable plasma cell disorder characterized by deposition of fibrils of misfolded immunoglobulin free light chains (FLC) in target organs, leading to failure.Cardiac involvement is common in AL amyloidosis and represents the single most adverse prognostic feature.A high index of clinical suspicion with rapid tissue diagnosis and commencement of combinatorial, highly effective cytoreductive therapy is crucial to arrest the process of amyloid deposition and preserve organ function.The clinical use of molecularly targeted drugs, such as proteasome inhibitors and immunomodulatory agents, monoclonal antibodies such as daratumumab, and risk-adjusted autologous stem cell transplant in eligible patients, has radically changed the natural history of AL amyloidosis.Here, we review the state-of-the-art treatment landscape in AL amyloidosis with an eye toward future therapeutic venues to impact the outcome of this devastating illness.
Modified FOLFIRINOX Versus CISGEM Chemotherapy for Patients With Advanced Biliary Tract Cancer (PRODIGE 38 AMEBICA): A Randomized Phase II Study
Authors: Jean marc Phelip, Jérôme Desrame, Julien Edeline, Emilie Barbier, Eric Terrebonne, Pierre Michel, Hervé Perrier, Laetitia Dahan, Vincent Bourgeois, Faiza Khemissa Akouz, Emilie Soularue, Valérie Lebrun Ly, Yann Molin, Thierry Lecomte, François Ghiringhelli, Romain Coriat, Samy Louafi, Cindy Neuzillet, Sylvain Manfredi, David Malka
Journal: Journal of Clinical Oncology (2021)

Whether triplet chemotherapy is superior to doublet chemotherapy in advanced biliary tract cancer (BTC) is unknown.In this open-label, randomized phase II-III study, patients with locally advanced or metastatic BTC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive oxaliplatin, irinotecan, and infusional fluorouracil (mFOLFIRINOX), or cisplatin and gemcitabine (CISGEM) for a maximum of 6 months. We report the results of the phase II part, where the primary end point was the 6-month progression-free survival (PFS) rate among the patients who received at least one dose of treatment (modified intention-to-treat population) according to Response Evaluation Criteria in Solid Tumors version 1.1 (statistical assumptions: 6-month PFS rate ≥ 59%, 73% expected).A total of 191 patients (modified intention-to-treat population, 185: mFOLFIRINOX, 92; CISGEM, 93) were randomly assigned in 43 French centers. After a median follow-up of 21 months, the 6-month PFS rate was 44.6% (90% CI, 35.7 to 53.7) in the mFOLFIRINOX arm and 47.3% (90% CI, 38.4 to 56.3) in the CISGEM arm. Median PFS was 6.2 months (95% CI, 5.5 to 7.8) in the mFOLFIRINOX arm and 7.4 months (95% CI, 5.6 to 8.7) in the CISGEM arm. Median overall survival was 11.7 months (95% CI, 9.5 to 14.2) in the mFOLFIRINOX arm and 13.8 months (95% CI, 10.9 to 16.1) in the CISGEM arm. Adverse events ≥ grade 3 occurred in 72.8% of patients in the mFOLFIRINOX arm and 72.0% of patients in the CISGEM arm (toxic deaths: mFOLFIRINOX arm, two; CISGEM arm, one).mFOLFIRINOX triplet chemotherapy did not meet the primary study end point. CISGEM doublet chemotherapy remains the first-line standard in advanced BTC.
P70.19 Clinicopathologic Characteristics of Patients With LRP1B Mutations in Chinese Non-Small Cell Lung Cancer Patients
Authors: G. Yu, W. Wang, C. Xu, D. Wang, Y. Zhu, W. Zhuang, M. Fang, G. Wang, Q. Wang, Y. Song, S. Lu
Journal: Journal of Thoracic Oncology (2021)