tbuckley/cabot-search huggingface dataset:
Charting New Phenomenological Paths for Empirical Research on Delusions
Authors: Rosa Ritunnano, Matthew Broome, Giovanni Stanghellini
Journal: JAMA Psychiatry (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 Psychiatry 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 Psychiatry journal
Genetically-Defined AML Subgroups Represent Diverse Epigenetic Heterogeneity Landscape
Authors: Sheng Li, Xiaowen Chen, Jihui Wang, Cem Meydan, Jacob L Glass, Alan H. Shih, Peter J.M. Valk, Ruud Delwel, Ross L. Levine, Christopher Mason, Ari Melnick
Journal: Blood (2017)
Controlling CRISPR with small molecule regulation for somatic cell genome editing
Authors: Namita Khajanchi, Krishanu Saha
Journal: Molecular Therapy (2021)

Biomedical research has been revolutionized by the introduction of many CRISPR-Cas systems that induce programmable edits to nearly any gene in the human genome. Nuclease-based CRISPR-Cas editors can produce on-target genomic changes but can also generate unwanted genotoxicity and adverse events, in part by cleaving non-targeted sites in the genome. Additional translational challenges for in vivo somatic cell editing include limited packaging capacity of viral vectors and host immune responses. Altogether, these challenges motivate recent efforts to control the expression and activity of different Cas systems in vivo. Current strategies utilize small molecules, light, magnetism, and temperature to conditionally control Cas systems through various activation, inhibition, or degradation mechanisms. This review focuses on small molecules that can be incorporated as regulatory switches to control Cas genome editors. Additional development of CRISPR-Cas-based therapeutic approaches with small molecule regulation have high potential to increase editing efficiency with less adverse effects for somatic cell genome editing strategies in vivo.
Abstract 386: Notch1 Signaling Negatively Modulates Repolarizing Kv Currents in Cardiomyocytes
Authors: Giulia Borghetti, Sergio Signore, Andrea Sorrentino, Polina Goichberg, Marcello Rota
Journal: Circulation Research (2016)

Notch1 is a critical signaling pathway during embryonic and early postnatal development and activity of this transduction system gradually declines after birth. Conversely, outward K + Kv currents are progressively increased in myocytes during postnatal life leading to shortening of the action potential (AP) duration and acquisition of the mature electrical phenotype. Thus, we tested the possibility that Notch1 signaling modulates the electrophysiological properties of developing cells by interfering with Kv current densities. For this purpose, molecular and physiological studies were conducted in vitro using mouse neonatal myocytes (NMs). These assays were complemented with tests in adult cells obtained from a conditional mouse model of Notch1 intracellular domain (NICD) overexpression. NMs were treated with a γ-secretase inhibitor (DAPT) to prevent the cleavage of Notch1 receptor and subsequent translocation of the active NICD to the nucleus. By RT-PCR, Notch1 targets Hes1 and Hey1 were reduced with DAPT-treatment, confirming the effective perturbation of Notch1 signaling. Importantly, inhibition of Notch signaling led to upregulation of the three splice variants of the Kv channel-interacting proteins 2 (KChIP2) gene, which controls the appearance of outward Kv currents in myocytes. By patch-clamp, Kv currents were identified in only 15% of NMs (n=20) cultured for 1-2 days in in control condition, whereas this fraction increased to 50% (n=18) in cells treated with DAPT. Thus, Notch inhibition promotes the expression of KChIP2 and appearance of Kv currents. To clarify these in vitro findings, the consequences of ectopic activation of Notch1 signaling on the electrical behavior of adult myocytes were established. By patch-clamp, NICD-overexpressing myocytes presented a &gt;2-fold longer duration of the early repolarization phase of the AP, with respect to cells from wild type hearts. This alteration was coupled with a &gt;50% reduction of Kv currents I to and I Kslow1 in NICD-overexpressing cells, with respect to wild-type myocytes. Thus, Notch signaling represses KChIP2 and Kv currents in cardiomyocytes representing an important modulator of the electrical phenotype of the developing heart.
SMOOTH-seq: single-cell genome sequencing of human cells on a third-generation sequencing platform
Authors: Xiaoying Fan, Cheng Yang, Wen Li, Xiuzhen Bai, Xin Zhou, Haoling Xie, Lu Wen, Fuchou Tang
Journal: Genome biology (2021)

Abstract There is no effective way to detect structure variations (SVs) and extra-chromosomal circular DNAs (ecDNAs) at single-cell whole-genome level. Here, we develop a novel third-generation sequencing platform-based single-cell whole-genome sequencing (scWGS) method named SMOOTH-seq (single-molecule real-time sequencing of long fragments amplified through transposon insertion). We evaluate the method for detecting CNVs, SVs, and SNVs in human cancer cell lines and a colorectal cancer sample and show that SMOOTH-seq reliably and effectively detects SVs and ecDNAs in individual cells, but shows relatively limited accuracy in detection of CNVs and SNVs. SMOOTH-seq opens a new chapter in scWGS as it generates high fidelity reads of kilobases long.
Viscoelastic hemostatic assays: Update on technology and clinical applications
Authors: David Faraoni, James A. DiNardo
Journal: American Journal of Hematology (2021)

Viscoelastic hemostatic assays (VHA) are point of care tests that allow for a global assessment of coagulation using whole blood. The technology to allow this assessment has evolved from the original thromboelastography (TEG, Haemonetic, Boston, MA) to now include thromboelastometry (ROTEM, Instrumentation Laboratory, Bedford, MA), and, most recently, the Quantra Hemostasis Analyzer (Hemosonics, Charlottesville, VA). Diagnosis and treatment algorithms incorporating viscoelastic hemostatic tests for bleeding patients in a variety of clinical situations have now been developed. The original ROTEM and TEG technologies have been updated with emphasis placed on a cartridge-based technologies. Results from the new devices show good correlation with those from the previous versions of the devices, while cartridge-based technology has increased device stability and enhanced portability to the bedside. In this article, we will review recent advances in TEG and ROTEM technology and introduce the Quantra Hemostasis Analyzer device.
Inflammatory cytokines TNF-α and IL-17 enhance the efficacy of cystic fibrosis transmembrane conductance regulator modulators
Authors: Tayyab Rehman, Philip H. Karp, Ping Tan, Brian J. Goodell, Alejandro A. Pezzulo, Andrew L. Thurman, Ian M. Thornell, Samantha L. Durfey, Michael E. Duffey, David A. Stoltz, Edward F. McKone, Pradeep K. Singh, Michael J. Welsh
Journal: Journal of Clinical Investigation (2021)

Without cystic fibrosis transmembrane conductance regulator–mediated (CFTR-mediated) HCO3– secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this time course matches the development of inflammation in CF airways. To learn whether inflammation alters CF ASL pH, we treated CF epithelia with TNF-α and IL-17 (TNF-α+IL-17), 2 inflammatory cytokines that are elevated in CF airways. TNF-α+IL-17 markedly increased ASL pH by upregulating pendrin, an apical Cl–/HCO3– exchanger. Moreover, when CF epithelia were exposed to TNF-α+IL-17, clinically approved CFTR modulators further alkalinized ASL pH. As predicted by these results, in vivo data revealed a positive correlation between airway inflammation and CFTR modulator–induced improvement in lung function. These findings suggest that inflammation is a key regulator of HCO3– secretion in CF airways. Thus, they explain earlier observations that ASL pH increases after birth and indicate that, for similar levels of inflammation, the pH of CF ASL is abnormally acidic. These results also suggest that a non-cell-autonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.
Abstract 12208: Role Of PKM2 and Oxidative DNA Damage in the Pathogenesis of Right Ventricular Failure Associated With Pulmonary Arterial Hypertension
Authors: Tsukasa Shimauchi, Junichi Omura, Sandra B Bonnet, Roxane Paulin, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet
Journal: Circulation (2019)

Introduction: Right ventricular failure (RVF) is the major prognostic factor for both morbidity and mortality in pulmonary hypertension. A better understanding of the molecular mechanisms accountin...
Inequalities in early childhood body-mass index Z scores in Victoria, Australia: a 15-year observational study
Authors: Melanie Nichols, Steven Allender, Boyd Swinburn, Liliana Orellana
Journal: The Lancet Public Health (2021)

Early childhood overweight and obesity increased substantially in high-income countries throughout the 1980s and 1990s. The flattening or reversal of this trend since the early 2000s might conceal widening inequalities. This study aimed to identify trends in body-mass index Z score (BMIz) among children aged 1-3·5 years in Victoria (Australia), by socioeconomic status and geographical location.This repeated, cross-sectional study used deidentified records of height, weight, and demographic information from electronic databases in the Victorian Maternal and Child Health system. Data from the consultations for children aged 1, 2, and 3·5 years were included in this analysis. We removed duplicate records; records with missing data for sex, age, weight, height, or postcode; and records with postcodes that were outside of Victoria. The coprimary outcomes were trends in mean BMIz (continuous linear models) and prevalence of high BMIz (>+1; generalised linear models), estimated for six independent age-sex groups. Secondary analysis was done for the prevalence of BMIz greater than 2. Effect modification by socioeconomic status and remoteness was evaluated.Electronic data were available for 48 local government areas collected between Jan 1, 2003, and Dec 31, 2017, representing approximately 63% of the Victorian population. Overall, 1 329 520 measurements from 675 991 children were included in the analysis. There were small, significantly decreasing trends in mean BMIz across all six age-sex groups, overall and in major cities. Similar patterns were observed for some subgroups in prevalence of high BMIz. These decreasing trends appear to be partly explained by migration. Conversely, in regional areas the trends in BMIz were consistently increasing in all age-sex groups and across socioeconomic strata, although not all groups were statistically significant. Inequalities in BMIz according to socioeconomic status persisted throughout the study period, such that the children from more advantaged areas had lower mean BMIz.This study showed that at a state level, mean BMIz and prevalence of high BMIz decreased in children aged 1, 2, and 3·5 years in Victoria between 2003 and 2017. We found metropolitan-regional differences to be key source of inequality in early childhood BMIz trends, alongside area-level socioeconomic status. These findings highlight the risk that analysis of overall trends in childhood BMIz might obscure important inequalities according to, for example, remoteness, socioeconomic status, and ethnicity. Future research requires monitoring data with large population samples to adequately examine differences in prevalence and trends between population subgroups.None.
Abstract 2614: A deep learning model-based lung cancer risk assessment for incidental pulmonary nodules
Authors: Pengyu Yuan, Tiancheng He, Hien Nguyen, Stephen T. Wong
Journal: Cancer Research (2021)

Abstract Lung cancer is the leading cause of cancer death among both men and women. The solitary pulmonary nodule (SPN) is frequently seen on radiographs and computed tomography (CT) and often provokes additional clinical and imaging activities as an SPN alerts possible early stage lung cancer. However, reliable diagnosis of malignant lung nodules in the workup of SPN is challenging, making it difficult for early stage cancer management to avoid morbidity due to malignant cancer, patient distress, and increased costs caused by more invasive and unwarranted procedures for benign cases. We developed a deep learning model based on convolutional neural networks (CNNs) to predict lung cancer risk for incidental SPN. The model can help better management of incidental lung cancer by providing a reliable characterization of SPNs. Deep learning models currently are applied to nodule detection in low-dose CT scans of lung cancer screening for at-risk population. Our work aims to investigate whether deep learning can differentiate benign from malignant incidental SPN during normal dose CT exams, where the number of patients with SPN is an order more than that of lung screening population. We collected an incidental SPN dataset containing 139 CT scans to generate the nodule malignancy prediction model using 3D CNN. This dataset was collected from either contrast or non-contrast CT scans with regular doses. All 139 patients went through surgeries to remove the tumors. CT images were collected within one year before the surgery. 90 cases are malignant and the rest are benign. Ground truth labels were obtained from biopsies. Data were preprocessed by resampling, normalization, and cropping to unique volume around the SPN. The radiologists annotated the SPN location. Since the two nodule classes are imbalanced, we did online data augmentation to increase the variety of lung nodule images and balance the two classes. We used 80% of the data for training and 20% for testing. The deep learning structure adapted is a 3D Resnet with 68 layers and 33M parameters. The area under the receiving operating characteristics curve (AUC) of the prediction result was 0.81 while the accuracy was 79.6%. Applying GradCam to visualize important regions in CT scans contributing to the final predictions, we found that our trained ResNet model focuses on meaningful areas in lung nodules and detects malignant SPNs in most cases. Our preliminary results shows the feasibility of using deep learning to predict incidental lung nodules and improve diagnostic speed and accuracy. Citation Format: Pengyu Yuan, Tiancheng He, Hien Nguyen, Stephen T. Wong. A deep learning model-based lung cancer risk assessment for incidental pulmonary nodules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2614.
Sialic acid conjugate-modified liposomal platform modulates immunosuppressive tumor microenvironment in multiple ways for improved immune checkpoint blockade therapy
Authors: Cong Li, Qiujun Qiu, Xin Gao, Xinyang Yan, Chuizhong Fan, Xiang Luo, Xinrong Liu, Shuo Wang, Xiaoxue Lai, Yanzhi Song, Yihui Deng
Journal: Journal of Controlled Release (2021)
The Intracellular TCR Signaling Pathway As a Novel Therapeutic Target in AITL Patients
Authors: Yalu Liu, Ning Ding, Xiaogan Wang, Lijuan Deng, Lingyan Ping, Yunfei Shi, Wen Zheng, Ningjing Lin, Xiaopei Wang, Meifeng Tu, Yan Xie, Weiping Liu, Zhitao Ying, Chen Zhang, Zhengying Pan, Xi Wang, Yuqin Song, Jun Zhu
Journal: Blood (2017)
AB0095 Endothelial protein c receptor associated invasiveness of rheumatoid synovial fibroblasts is driven by group v secretory phospholipase a2
Authors: M. Xue, K. Shen, K. McKelvey, J. Juan Li, Y.-K. A. Chan, V. Hatzis, L. March, C. B. Little, M. Tonkin, C. J. Jackson
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To investigate the expression and function of endothelial protein C receptor (EPCR) on synovial fibroblasts (SF) from patients with rheumatoid arthritis (RA). <h3>Methods</h3> Human SF were isolated from synovial tissues with RA or osteoarthritis (OA) and treated with siRNAs/blocking antibody to EPCR, activated protein C (APC), tumor necrosis factor (TNF)-a, group V secretory phospholipase A<sub>2</sub> (sPLA<sub>2</sub>V) or co-incubated with human articular cartilage. Cell proliferation and migration/invasion were measured by MTT and collagen gel assays, respectively and cartilage degradation by glycoaminoglycan release. Cytokines, EPCR, MAP kinases, nuclear factor (NF)-kB and cadherin-11were detected by ELISA, RT real time PCR, Western blot or immunostaining. <h3>Results</h3> EPCR was expressed by both OASF and RASF but was markedly increased in RASF. When EPCR was inhibited by siRNA or blocking antibody, cell growth, invasion and cartilage degradation were reduced by more than 30%. In addition, interleukin (IL)-1β, cadherin-11 and activation of ERK, p38, JNK and NF-kBwere significantly reduced in both control and TNF-astimulated conditions. Further analysis revealed that sPLA<sub>2</sub>V was expressed by RASF and blocked APC binding to RASF. Suppression of sPLA<sub>2</sub>Vreduced cell proliferation and cartilage degradation. However, when EPCR and sPLA<sub>2</sub>V were inhibited together, the abilityof RASFto suppress cartilage degradation was abolished indicating that EPCR-associated cartilage degradation is driven by sPLA<sub>2</sub>V. <h3>Conclusions</h3> Our results demonstrate that EPCR is over expressed by RASF. Suppressing EPCR inhibits the invasion, inflammation and cartilage degradation by RASF. This function of EPCR, which is contrary to its cytoprotective role in other settings, is likely driven by sPLA<sub>2</sub>V. <h3>Disclosure of Interest</h3> None Declared
Prevalence and risk factors of mcr-1-positive volunteers after colistin banning as animal growth promoter in China: a community-based case–control study
Authors: Ziquan Lv, Yingbo Shen, Weiwen Liu, Hailing Ye, Dejun Liu, Juan Liu, Yulin Fu, Changfeng Peng, Kun Chen, Xiangxiao Deng, Bang Liu, Jie He, Lu Yang, Chunyan Xu, Chang Cai, Yang Wang, Yuebin Ke, Jianzhong Shen
Journal: Clinical Microbiology and Infection (2021)
High Out-of-pocket Health Care Cost Burden Among Medicare Beneficiaries With Diabetes, 1999–2017
Authors: Joohyun Park, Ping Zhang, Yu Wang, Xilin Zhou, Kevin A. Look, Elizabeth T. Bigman
Journal: Diabetes Care (2021)

We examined the magnitude of and trends in the burden of out-of-pocket (OOP) costs among Medicare beneficiaries age 65 years or older with diabetes overall, by income level, by race/ethnicity, and compared with beneficiaries without diabetes.Using data from the 1999-2017 Medicare Current Beneficiary Survey, we estimated average annual per capita OOP costs and percentage of beneficiaries experiencing high OOP burden, defined as OOP costs >10% or >20% of household income. We used joinpoint regression to examine the trends and generalized linear model and logistic regression for comparisons between beneficiaries with and without diabetes. Cost and income estimates were adjusted to 2017 USD.Total OOP costs were $3,609-$5,283, with significant increases until 2005 followed by a leveling off. The prevalence of high OOP burden was 57%-72% at the 10% income threshold and 29%-41% at the 20% threshold, with significant increasing trends until 2003 followed by decreases. Total OOP costs were the highest in the ≥75% income quartile, whereas prevalence of high OOP burden was highest in the <25% and 25-50% income quartiles. Non-Hispanic Whites had the highest OOP costs and prevalence of high OOP burden. Beneficiaries with diabetes had significantly higher OOP costs ($498, P < 0.01) and were more likely to have high OOP burden than those without diabetes (odds ratios 1.32 and 1.25 at >10% and >20% thresholds, respectively, P < 0.01).Over the past two decades, Medicare beneficiaries age 65 years or older with diabetes have faced substantial OOP burden, with large income-related disparities.
Abstract 387: Cardiac Myosin-binding Protein C Structural Dynamics - a Time-resolved FRET Biosensor for Enhanced Contractility in Heart Failure Therapeutic Discovery
Authors: Thomas A Bunch, Victoria C Lepak, Brett A Colson
Journal: Circulation Research (2016)

We have created a high-resolution time-resolved spectroscopy molecular biosensor for heart failure therapeutic discovery based on the structural dynamics of cardiac myosin-binding protein C (cMyBP-C). Drugs of interest mimic phosphorylation states of cMyBP-C, which influences myocardial contractility. β-adrenergic stimulation enhances contractility in myocardium, in part due to Protein Kinase A (PKA)-mediated phosphorylation of cMyBP-C. Recent structural and functional results have provided an understanding for how cMyBP-C physiologically regulates inotropy and lusiotropy in the heart by modulating actin-myosin interactions. Phosphorylation introduces a structural change within the regulatory M domain of cMyBP-C, leading to altered actin-myosin binding, and regulation of myocardial contraction. Previous molecular dynamics simulations suggested a specific rotation within the M domain upon phosphorylation that facilitates bending and exposes a putative binding site that is only accessible in the phosphorylated molecule. We hypothesized that these structural rearrangements in nanometer spatial orientation could be measured spectroscopically in mechanistic studies via introduction of site-directed probes within the M domain of cMyBP-C using time-resolved fluorescence resonance energy transfer (TR-FRET). Moreover, we hypothesized that this fluorescently-labeled recombinant muscle protein could be used as a TR-FRET biosensor for detecting potential drugs that alter the M domain structure in specific ways. These drugs will be particularly relevant to enhancement of myocardial contractility and represent novel therapeutics for heart failure and cardiomyopathy. Here, we engineered pairs of cysteine residues within the M domain for FRET labeling and tested the effects of phosphorylation to influence the tertiary structure and dynamics of cMyBP-C. We have characterized cMyBP-C’s molecular basis for fine-tuning contraction and our biosensor is well aligned for high-throughput spectroscopic screens for drugs that perturb structure specific to phosphorylation state. Compound discovery using this assay is applicable to development of novel cardiac disease therapies by enhancing contractility to alleviate dysfunction.