tbuckley/cabot-search huggingface dataset:
Denoising Autoencoder, A Deep Learning Algorithm, Aids the Identification of A Novel Molecular Signature of Lung Adenocarcinoma
Authors: Jun Wang, Xueying Xie, Junchao Shi, Wenjun He, Qi Chen, Liang Chen, Wanjun Gu, Tong Zhou
Journal: Genomics Proteomics & Bioinformatics (2020)

Abstract Precise biomarker development is a key step in disease management. However, most of the published biomarkers were derived from a relatively small number of samples with supervised approaches. Recent advances in unsupervised machine learning promise to leverage very large datasets for making better predictions of disease biomarkers. Denoising autoencoder (DA) is one of the unsupervised deep learning algorithms, which is a stochastic version of autoencoder techniques. The principle of DA is to force the hidden layer of autoencoder to capture more robust features by reconstructing a clean input from a corrupted one. Here, a DA model was applied to analyze integrated transcriptomic data from 13 published lung cancer studies, which consisted of 1916 human lung tissue samples. Using DA, we discovered a molecular signature composed of multiple genes for lung adenocarcinoma (ADC). In independent validation cohorts, the proposed molecular signature is proved to be an effective classifier for lung cancer histological subtypes. Also, this signature successfully predicts clinical outcome in lung ADC, which is independent of traditional prognostic factors. More importantly, this signature exhibits a superior prognostic power compared with the other published prognostic genes. Our study suggests that unsupervised learning is helpful for biomarker development in the era of precision medicine.
Abstract 13081: Predictive Value of Visceral-to-subcutaneous Fat Ratio for Long-term Clinical Outcomes in Patients With Suspected Coronary Artery Disease
Authors: Keisuke Machida, Kyuhachi Otagiri, Tadashi Itagaki, Takahiro Takeuchi, Hiroshi Kitabayashi
Journal: Circulation (2020)

Introduction: Although visceral fat accumulation is an important risk factor for coronary artery diseases (CAD), the relationship between visceral fat accumulation and its long-term outcomes has not been extensively investigated. Hypothesis: In patients with suspected CAD, the distribution of subcutaneous fat and visceral fat is associated with cardiovascular events. Methods: Computed tomography (CT) angiographies (CTA) were performed on 945 consecutive patients with suspected CAD. Plain abdominal CT scanning was performed to measure the patients’ visceral fat area (VFA) and subcutaneous fat area (SFA). The VFA/SFA (V/S) ratios were calculated to assess the visceral fat accumulation. Based on the results of the CTA, the prevalence of CAD was assessed. The patients were classified into low (&lt;0.627), and high (≥0.627) V/S ratio groups, based on their median value, and the association between V/S ratio and long-term outcomes was evaluated. The primary endpoints were major cardiac adverse events (MACE), including all-cause death, new-onset acute coronary syndrome (ACS), emergent hospitalization due to cardiovascular disease, and any coronary revascularization. Results: The average follow-up period was 845.3 days. The baseline characteristics for patients in the high V/S ratio group were worse than those for patients in the low high V/S ratio group. As compared to the low V/S ratio group, a higher incidence of MACE and ACS, and a higher tendency of mortality was observed in the high V/S ratio group. After adjusting for traditional coronary risk factors, the V/S ratio was independently associated with incidence of MACE, ACS, and increase of mortality (table). Conclusions: The present study suggests that the V/S ratio is an independent predictor of long-term outcomes in patients with suspected CAD. The visceral fat accumulation indicated by high V/S ratio signifies a potential risk and may contribute to the future cardiovascular events in patients with suspected CAD.
NFB-07. USE OF PEGYLATED INTERFERON α- 2b IN PEDIATRIC PATIENTS AFFECTED BY UNRESECTABLE PLEXIFORM NEUROFIBROMAS: MONOCENTRIC EXPERIENCE
Authors: Antonella Cacchione, Maria Chiara Lodi, Giada Del Baldo, Andrea Carai, Giovanna Stefania Colafati, Francesca Diomedi Camassei, Franco Locatelli, Angela Mastronuzzi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is autosomal dominant neurogenetic disorder characterized by progressive cutaneous, neurologic, skeletal, and neoplastic manifestations. Plexiform neurofibromas (PN) are one of the different types of neurofibromas that occur in these patients. Complete surgical resection is difficult due to the tumor infiltrative behavior. We evaluated pegylated interferon- α-2b (PI) in patients with unresectable progressive or symptomatic PN. METHODS Pediatric patients (1–21 years old) affected by unresectable PN, followed at Bambino Gesù Hospital, were treated with PI. We administered PI as a weekly subcutaneous injection at a beginning dose of 1.0 mcg/kg/wk, increased to 3.0 mcg/kg/wk if well tolerated. Paracetamol (15mg/kg) was given 30 minutes prior the dose of PI and then every 4–6 hours as needed. Patients were evaluated with Magnetic Resonance Imaging (MRI) every 12 months after treatment start in case of stable disease. RESULTS 10 patients (3 females, 7 males) were enrolled. Median age was 12 years old. The median duration of treatment was 12,6 months. Grade 3 neutropenia (30%) and increased liver transaminases level (20%) were the most common toxicity. 6/10 patients experienced an improvement about pain. 7/10 patients showed clinical response. 1/10 patient had a radiological response at MRI, 1/10 experienced progression disease and 8/10 showed a stable disease at MRI evaluation. CONCLUSIONS Our study demonstrated that PI could be a suitable treatment for unresectable PN in terms of stabilization of the tumour size due to its antitumor activity although clinical response does not correlate with radiographic changes.
Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study
Authors: H. Gogas, B. Dréno, J. Larkin, L. Demidov, D. Stroyakovskiy, Z. Eroglu, P. Francesco Ferrucci, J. Pigozzo, P. Rutkowski, J. Mackiewicz, I. Rooney, A. Voulgari, S. Troutman, B. Pitcher, Y. Guo, Y. Yan, M. Castro, S. Mulla, K. Flaherty, A. Arance
Journal: Annals of Oncology (2020)
Negligible risks of hepatocellular carcinoma during biomarker-defined immune-tolerant phase for patients with chronic hepatitis B
Authors: Mi Young Jeon, Beom Kyung Kim, Jae Seung Lee, Hye Won Lee, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Seung Up Kim
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: The immune-tolerant (IT) phase of chronic hepatitis B (CHB) patients is not generally indicative of antiviral therapy (AVT). We assessed and compared the risk of hepatocellular carcinoma (HCC) during the IT-phase stringently defined by a low fibrosis-4 (FIB-4) index, compared to that in patients undergoing AVT.Methods: Among 125 untreated patients that were hepatitis B e-antigen positive, hepatitis B virus-DNA &gt;20,000 IU/mL, with normal alanine aminotransferase level from 2012 to 2018, those with a FIB-4 index of &lt;1.45 were classified into the IT-group. The cumulative probability of HCC was estimated using Kaplan-Meier analysis. All patients were assessed until HCC development (intention-to-treat [ITT] analysis), whereas those suspected of experiencing CHB phase switch were assessed using the per-protocol (PP) and censored at the time of phase switch.Results: The cumulative probability of HCC at 1-, 3-, and 5-years among the IT-group was zero, compared to AVT-treated patients with FIB-4 indices &lt;1.45 during the same period: 0.2%, 0.6%, and 1.4%, respectively (P=0.264 for ITT and P=0.533 for PP). Among the initially screened 125 untreated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to the IT-group (P=0.005). Furthermore, among AVT-treated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to their counterpart (P&lt;0.001).Conclusions: The risk of HCC was negligible in the IT-group stringently defined by a low FIB-4 index. However, given that a higher HCC risk exists among untreated patients with higher FIB-4, appropriate criteria for AVT should be established.
TAMI-59. METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA
Authors: Antony Michealraj, Sachin Kumar, Leo Kim, Jeremy Rich, Michael Taylor
Journal: Neuro-Oncology (2020)

Abstract Ependymomas are malignant glial tumors that occur throughout the central nervous system. Of the nine distinct molecular types of ependymoma, Posterior Fossa A(PFA) ependymomas, found in the hindbrain of infants and young children, are the most prevalent type. They rarely harbor recurrent somatic single nucleotide or copy number aberrations, but rather display epigenetic dysregulations. Transcriptional analyses show that PFAs, but not other molecular ependymoma variants, have elevated hypoxic signaling. We hypothesized that the metabolic environment of the developing human fetal hindbrain contributes to PFA ependymomas through the intermediary metabolic mechanism. Hypoxia microenvironment is essential for PFA survival and upholding their epigenetic dysregulation. Hypoxia blocks methyltransferase activity by upregulating EZHIPs expression and restricting SAM abundance. Fine-tuning the abundance of a-KG and acetyl-CoA, hypoxia fuels demethylase, and acetyltransferase activity which collectively resulting in H3K27 hypomethylation and hyperacetylation. Genome-wide essentially screen further underscore that minimal basal level of H3K27me3 is essential for PFA survival and further attenuation of H3K27me3 decreases the fitness of PFAs. PFA Ependymomas have a unique epigenome, suggesting a model in which they thrive in a narrow Goldilocks zone, with deviation to either increased or decreased H3K27me3 levels leading to diminished cellular fitness. PFAs are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation and increase histone demethylation and acetylation at H3K27. PFAs initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3 and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA growth. Microenvironmental regulation of PFA ependymoma epigenome appears to play a major role in tumorigenesis. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
THU0349 THE RELATIONSHIP BETWEEN DISEASE ACTIVITY AND SEVERITY IN SYSTEMIC SCLEROSIS: A PROSPECTIVE ANALYSIS OF 278 PATIENTS
Authors: Y. Yalçinkaya, N. Aliyeva, S. Amikishiyev, Y. Cagatay, B. Artim-Esen, A. Gul, L. Ocal, M. Inanc
Journal: Annals of the Rheumatic Diseases (2020)

Background: Evaluating disease activity and severity in systemic sclerosis (SSc) is crucial to define the patients who are candidate for treatment options. Objectives: We aimed to investigate the relationship between disease activity and severity in SSc in a large cohort. Methods: This is a cross-sectional prospective analysis of 278 (253 females) patients fulfilling ACR/EULAR (2013) classification criteria for SSc. Disease activity and severity were calculated seperately for cutaneous subsets (EscSG and Medsger). The patients were grouped as inactive if EscSG score=0, mildly active if EscSG score&gt;0&lt;3, active if EscSG score≥3. Results: The mean age, duration of Raynaud’s and non-Raynaud features were 48.5±13.1, 12.1±9.8 and 8.3±7.5 years respectively. Characteristics of the SSc patients were summarized in table-1. Ninety-three (34%) and 151(54%) patients were evaluated as having active and mildly active disease. Only 34(12%) patients had inactive disease. The patients with diffuse cutaneous involvement (dcSSc) who were active had higher modified Rodnan Skin score(mRSS) and severity scores of general, skin and joint-tendon involvements; the patients who had mildly active disease also had higher scores of mRSS and severity scores of skin compared to those with inactive disease (table-2).The patients with limited cutaneous involvement (lcSSc) who were assessed as having active disease had higher mRSS and higher severity scores of general, skin, peripheral vascular, lung, joint-tendon and gastrointestinal involvements; the patients who had mildly active disease also had higher scores of mRSS and severity scores of skin, lung, joint-tendon and gastrointestinal involvements compared to those with inactive disease (table-2). Conclusion: One third of our cohort was found to have active disease despite treatment and only 12% had inactive disease. Skin involvement and severity of different organs were shown to be higher in patients with active disease in both cutaneous subsets, together with severity of lung, peripheral vascular and gastrointestinal involvements in active lcSSc. LcSSc and dcSSc patients who had mildly active disease also had severe disease similar to those with active patients. Disease activity and severity should be assessed as separate measurements to highlight the course of the disease and may guide to the management of patients with SSc. Disclosure of Interests: None declared
Telehealth Practice Among Health Centers During the COVID-19 Pandemic — United States, July 11–17, 2020
Authors: Hanna B. Demeke, Leah Zilversmit Pao, Hollie Clark, Lisa Romero, Antonio Neri, Rhea Shah, Kendra B. McDow, Erica Tindall, Naureen J. Iqbal, Kendra Hatfield-Timajchy, Joshua Bolton, Xuan Le, Brionna Hair, Stephanie Campbell, Cuong Bui, Paramjit Sandhu, Isaac Nwaise, Paige A. Armstrong, Michelle A. Rose
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Early in the coronavirus disease 2019 (COVID-19) pandemic, in-person ambulatory health care visits declined by 60% across the United States, while telehealth* visits increased, accounting for up to 30% of total care provided in some locations (1,2). In March 2020, the Centers for Medicare & Medicaid Services (CMS) released updated regulations and guidance changing telehealth provisions during the COVID-19 Public Health Emergency, including the elimination of geographic barriers and enhanced reimbursement for telehealth services† (3-6). The Health Resources and Services Administration (HRSA) administers a voluntary weekly Health Center COVID-19 Survey§ to track health centers' COVID-19 testing capacity and the impact of COVID-19 on operations, patients, and staff. CDC and HRSA analyzed data from the weekly COVID-19 survey completed by 1,009 HRSA-funded health centers (health centers¶) for the week of July 11-17, 2020, to describe telehealth service use in the United States by U.S. Census region,** urbanicity,†† staffing capacity, change in visit volume, and personal protective equipment (PPE) supply. Among the 1,009 health center respondents, 963 (95.4%) reported providing telehealth services. Health centers in urban areas were more likely to provide >30% of health care visits virtually (i.e., via telehealth) than were health centers in rural areas. Telehealth is a promising approach to promoting access to care and can facilitate public health mitigation strategies and help prevent transmission of SARS-CoV-2 and other respiratory illnesses, while supporting continuity of care. Although CMS's change of its telehealth provisions enabled health centers to expand telehealth by aligning guidance and leveraging federal resources, sustaining expanded use of telehealth services might require additional policies and resources.
Emerging roles of SIRT6 in human diseases and its modulators
Authors: Gang Liu, Haiying Chen, Hua Liu, Wenbo Zhang, Jia Zhou
Journal: Medicinal Research Reviews (2020)

Abstract The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty‐acylation, and mono‐ADP‐ribosylation) play a pivotal role in regulating lifespan and several fundamental processes controlling aging such as DNA repair, gene expression, and telomeric maintenance. Over the past decades, the aberration of SIRT6 has been extensively observed in diverse life‐threatening human diseases. In this comprehensive review, we summarize the critical roles of SIRT6 in the onset and progression of human diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative diseases, viral infections, renal and corneal injuries, as well as the elucidation of the related signaling pathways. Moreover, we discuss the advances in the development of small molecule SIRT6 modulators including activators and inhibitors as well as their pharmacological profiles toward potential therapeutics for SIRT6‐mediated diseases.
Abstract P548: Poorer Objective Sleep is Associated With Greater Arterial Stiffness and Worsening Cardiac Diastolic Function
Authors: Megan E Petrov, Shawn Youngstedt, Farouk Mookadam, Nana Jiao, Lance M Lim, Siddhartha S Angadi
Journal: Circulation (2020)

Aim: Few studies have examined the association between objective sleep metrics and arterial and echocardiographic (left ventricular systolic/diastolic function) markers of sub-clinical cardiovascular disease (CVD). The present study examined the association of wrist actigraphy-assessed sleep metrics with arterial stiffness, endothelial dysfunction, and left ventricular systolic/diastolic function. Methods: Fifteen young, healthy adults (21-39y; 60% women) with no history of CVD, and no current sleep-disordered breathing (WatchPat200, Itamar Medical) or sleep complaints wore Actiwatch Spectrum Plus actigraphs for eight nights (Philips Respironics, Bend OR) with accompanying sleep logs. Participants underwent fasting vascular testing including central augmented aortic pressure (AP), carotid-femoral pulse wave velocity (cfPWV) to assess arterial stiffness (SphymocorXCEL TM ), brachial artery flow mediated dilation (FMD) to assess endothelial function, and 2D echocardiography to assess left ventricular function (Terason uSmart 3300 TM ). Left ventricular function was assessed by ejection fraction (EF%), left atrial volume index (LAVI), deceleration time (DT), and mitral valve E/e’ ratio (MVE/e’) using standardized methods. Bivariate correlations investigating the association between mean total sleep time (TST), sleep efficiency % (SE), sleep-onset latency (SOL), and wake after sleep time (WASO) with cardiovascular indices were conducted. Curvilinear regression models examining quadratic relationships between TST and the cardiovascular indices were conducted. Results: On average, participants obtained 6 hrs 44 min of TST (SD=29.1), with 86.0% SE (SD=3.1), 10.6 min SOL (SD=8.5), and 37.0 min WASO (SD=11.6). cfPWV (range: 4.8-7.5), EF% (range: 60.0-72.0), LAVI (range: 15.0-26.7 mL/m 2 ), and MVE/e’ (range: 3.2-7.8) were all within normal ranges according to age and sex normative standards. Mean FMD was 9.2% (SD=4.62, range: 4.3-19.8). Correlations indicated that greater SOL was associated with greater cfPWV (r=.63, p=0.01), and AP (r=.57, p=0.03). Lower SE (r= -.70, p=0.003) and higher WASO (r=.71, p=0.003) were associated with higher MVE/e’. WASO was associated with higher DT (r=.57, p=0.04). Curvilinear regression models revealed a quadratic relationship between TST and cfPWV (F[2,11]=9.78, p=0.004) such that shorter and longer TST were associated with greater cfPWV. No sleep metrics were associated with FMD, EF%, or LAVI. Conclusions: Among normal sleeping, apparently healthy young adults, with no history of CVD, lower levels of objective sleep quality and both shorter and longer sleep duration were associated with greater arterial stiffness, whereas only lower levels of objective sleep quality were related to worsening left ventricular diastolic dysfunction. These data may have implications for CVD risk reduction in young, healthy adults.
Abstract 15090: Evaluation of Right Bundle Branch Block for Risk Prediction and Guiding Revascularization Strategy in Patients with Non-ST-Elevation Acute Coronary Syndrome in the TACTICS-TIMI 18 Trial
Authors: Jacob A Udell, Michelle L O'Donoghue, Eugene Braunwald, Benjamin M Scirica, Stephen D Wiviott, Sameer Bansilal, Elaine B Hoffman, Marc S Sabatine, Christopher P Cannon
Journal: Circulation (2012)

Background: Although a new left bundle branch block (BBB) is known to be a high-risk presentation of MI, less is known about right BBB. We hypothesized that the presence of RBBB would represent a h...
IMMU-32. NON-METABOLIC IDO ACTIVITY INCREASES COMPLEMENT FACTOR H LEVELS WHICH ENHANCES IMMUNOSUPPRESSION IN HUMAN GLIOBLASTOMA
Authors: Lijie Zhai, Galina Gritsina, Brenda Nyugen, April Bell, Erik Ladomersky, Lakshmi Bollu, Kristen Lauing, Derek Wainwright
Journal: Neuro-Oncology (2020)

Abstract Indoleamine 2,3 dioxygenase 1 (IDO) is an immunosuppressive factor expressed in ≥90% of patient resected glioblastoma (GBM). Canonically, IDO suppresses the immune response by metabolizing the essential amino acid, tryptophan, into the downstream metabolite, kynurenine. Based on the in vivo finding that the genetic knockout of tumor cell IDO does not change brain tumor tryptophan and kynurenine levels in syngeneic mice, we recently questioned the mechanistic role of IDO in GBM. To determine whether tumor cell tryptophan metabolism is responsible for the pathogenic effects of IDO, we created IDO-deficient murine GBM cells that were reconstituted with either (i) empty expression vector, (ii) a vector expressing wild-type IDO, (iii) or a vector expressing enzyme-inactive IDO. GBM cell IDO expression increased Tregs and decreased survival, but did so independent of tryptophan metabolism. To understand how IDO causes these effects, we performed Clariom D microarray analysis of human GBM cells and discovered that complement factor H (CFH) is significantly increased in GBM cells expressing IDO but decreased by treatment with IDO siRNA. Notably, CFH siRNA decreased CFH- but not IDO-expression in GBM cells. We next found that GBM cell IDO regulates CFH levels independent of tryptophan metabolism. To determine the effects of CFH on tumor outgrowth, we intracranially-engrafted syngeneic mice with IDO-deficient murine GBM cells reconstituted with either empty expression vector or a vector expressing CFH splice variant 2. Tumor CFH significantly decreased survival from GBM bearing mice similar to that of patient-resected GBM with high CFH levels whereby patients present with a faster rate to tumor recurrence. In summary, our study is the first to report an IDO-dependent non-metabolic regulation of CFH in tumor cells and highlights a new immunotherapeutic target in patients with incurable GBM.