tbuckley/cabot-search huggingface dataset:
IMMU-38. DEEP IMMUNOPROFILING OF HUMAN GLIOBLASTOMA (GBM) REVEALS DIFFERENCES IN THE TUMOR IMMUNE CELL INFILTRATE IN PATIENTS WITH HIGH VS. LOW PLASMA CELL-FREE DNA (CFDNA)
Authors: Stephen J Bagley, Cecile Alanio, Jacob Till, Aseel Abdalla, Zev Binder, Arati Desai, Steven Brem, Donald M O’Rourke, Erica Carpenter, E John Wherry
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND We have previously demonstrated that high baseline plasma cfDNA concentration is associated with poor survival in patients with newly diagnosed GBM. The mechanism of this association remains unknown. To explore whether differences in the immune landscape between high- vs. low-cfDNA patients may play a role in their divergent clinical outcomes, we phenotyped tumors from patients with high vs. low cfDNA using mass cytometry by time of flight (CyTOF). METHODS We performed CyTOF on frozen tumor infiltrate suspension from a pilot cohort of patients with previously untreated GBM with known baseline plasma cfDNA concentration (Bagley, Clin Cancer Res 2020). CyTOF was used to simultaneously measure expression of 39 molecules related to immune cell lineage, differentiation state, and function. Differences in immune cell infiltrates between high- and low-cfDNA patients were assessed using Mann-Whitney U tests. RESULTS Four patients with high cfDNA (median 57, range 33-90 ng/mL) were compared to six patients with low cfDNA (median 12, range 7-16 ng/mL). Immune cell infiltrates with increased adaptive cells (high monocytes and T cells, p=0.05) were present in high-cfDNA compared to low-cfDNA patients. While &amp;gt; 70% of the infiltrating T cells were exhausted in both groups, the pattern of exhaustion was significantly different in high- vs. low-cfDNA patients, with less CXCR5+CD69+ and more CXCR5-CD69- (p=0.008) progenitor exhausted T cells in cfDNA-high patients. CONCLUSIONS In this GBM pilot study, we demonstrated differences in the tumor immune infiltrate in patients with high vs. low baseline plasma cfDNA concentration. Preclinical studies will be needed to determine if this explains the association between high plasma cfDNA and poor outcomes previously observed in patients. Our results may have implications for the use of cfDNA concentration as a predictive biomarker for immunotherapy, as tumors with more intermediate progenitor (CXCR5-CD69-) exhausted T cells may respond better to PD-1 checkpoint blockade.
Global cancer research in the post-pandemic world
Authors: Deborah Mukherji, Raul Hernando Murillo, Mieke Van Hemelrijck, Verna Vanderpuye, Omar Shamieh, Julie Torode, C S Pramesh, Aasim Yusuf, Chris M Booth, Ajay Aggarwal, Richard Sullivan
Journal: The Lancet Oncology (2021)
Abstract MP245: Tet Proteins Regulate Second Heart Field Multipotent Progenitors Differentiating To Myocytes
Authors: Shaohai Fang, Jia Li, Jeff D Steimle, Lei Guo, Yuhan Yang, Tingting Hong, Rui Wang, Wei Han, Yubin Zhou, Jun Wang, James F Martin, Yun Huang
Journal: Circulation Research (2021)

DNA methylation and demethylation play an important role in shaping the epigenetic landscape and chromatin accessibility to control gene expression during development in mammals. Ten-eleven Translocation (Tet1, Tet2 and Tet3) is a family of dioxygenases that catalyze DNA methylation oxidation with ultimate DNA demethylation. Our previous study showed that cardiac-specific deletion of Tet2 and Tet3 could disrupt YY1-mediated long range chromatin interactions during heart development and lead to ventricular non-compaction cardiomyopathy. However, it is still unclear whether and how Tet protein mediated epigenetic modifications contribute to cardiac lineage specification during embryonic development. In this study, we generated cardiac specific Tet1-3 triple deficient (Tet-TKO) mouse lines using various cardiac specific Cres to evaluate the function of Tet protein in regulating cardiac lineage specification. We observed developmental defects at outflow tract (OFT) in Tet-TKO embryos, suggesting that Tet deficiency affects the second heart field (SHF) development. Single cell RNA-seq analysis further revealed the accumulation of multipotent SHF progenitors and subsequent halt of myocyte differentiation upon Tet depletion. At the molecular level, we found that Tet ablation perturbs the transcriptional network of Islet1, a transcription factor that is crucial for cardiac development in embryos. Overall, our study demonstrates a critical role of Tet-mediated epigenetic regulation for embryonic cardiac development.
Abstract 10356: Impact of Statin Therapy in Heart Failure Patients: Results of a Large Real-World Experience
Authors: Jeffrey L Anderson, Heidi T May, Viet T Le, Joseph B Muhlestein, Benjamin D Horne, Tami L Bair, Stacey Knight, Kirk U Knowlton
Journal: Circulation (2021)

Introduction: The use of statins in patients (pts) with heart failure (HF) is controversial. In patients without HF, statins reduce the risk of atherosclerotic cardiovascular disease (ASCVD), including HF-related events. In contrast, no benefit was observed in statin-treated HF pts in the CORONA and GISSI-HF trials. However, issues with generalizability may limit the applicability of these trial results in clinical practice. Therefore, we analyzed the impact of statin therapy in systolic HF pts in a large real-world experience. Methods: We searched Intermountain Healthcare medical records for pts with a diagnosis of HF and a reported ejection fraction of &lt;=40%. We compared outcomes (MACE=death, MI, stroke) at a median of 4.5 years follow-up in those who were and were not prescribed a statin. Statin use was defined as use at or after a HF diagnosis but prior to 60-days before MACE or end of follow-up. Cox hazard regression analysis was used to determine hazard ratios. Results: A total of 15,010 pts were studied. Baseline demographics and outcomes are shown in the Table. Statin use was associated with more frequent ASCVD risk factors yet a lower MACE risk during follow-up. Benefit was similar for primary and secondary prevention pts and for prior and new statin prescriptions. By time-varying hazard ratio (HR) analysis, the longer the pt was on a statin, the greater the reduction in risk of MACE (p&lt;0.0001). Conclusion: These results suggest a potential benefit of selective statin use in the real-world management of HF pts with ASCVD or at high-ASCVD risk. These novel observations deserve validation in additional real-world experiences.
Abstract 12061: Myocardial Scar and Revascularization on Mortality in Ischemic Cardiomyopathy:Late Gadolinium Enhancement Cardiac Magnetic Resonance Study
Authors: Hanbit Park, Do-Yoon Kang, Jung-Min Ahn, Dong Hyun Yang, Hyun Jung Koo, Joon-Won Kang, Pil Hyung Lee, Sang Eun Lee, Min-Seok Kim, Soo-Jin Kang, Dukwoo Park, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Ho Jin Kim, Joon Bum Kim, Sung-Ho Jung, Suk Jung J Choo, Cheol- Hyun Chung, Jae Won LEE, Jae-Joong Kim, Seong-Wook Park, Seung-jung Park
Journal: Circulation (2021)

Background: Myocardial viability test to guide revascularization remains uncertain in patients with ischemic cardiomyopathy. We aimed to evaluate the different impacts of revascularization on cardiac mortality according to the extent of myocardial scar assessed by cardiac magnetic resonance with late gadolinium enhancement (LGE-CMR) in patients with ischemic cardiomyopathy. Methods: A total of 404 consecutive patients with significant coronary artery disease and an ejection fraction ≤35% were assessed by LGE-CMR before revascularization. Of them, 306 patients underwent revascularization and 98 patients received medical treatment alone. The primary outcome was cardiac death. Results: During a median follow-up of 6.3 years, cardiac death occurred in 158 (39.1%) patients. Revascularization was associated with a significantly lower risk of cardiac death than medical treatment alone in the overall population (adjusted hazard ratio [aHR], 0.29; 95% confidence interval [CI], 0.19-0.45; P &lt; 0.001). There was a significant interaction between the number of segments with 76%-100% transmural LGE and revascularization on the risk of cardiac death (P = 0.037 for interaction). In patients with limited myocardial scar (&lt; 6 segments with 76%-100% transmural LGE, N = 354), revascularization had a significantly lower risk of cardiac death than medical treatment alone (aHR, 0.24; 95% CI, 0.15-0.37; P &lt; 0.001); in patients with extensive myocardial scar (≥ 6 segments with 76-100% transmural LGE, N = 50), there was no significant difference between revascularization and medical treatment alone regarding the risk of cardiac death (aHR, 1.33; 95% CI, 0.46-3.80; P = 0.60). Conclusions: Assessment of myocardial scar by LGE-CMR may be helpful in the decision-making process for revascularization in patients with ischemic cardiomyopathy.
Time waits for no one
Authors: Pat Lok
Journal: BMJ (2021)

Medical students are always constrained by time. Too little time—too much content to revise, too many papers to write, and audits to do. The medical degree is notoriously long, ranging from four to six years depending on your qualifications. Could medical degrees be shortened yet still achieve similar outcomes? A US study reported that graduates of three year medical school programmes are as well prepared for residency as those who graduate from four year programmes.1 They also had less student debt and were more likely to enter primary care fields …
CTIM-25. A RANDOMIZED PHASE 3 STUDY OF NIVOLUMAB OR PLACEBO COMBINED WITH RADIOTHERAPY PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA WITH METHYLATED MGMT PROMOTER: CHECKMATE 548
Authors: Michael Weller, Michael Lim, Ahmed Idbaih, Joachim Steinbach, Gaetano Finocchiaro, Raju Raval, Lynn Ashby, George Ansstas, Joachim Baehring, Jennie Taylor, Jerome Honnorat, Kevin Petrecca, Filip de Vos, Antje Wick, Ashley Sumrall, Mustimbo Roberts, Ruta Slepetis, Deepti Warad, Michelle Lee, David Reardon, Antonio Omuro
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Novel therapies are needed in newly diagnosed glioblastoma as nearly all patients experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ), including patients with tumors with methylated MGMT promoter, a positive prognostic factor and predictor of benefit with TMZ. Here, we report the final analysis of progression-free survival (PFS), overall survival (OS), and safety from an international randomized, single-blind phase-3 study of nivolumab (NIVO)+RT+TMZ in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter (CheckMate 548; NCT02667587). METHODS Patients (N=716) aged ≥ 18y were randomized 1:1 regardless of tumor PD-L1 expression to NIVO (240 mg Q2W×8, then 480 mg Q4W) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 QD during RT, then 4-week break, then 150–200 mg/m2 QD on days 1–5 of every 28-day cycle for 6 cycles) or placebo (PBO)+RT+TMZ. The dual-primary endpoints were PFS by blinded independent central review and OS, both overall and without baseline corticosteroids. RESULTS As of December 22, 2020, median PFS was 10.6 months (95% CI, 8.9–11.8) with NIVO+RT+TMZ and 10.3 months (95% CI, 9.7–12.5) with PBO+RT+TMZ (HR, 1.06 [95% CI, 0.90–1.25]). Median OS was 28.9 months (95% CI, 24.4–31.6) with NIVO+RT+TMZ and 32.1 months (95% CI, 29.4–33.8) with PBO+RT+TMZ (HR, 1.10 [95% CI, 0.91–1.33]). Among patients without baseline corticosteroids, median OS was 31.3 months (95% CI, 28.6–34.8) with NIVO+RT+TMZ and 33.0 months (95% CI, 31.0–35.1) with PBO+RT+TMZ (HR, 1.12 [95% CI, 0.87–1.43]). Grade 3–4 treatment-related adverse events were 52.4% and 33.6% with NIVO+RT+TMZ and PBO+RT+TMZ, respectively. CONCLUSIONS NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter. No new safety signals were observed with NIVO. The role of immunotherapy in this treatment landscape remains an area for further investigation.
Abstract 10994: The Interaction of the Transcriptional Coactivator P300 with the Chromatin Remodeling Factor Brg1 Increases the Acetylation of the Histone H3 Globular Domain in Heart Failure
Authors: sho uehara, Tatsuya Morimoto
Journal: Circulation (2021)

Background: Epigenetic regulatory mechanisms such as histone post-translational modifications are involved in the development of heart failure. Although the acetylation of tail domains, such as H3K9, has been extensively studied, that of H3K122, the globular domain, has received much less attention. Acetylation of the globular domain directly activates transcription by destabilizing histone-DNA binding. However, the mechanism of the acetylation of these domains during the transition from left ventricular hypertrophy (LVH) to heart failure (HF) remains unknown. Methods and Results: Primary cultured cardiomyocytes prepared from neonatal rats were treated with phenylephrine (PE). PE increased the acetylation of H3K9 and H3K122. The acetylation of H3K9 and H3K122 on the promoters of ANF and BNP , which are hypertrophic reaction genes, was increased in cardiomyocyte hypertrophy. To investigate whether the transcriptional coactivator p300 is involved in the acetylation of H3K9 and H3K122, p300 knockdown was used. p300 knockdown suppressed PE-induced cardiomyocyte hypertrophy and the acetylation of H3K9 and H3K122. In Dahl-salt sensitive rats, in vivo chromatin-immunoprecipitation assays revealed that the acetylation of H3K9 on the promoter of the hypertrophic response genes was significantly increased in LVH, but the acetylation of H3K122 was not increased in LVH. However, H3K122 acetylation was significantly increased in HF. On the other hand, there was no difference in the amount of p300 recruitment in LVH and HF. Interestingly, immunoprecipitation -WB showed that binding of p300 with BRG1, a key component of the SWI/SNF complex, was enhanced in HF. The recruitment of BRG1 was increased significantly in HF compared to LVH. Moreover, PFI-3, a BRG1 inhibitor, significantly suppressed PE-induced increases in cardiomyocyte surface area, the mRNA levels of ANF and BNP, and the acetylation of H3K9 and H3K122 in cultured cardiomyocytes. Conclusion: This study demonstrates that the acetylation of H3K122 is enhanced via the interaction of p300 and BRG1 in heart failure, providing novel insights into the epigenetic regulatory mechanism governing transcriptional activity in these processes.
Abstract 13366: Cardiovascular Risk Profile of Middle Eastern Immigrants Living in the United States
Authors: Tamer Yahya, Isaac Acquah, Kobina Hagan, Zulqarnain Javed, Mohamad Taha, Javier Valero Elizondo, Mouaz Al-Mallah, Mohammed Chamsi Pasha, Nadeen N Faza, William A Zoghbi, Miguel Cainzos Achirica, Khurram Nasir
Journal: Circulation (2021)

Introduction: Middle Eastern (ME) immigrants are one of the fastest-growing groups in the US. Several studies have noted a relatively high burden of CVD in ME countries. In the US, while their risk profile has been partially described as part of immigrant studies, the burden of risk factors and ASCVD have not been studied in detail among ME immigrants. Methods: We used 2012-2018 data from the National Health Interview Survey (NHIS), a US nationally representative survey. ME origin was ascertained through self-reported region of birth. ASCVD and CVD risk factors were also self-reported. We compared these to US-born non-Hispanic white (NHW) individuals in the US, using chi-square tests and logistic regression models. Results: Among 139,778 adults included, 886 (representing 1.3 million individuals, mean age 46.8) were of ME origin, and 138,892 were US-born NHWs (representing 150 million US adults, mean age 49.3). ME participants were more likely to have higher education, lower income and be uninsured. The age-adjusted prevalence of hypertension (22.7% vs 27.8%) and obesity (22.1% vs 32%) were significantly lower in MEs vs NHWs participants, respectively. There were no significant differences between the groups in the age-adjusted prevalence of ASCVD, diabetes, hyperlipidemia, and smoking. Only physical inactivity was higher among ME individuals (Fig) . In multivariable analyses, ME participants had lower odds of hypertension (OR 0.71, 95% CI 0.61, 0.83) and obesity (OR 0.61, 95% CI 0.52, 0.72), and higher odds of physical inactivity (OR 1.30, 95% CI 1.11, 1.53), with no significant differences in the other factors or ASCVD (Fig) . Conclusions: ME immigrants in the US exhibit a more favourable cardiovascular risk profile compared to NHWs. Further studies are needed to determine whether this finding is related to lower risk, selection of a healthier ME subgroup in NHIS, or possible under-detection of cardiovascular risk factors in ME immigrants living in the US.
Abstract 13338: Sociodemographic Differences in the Associations Between Omega-3 Polyunsaturated Fatty Acid Levels and Lipid Profiles in the United States
Authors: Daniel W Riggs, Aruni Bhatnagar, Jason Hellmann
Journal: Circulation (2021)

Introduction: Omega-3 (n-3) fatty acids have been shown to improve cardiovascular disease related lipid profiles, however, it is unclear whether these benefits vary by sociodemographic status. Therefore, we conducted a cross-sectional study to examine sociodemographic differences in n-3 fatty acids and their associations with lipid profiles in the general US population. Methods: Data from 2,444 participants in the 2011-2012 National Health and Nutrition Examination Survey were used in the study. Omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were measured in serum and analyzed as a percentage of total fatty acids. The primary outcomes included LDL/HDL ratio, total cholesterol/HDL ratio, and log of triglycerides/HDL ratio. Survey weighted regression with domain analysis were used to test for sociodemographic differences in associations. Results: We found that males had significantly lower levels of total n-3 fatty acids than females. Compared with Non-Hispanic Whites, Mexican Americans had lower levels of n-3 fatty acids, while Non-Hispanic Asians had higher levels. Omega-3 levels were also highest in college graduates and participants with a household income greater than $65,000. After adjusting for relevant confounders, we found an inverse association between DHA and LDL/HDL (-0.14 per 1% higher relative DHA; 95% CI:-0.25,-0.02), total cholesterol/HDL (-0.31; 95% CI: -0.45,-0.17), and triglyceride/HDL (-0.26; -0.34,-0.17). We also found an inverse association between EPA and triglyceride/HDL (-0.15; 95% CI: -0.26, -0.5). No associations were found with DPA. Subgroup analysis revealed that the association between DHA and LDL/HDL ratio was only significant in females, Non-Hispanic Whites, those with an annual household income greater than $65,000, and college graduates. Subgroup analysis of total cholesterol/HDL revealed an inverse association with EPA in females, Non-Hispanic Blacks, and college graduates. Conclusions: In the United States, the beneficial effects of n-3 fatty acids on lipid profiles vary by sociodemographics. These results may be due to sociodemographic inequalities in n-3 fatty acid consumption.
Factors Associated With Risk of Postdischarge Thrombosis in Patients With COVID-19
Authors: Pin Li, Wei Zhao, Scott Kaatz, Katie Latack, Lonni Schultz, Laila Poisson
Journal: JAMA Network Open (2021)

COVID-19 is associated with a high incidence of thrombotic events; however, the need for extended thromboprophylaxis after hospitalization remains unclear.To quantify the rate of postdischarge arterial and venous thromboembolism in patients with COVID-19, identify the factors associated with the risk of postdischarge venous thromboembolism, and evaluate the association of postdischarge anticoagulation use with venous thromboembolism incidence.This is a cohort study of adult patients hospitalized with COVID-19 confirmed by a positive SARS-CoV-2 test. Eligible patients were enrolled at 5 hospitals of the Henry Ford Health System from March 1 to November 30, 2020. Data analysis was performed from April to June 2021.Anticoagulant therapy after discharge.New onset of symptomatic arterial and venous thromboembolic events within 90 days after discharge from the index admission for COVID-19 infection were identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes.In this cohort study of 2832 adult patients hospitalized with COVID-19, the mean (SD) age was 63.4 (16.7) years (IQR, 53-75 years), and 1347 patients (47.6%) were men. Thirty-six patients (1.3%) had postdischarge venous thromboembolic events (16 pulmonary embolism, 18 deep vein thrombosis, and 2 portal vein thrombosis). Fifteen (0.5%) postdischarge arterial thromboembolic events were observed (1 transient ischemic attack and 14 acute coronary syndrome). The risk of venous thromboembolism decreased with time (Mann-Kendall trend test, P < .001), with a median (IQR) time to event of 16 (7-43) days. There was no change in the risk of arterial thromboembolism with time (Mann-Kendall trend test, P = .37), with a median (IQR) time to event of 37 (10-63) days. Patients with a history of venous thromboembolism (odds ratio [OR], 3.24; 95% CI, 1.34-7.86), peak dimerized plasmin fragment D (D-dimer) level greater than 3 μg/mL (OR, 3.76; 95% CI, 1.86-7.57), and predischarge C-reactive protein level greater than 10 mg/dL (OR, 3.02; 95% CI, 1.45-6.29) were more likely to experience venous thromboembolism after discharge. Prescriptions for therapeutic anticoagulation at discharge were associated with reduced incidence of venous thromboembolism (OR, 0.18; 95% CI, 0.04-0.75; P = .02).Although extended thromboprophylaxis in unselected patients with COVID-19 is not supported, these findings suggest that postdischarge anticoagulation may be considered for high-risk patients who have a history of venous thromboembolism, peak D-dimer level greater than 3 μg/mL, and predischarge C-reactive protein level greater than 10 mg/dL, if their bleeding risk is low.
“Magnetism‐Optogenetic” System for Wireless and Highly Sensitive Neuromodulation
Authors: Yu Tian, Yingying Zhang, Xinyu Zhang, Huizhuo Pan, Lili Zhang, Shuang Liu, Yulan Chen, Lin Su, Peiqi Zhao, Jin Chang, Hanjie Wang
Journal: Advanced Healthcare Materials (2021)

Neuromodulation is becoming more and more important in studying brain function, disease treatment, and brain-computer interfaces. However, traditional regulation methods cannot effectively achieve both wireless regulation and highly sensitive response, which are essential factors in neuromodulation. In this paper, a "magnetism-optogenetic" system is constructed, which uses a magnetic field to drive mechanoluminescent materials (ZnS:Cu) to generate light, thus stimulating photogenetic proteins. This system effectively combines the wireless magnetic regulation with the high sensitivity of optogenetics. The results show that the luminous intensity of this system changes with the power of an external magnetic field. In addition, under the continuous stimulation of the wireless magnetic field, this system can activate hippocampal-related neural responses and induce the expression of C-fos. In the end, this system can further regulate the movement behavior of rats with C1V1 protein expression in the primary motor cortex. This new magnetism-optogenetic system will provide an excellent reference for wireless and highly sensitive neuromodulation.