tbuckley/cabot-search huggingface dataset:
EXTH-73. PROTEASOME INHIBITION EXPOSES SELECTIVE VULNERABILITY IN CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Yohei Miyake, Masahito Kawazu, Hiroaki Wakimoto, kensuke Tateishi, Tetsuya Yamamoto
Journal: Neuro-Oncology (2021)

Abstract Central nervous system lymphoma (CNSL), including primary and secondary CNSL, has a poor prognosis despite standard intensive chemotherapy. Since the majority of CNSL tumors are highly dependent on NF-κB signaling pathway for survival, Bruton’s kinase inhibitors, which target upstream in the NF-κB pathway, have demonstrated favorable clinical response in PCNSL patients. However, early recurrence is frequently observed. Therefore, novel therapeutic strategies are required in this progressive CNS disease. To understand the underlying tumor biology and explore a novel therapeutic strategy of CNSL, we previously established a panel of patient-derived xenograft (PDX) models, from both immunocompetent and Epstein-Barr virus (EBV)-positive CNSL patients. We confirmed that these PDX models highly recapitulated the phenotypic and genetic features of patient tumors. Using 19 PDX models, including 17 originally established PDXs, we found that NF-κB pathway related genomic alterations and AKT/mTOR signaling did not correlate with sensitivity to BTK inhibitors. We also found that RelA/p65 dephosphorylation as a biomarker of CNSL cells, which are responding to ibrutinib. Through high-throughput and NF-κB pathway-targeted drug screenings, we discovered that proteasome inhibitors suppressed cell viability across all CNSL models. The therapeutic effect, observed at a lower nanomolar range, was mediated by inhibition of the canonical NF-κB and AKT/mTOR pathways and was reversed by silencing of MYD88/CD79B in immunocompetent CNSL or LMP1 in EBV-positive CNSL. The second-generation proteasome inhibitor marizomib prolonged overall survival in CNSL orthotopic xenograft models through simultaneous suppression of RelA/p65 and AKT/mTOR signaling. Proteasome inhibition deregulated Mcl-1 and mediated caspase-dependent apoptosis, which was further enhanced by Bcl-2 family inhibition. Our results demonstrate the potential of proteasome inhibition as a novel therapeutic strategy in patients with immunocompetent and EBV-positive CNSL.
Cutaneous Melanoma: Management of Melanoma Brain Metastases and Molecular Testing
Authors: Douglas B. Johnson, Susan M. Swetter, April K.S. Salama, Evan Wuthrick
Journal: Journal of the National Comprehensive Cancer Network (2021)

Several advances in diagnosis and treatment of cutaneous melanoma were discussed at the NCCN 2021 Virtual Annual Conference. First, advances in immunotherapies and targeted agents have enhanced the role of systemic therapies in the up-front management of brain metastases in melanoma while improving survival. With dual-agent immune checkpoint inhibitors, more than half of patients with asymptomatic brain metastases that are not in high-risk anatomic areas of the brain respond to treatment, and these responses appear to be durable, sparing many patients from neurosurgery and/or stereotactic radiosurgery. In addition, molecular tests increasingly have implications for clinical decision-making in later-stage disease. The most important genetic mutation in melanoma is the BRAF V600 mutation, which can be found in approximately 40% to 50% of cutaneous melanomas.
Abstract 12762: Higher Incidence of Heart Failure and Arrhythmias in Atrial Fibrillation Patients Hospitalized With COVID-19
Authors: Leanne Pereira, Awfa Zain elabidin, Vahid Namdarizandi, Vivek Sharma, Michael Fatuyi, Shalemar Ann Kasan, Bassman Tappuni, Belal Kaseer, Dominique Brandt, Kamal Shemisa
Journal: Circulation (2021)

Introduction: Atrial fibrillation (Afib) is a common arrhythmia with significant morbidity and mortality. The cardiovascular effect of COVID-19 infection in patients with known Afib is poorly understood. The aim of this study was to analyze the cardiovascular outcomes of patients with a history of Afib who were admitted with COVID-19 infection. Methods: A retrospective cohort study of patients hospitalized between January 1 and July 31, 2020 with COVID-19 infection confirmed by polymerase chain reaction (PCR) testing of nasopharynx sample was stratified by history of Afib, and analyzed for patient characteristics and cardiovascular outcomes using Mann-Whitney &amp; χ 2 tests. A p value of &lt;0.05 was used for statistical significance. Results: Among the 321 patients admitted with a positive COVID-19 test, 12% (38) had a history of Afib. This subgroup was significantly older, median age 84.5 vs. 61 and were predominantly male, 66 vs. 34%. They showed a higher prevalence of heart failure with reduced ejection fraction (HFrEF) (26 vs. 6%) and with preserved ejection fraction (HFpEF) (34 vs. 13%), CAD (34 vs. 17%), chronic kidney disease (45 vs. 20%), and dyslipidemia (66 vs. 35%) compared to those admitted without a history of Afib. These patients had a wider QRS interval 101 (88-134) vs. 94 (86-104) and more elevated BNP levels 278 (109-696.5) vs. 234 (35-158). They were also more likely to experience Afib (53 vs. 7%) and ventricular arrhythmias (18 vs. 6%) during hospitalization, but they did not show any statistical difference in terms of mortality rate, ICU admission, use of mechanical ventilation, or 30-day hospital readmission. Conclusion: Patients admitted with COVID-19 with a history of Afib were older and had comorbid cardiovascular disease. Heart failure risk markers such as wider QRS interval and higher BNP levels were more common in the history of Afib subgroup of patients. These patients had a higher incidence of heart failure and arrhythmias but not mortality.
Abstract 11289: Sedentary Time in Uganda: Influence of Sex and HIV Status and Associations with Atherosclerotic Cardiovascular Disease Risk
Authors: Christine Horvat Davey, Allison R Webel, Ellen Brinza, Cissy Kityo, Rashidah Nazzinda, Chris T Longenecker
Journal: Circulation (2021)

Introduction: Sub-Saharan Africa (SSA) is disproportionately impacted by HIV and HIV-related atherosclerotic cardiovascular disease (ASCVD). Since physical activity may prevent ASCVD events, it is important to understand how physical activity and inactivity relate to ASCVD risk among men and women with and without HIV in SSA. Methods: One hundred people with HIV (PWH) and 100 people without HIV (PWOH) matched by age and sex were enrolled into this observational study in Kampala, Uganda. Physical activity was objectively measured by actigraphy for 7 days, including steps per day, light activity time, moderate-to-vigorous activity time and sedentary time. ASCVD risk was assessed using the pooled-cohort equations. Coronary artery disease was quantified by cardiac computed tomography angiography. Multivariable linear and logistic regression models were used to determine the relationship between physical activity, ASCVD risk, and subclinical coronary disease. Results: Median age was 57 years; 63% were female and median ASCVD risk score was 7.9%. All PWH were on antiretroviral therapy and 86% had undetectable HIV viral load. Physical activity patterns were similar by HIV status (all p&gt;0.2). Compared to males, females took more steps per day ( p =0.001) and engaged in more light activity time ( p &lt;0.001), but less moderate-to-vigorous activity time ( p &lt;0.001). Sedentary time was similar by HIV status and sex (both p&gt;0.8). After adjusting for moderate-to-vigorous activity time, sedentary time remained positively associated with ASCVD risk (standardized β=0.334, p &lt;0.001). In stratified models, sedentary time was associated with ASCVD risk in females (β=0.258, p =0.028) but not males (p=0.194) and in PWOH (β=0.430, p=0.001) but not PWH (p=0.380). Sedentary time was associated with the presence of coronary artery disease plaque, even after adjustment for ASCVD risk score (adjusted OR= 1.039 per hour of sedentary time, p =0.018). Conclusions: Sedentary time is strongly associated with atherosclerotic cardiovascular disease risk in Uganda, particularly among females, but less so among PWH. Future studies should consider the influence of sex and HIV status while developing targeted strategies to improve physical activity and reduce sedentary time.
Abstract P473: Obstructive Sleep Apnea Results In Microbial Bile Acid Biotransformations To Promote Atherosclerosis
Authors: Amulya Lingaraju, Stephany Flores Ramos, Emily Gentry, Orit Poulsen, Pieter C Dorrestein, Gabriel G Haddad, Amir Zarrinpar
Journal: Circulation Research (2021)

Obstructive sleep apnea (OSA) is an independent exacerbator of cardiovascular disease (CVD). However, it is unclear how OSA or it’s characteristic components, intermittent hypoxia and hypercapnia (IHC), increase CVD risk. Our previous work has shown that IHC reproducibly changes the gut microbiome dynamics in murine models of atherosclerosis and that these changes could affect host cardiovascular physiology through bile acids and phosphocholines. In our initial targeted metabolomics approach, changes in particular bile acids, such as taurocholic acid, taurodeoxycholic acid, and muricholic acid, were associated with and were predictive of IHC exposure in atherosclerotic Ldlr-/- mice. In a more recent study, we identified the formation of novel, microbially-synthesized conjugated bile acids by the gut microbiome that are more potent farnesoid X receptor agonists than other previously described bile acids, and thus, potentially can affect atherosclerosis formation. To determine whether these novel bile acids are associated with IHC-induced atherosclerosis, we characterized luminal bile acid changes in Ldlr-/- mice in an OSA model. We hypothesize that IHC alters the amount of microbially-synthesized novel bile acids and that these bile acids are associated with IHC-induced atherosclerosis. To test this hypothesis, we subjected atherogenic diet-fed Ldlr-/- mice to either room-air (control) or IHC conditions (n=10/condition) and assessed atherosclerotic lesion formation after 12 weeks post-diet. Mice under IHC conditions had significantly higher aortic lesion formation compared to controls. Assessment of fecal bile acid metabolites indicated changes in novel bile acid levels under IHC conditions. Moreover, correlational analysis showed that these novel bile acid changes were positively correlated with atherosclerotic lesion amounts, mainly driven by IHC conditions. Our results demonstrate that bile acid changes through microbial biotransformations occur under IHC conditions and could be the mechanistic link between OSA-induced microbiome changes and atherosclerosis.
Abstract 11332: Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes
Authors: Barbara Gonzalez Teran, Maureen Pittman, Reuben Thomas, Franco Felix, Desmond Richmond-Buccola, Krishna Choudhary, Elisabetta Moroni, Colombo Giorgio, Arun Padmanabhan, Mauro Costa, Yu Huang, Michael Alexanian, Clara Lee, Bonie Cole, Kaitlen Samse-Knapp, Michael McGregor, Casey Gifford, Ruth Huttenhain, Bruce Gelb, Bruce Conklin, Brian L Black, Benoit Bruneau, Nevan Krogan, Katherine Pollard, Deepak Srivastava
Journal: Circulation (2021)

Congenital heart disease (CHD) is present in 1% of live births, yet despite large-scale genomic sequencing efforts, identification of causal mutations remains a challenge. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of GATA4 and TBX5, two transcription factors whose mutation cause CHDs. Defining the GATA4 or TBX5 interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating the results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants associated with CHD. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the GLYR1 missense variant identified disrupted interaction with GATA4 and impaired transcriptional co-regulation in cardiomyocyte differentiation in vitro and cardiogenesis in vivo. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease.
Abstract 10826: Lineage Specific Integrin Alpha V Augmentation Promotes Tgf-β Induced Integrin-FAK-Aktthr308 Signaling Pathway
Authors: Ken Nakamura, Nobu Yokoyama, Albert J Pedroza, Alex R Dalal, Tetsuro Uchida, Michael P Fischbein
Journal: Circulation (2021)

Introduction: Marfan syndrome (MFS) patients classically develop focal aortic root aneurysms. Aortic root smooth muscle cells (SMCs) develop predominately from second heart field (SHF), whereas asc...
Abstract 10259: Better Prediction of Stroke in Atrial Fibrillation with Incorporation of Malignancy in Cha2ds2vasc Score: Mcha2ds2vasc Score
Authors: Rohit Moudgil, Brandon Bungo, Pulkit Chaudhury, Michael Arustamyan, Rishi Rikhi, Muzna Hussain, Patrick H Collier, Mohamed H Kanj, Alok Khorana, Amgad Mentias
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) is associated with an increased risk of stroke. Despite a large body of evidence linking malignancy and thrombosis, malignancy is not part of the scoring system. Hypothesis: Malignancy is an independent risk factor for the development of thromboembolic stroke in patients with AF. Methods: SEER database was utilized to identify patients with lung, colon, breast, and prostate cancers with AF and no prior diagnosis of stroke. These patients were compared to controls within the dataset. The primary endpoint was ischemic stroke. Rates of stroke per 100 person-years were calculated for each group. Cox regression modeling and a nested model comparing CHA 2 DS s VASc score (Model 1) with a complete model including cancer diagnosis (Model 2) were performed. Models were compared using Akaike Information Criterion (AKI) and Net Reclassification Index (NRI). A propensity matched cohort with equivalent CHA 2 DS 2 VASc scores determining stroke-free survival was also performed. Results: A total of 101,185 patients were included in the analysis, with 48,242 in the Cancer Group and 52,943 in the Non-cancer Group. Stroke rate per 100 person-years was significantly higher in the Cancer Group (2.962) compared with the Non-cancer Group (2.377) (IRR 1·25, 95% CI [1·18-1·31]). The CHA 2 DS 2 VASc model (Model 1) was compared against a model including cancer (Model 2) showing an improved predictability as assessed by both NRI (12·2, 95% CI [10·7-13·7, p&lt;0.01) and AKI. Cox regression analysis calculated a hazard ratio of 1.085 for Cancer (95% CI [1·029-1·44], p = 0·0027), which was comparable to age &gt; 75, female sex, and diabetes. Propensity matched Kaplan-Meier curve demonstrated decreased probability of stroke-free survival in the Cancer Group (p=0·00045). Conclusion: Cancers increase the risk of stroke in patients with AF. Consideration should be given for the addition of malignancy to the clinical scoring systems.
Adverse pregnancy outcomes in women with diabetes-related microvascular disease and risks of disease progression in pregnancy: A systematic review and meta-analysis
Authors: Sophie Relph, Trusha Patel, Louisa Delaney, Soha Sobhy, Shakila Thangaratinam
Journal: PLoS Medicine (2021)

The rise in the global prevalence of diabetes, particularly among younger people, has led to an increase in the number of pregnant women with preexisting diabetes, many of whom have diabetes-related microvascular complications. We aimed to estimate the magnitude of the risks of adverse pregnancy outcomes or disease progression in this population.We undertook a systematic review and meta-analysis on maternal and perinatal complications in women with type 1 or 2 diabetic microvascular disease and the risk factors for worsening of microvascular disease in pregnancy using a prospective protocol (PROSPERO CRD42017076647). We searched major databases (January 1990 to July 2021) for relevant cohort studies. Study quality was assessed using the Newcastle-Ottawa Scale. We summarized the findings as odds ratios (ORs) with 95% confidence intervals (CIs) using random effects meta-analysis. We included 56 cohort studies involving 12,819 pregnant women with diabetes; including 40 from Europe and 9 from North America. Pregnant women with diabetic nephropathy were at greater risk of preeclampsia (OR 10.76, CI 6.43 to 17.99, p < 0.001), early (<34 weeks) (OR 6.90, 95% CI 3.38 to 14.06, p < 0.001) and any preterm birth (OR 4.48, CI 3.40 to 5.92, p < 0.001), and cesarean section (OR 3.04, CI 1.24 to 7.47, p = 0.015); their babies were at higher risk of perinatal death (OR 2.26, CI 1.07 to 4.75, p = 0.032), congenital abnormality (OR 2.71, CI 1.58 to 4.66, p < 0.001), small for gestational age (OR 16.89, CI 7.07 to 40.37, p < 0.001), and admission to neonatal unit (OR 2.59, CI 1.72 to 3.90, p < 0.001) compared to those without nephropathy. Diabetic retinopathy was associated with any preterm birth (OR 1.67, CI 1.27 to 2.20, p < 0.001) and preeclampsia (OR 2.20, CI 1.57 to 3.10, p < 0.001) but not other complications. The risks of onset or worsening of retinopathy were increased in women who were nulliparous (OR 1.75, 95% CI 1.28 to 2.40, p < 0.001), smokers (OR 2.31, 95% CI 1.25 to 4.27, p = 0.008), with existing proliferative disease (OR 2.12, 95% CI 1.11 to 4.04, p = 0.022), and longer duration of diabetes (weighted mean difference: 4.51 years, 95% CI 2.26 to 6.76, p < 0.001) compared to those without the risk factors. The main limitations of this analysis are the heterogeneity of definition of retinopathy and nephropathy and the inclusion of women both with type 1 and type 2 diabetes.In pregnant women with diabetes, presence of nephropathy and/or retinopathy appear to further increase the risks of maternal complications.
NCMP-07. IDH MUTANT GLIOMAS PROMOTE EPILEPTOGENESIS VIA D-2-HYDROXYGLUTARATE DEPENDENT MTOR HYPER-ACTIVATION
Authors: Armin Mortazavi, Islam Fayed, Muzna Bachani, Tyrone Dowdy, Jahandar Jahanipour, Anas Khan, Chungzhang Yang, Dragan Maric, Mioara Larion, Alexander Ksendzovsky, Kareem Zaghloul
Journal: Neuro-Oncology (2021)

Abstract Uncontrolled seizures in patients with low grade gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Albeit there are multiple features that contribute to tumor related epileptogenesis, IDH mutations are determined to be an independent factor, although the pathogenesis remains poorly understood. Here, we hypothesize that the active metabolite D-2-hydroxyglutarate (D-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures. We use a complementary study of in vitro cortical cultures and electrographically sorted human cortical tissue from patients (n=5) with IDH-mutant gliomas to test this hypothesis. We demonstrate that D-2-HG leads to increased neuronal spiking activity (p&amp;lt; 0.0001) and promotes a distinct metabolic profile in surrounding neurons and upregulation of mTOR signaling (p&amp;lt; 0.0001), which is consistent in human epileptic cortex compared to peritumoral nonepileptic cortex. Furthermore, increases in neuronal activity are induced by mTOR activation and reversed with mTOR inhibition. Together, our data suggest that metabolic disruptions and mTOR signaling upregulation in the surrounding cortex due to D-2-HG may be a driving event for epileptogenesis in patients with IDH-mutant low grade gliomas.
Abstract 12794: CD14+ CD16++ Monocytes Predict Clinical Outcomes in Patients With ST-Elevation Myocardial Infarction
Authors: Mohamed AboAly, Elica Shokri, mohammed anwer, Samiullah Arshad, Lakshman Chelvarajan, Ahmed Abdel-latif
Journal: Circulation (2021)

Introduction: Nonclassical monocytes (CD14+CD16++) play different roles in cardiovascular disease progression. CD14+CD16++ cells can have both proinflammatory functions and atheroprotective properties. Hypothesis: The predictive value of CD14+CD16++ cells to clinical outcomes in patient with STEMI has not been well studied. Methods: We recruited 100 patients with STEMI who underwent primary PCI. Blood samples were collected at the time of presentation to the hospital (within 6 hours from onset of symptoms) then at 3, 6, 12 and 24 hours after presentation. Monocytes were defined as CD45+/HLA-DR+ and then subdivided based on the expression of CD14, CD16, CCR2, CD11b and CD42. The primary endpoint was a composite endpoint of all-cause death, hospitalization for heart failure, stent thrombosis, in-stent restenosis, and recurrent myocardial infarction. Univariate and multivariate cox proportional hazards models were performed, including age, sex, body mass index, diabetes mellitus, hypertension, congestive heart failure, and troponin-I. Results: The mean age of our cohort was 58.9 years old and 25% of our patients were females. Patients with high level (above the median) of CD14+CD16++ monocytes showed increased risk for the primary endpoint in comparison to patients with low level; adjusted hazard ratio (aHR) for CD14+/ CD16++ cells is 4.3 (95% confidence interval [95%CI] 1.2-14.8, p= 0.02), aHR for CD14+/ CD16++/CCR2+ cells is (95%CI 1.06-13.7, p= 0.04), aHR for CD14+/ CD16++/CD42b+ cells was 3.3 (95%CI 1.07-10.6, p=0.03), aHR for CD14+/ CD16++/CD11b+ is 5.1 (95%CI 1.4-18.0, p=0.009), and aHR for CD14+ HLA-DR+ is 7.5 (95% 2.0 -28.5, p=0.002). Conclusions: Our study shows that CD14+ CD16++ Monocytes and their subsets expressing CCR2, CD42 and CD11b could be important predictors of clinical outcomes in patients with STEMI. Further studies with larger sample sizes and different coronary artery disease phenotypes are needed to verify our findings.
NIMG-53. RATIO OF T1-WEIGHTED TO T2-WEIGHTED SIGNAL INTENSITY AND IDH MUTATION IN GLIOMA
Authors: Manabu Kinoshita, Masato Uchikoshi, Koji Takano, Mio Sakai, Hideyuki Arita, Katsuyuki Nakanishi, Yonehiro Kanemura, Haruhiko Kishima
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Identifying IDH mutation status before treatment is essential for Lower-grade glioma (LrGG) treatment. We have previously revealed that IDH mutated LrGG consists of tumor tissues with significantly longer T1 and T2 relaxation time and is a useful radiological feature to identify IDH mutation status. The ratio of T1-weighted to T2-weighted signal intensity (rT1/T2) is a way to retrieve semi-quantitative relaxation time information of the tissue bypassing the need to perform relaxometry. This investigation aimed to elucidate the correlation between rT1/T2 and T1-, T2-relaxation time (-relax) in glioma tissue and to explore the possibility of rT1/T2 as a radiological surrogate marker to identify IDH mutation status in LrGG. MATERIALS AND METHODS We analyzed 8 LrGGs (IDHwt:4, IDHmt:2, IDHmt&amp;1p19q-CODEL:2) in which relaxometry was performed. rT1/T2 maps were reconstructed as described in previous literature. Regions-of-interest were designed based on T2WI and FLAIR. The correlations between rT1/T2 and T1- and T2-relax were analyzed. Furthermore, We also investigated the correlation of IDH mutation status and rT1/T2. RESULTS 106,488 voxels were analyzed. The correlation between rT1/T2 and T1- and T2-relax were rT1/T2=1.6e-0.0003T1-relax and rT1/T2=1.2e-0.002T2-relax (R=0.77 and 0.70). rT1/T2 of IDH-wildtype tumor was significantly higher than that of IDH-mutant tumor (1.0 vs. 0.75, p&amp;lt; 0.0001). Voxel-wise analysis of rT1/T2 map was able to discriminate IDH-wildtype tumor from the mutant tumor with an AUC of 0.82. CONCLUSIONS rT1/T2, which can be calculated from MRI acquired during routine clinical practice, is a promising radiological surrogate marker to identify IDH mutation status in LrGG.