tbuckley/cabot-search huggingface dataset:
Abstract 12091: Incidence and Predictors of Progression to Chagas Cardiomyopathy: Long-Term Follow-Up of a Large Cohort of <i>Trypanosoma cruzi-</i> Infected Individuals
Authors: Maria P Nunes, Lewis Buss, JosÃ© Luiz Padilha da Silva, Claudia Oliveira, Clareci Cardoso, Bruno Brito, Ariela Ferreira, Lea Oliveira, Ana Bierrenbach, Fabio Fernandes, Viviane Hotta, Luiz Mario Martinelli, Maria Carolina Soeiro, Adriana Brentegani, Vera Salemi, Marcia Menezes, Antonio Ribeiro, Ester Sabino
Journal: Circulation (2021)

Introduction: There are few contemporary prospective cohorts of Trypanosoma cruzi ( T.cruzi )-infected individuals. This study aimed to determine the incidence of new-onset cardiomyopathy and death attributable to T. cruzi infection. Methods: We enrolled 1088 individuals: 499 T. cruzi -seropositive blood donors identified in routine donor screening, 488 age- and sex-matched T. cruzi - seronegative blood donors, and 101 patients with established Chagas cardiomyopathy recruited from a tertiary center. Subjects underwent cardiovascular evaluation with ECG and echocardiogram at the baseline (2008-2010) and follow-up (2018-2019) visits. Cardiomyopathy was diagnosed based on ECG and echocardiographic findings at baseline and follow-up. Vital status was determined by linkage with the national Brazilian mortality system. Results: Mortality was 80.9 deaths/1000 person-years (py) in established cardiomyopathy and 15.1 deaths/1000py in T. cruzi -seropositive donors with cardiomyopathy at baseline. The mortality rate among T. cruzi -seropositive blood donors without cardiomyopathy at baseline and T. cruzi -seronegative controls was similar, with mortality rates of 3.67 and 3.62 events/1000 py, respectively. In T. cruzi -seropositive donors, age (hazard ratio [HR] = 1.05 per year), anti-T.cruzi antibody level (HR = 1.40 per unit increase in serology assay signal/cut off) and the presence of cardiomyopathy at baseline (HR = 3.01) were independent predictors of mortality. The incidence of new-onset cardiomyopathy in T. cruzi -seropositive donors was 13.8 events/1000 py (95% CI 9.5-19.6) compared with 4.6 events/1000 py (95% CI 2.3-8.3) in controls, with an absolute incidence difference attributable to T. cruzi infection of 9.2 (95% CI 3.6 - 15.0) events/1000py. T. cruzi antibody level at baseline was the main independent predictor of subsequent new-onset cardiomyopathy with an adjusted odds ratio of 1.37 (95% CI 1.07-1.76) per unit increase in antibody level. Conclusions: We present a comprehensive description of the natural history of T. cruzi infection in a contemporary patient population. The results highlight the central importance of total anti- T. cruzi antibody titer as a marker of Chagas disease activity and risk of progression.
Abstract 13963: Smooth Muscle Cells Promote Hypertensive Cardiac Hypertrophy Through Sox6 Signaling
Authors: Jose A Gomez, Pierina Barturen-Larrea, Alan Payne, Conrad Hodgkinson
Journal: Circulation (2021)

Introduction: Hypertension is the predominant risk factor for mortality. To compensate for pressure overload and reduce stress on the left ventricle, cardiomyocytes become hypertrophic. Recently, several laboratories have suggested that cardiomyocyte hypertrophy is regulated by factors released from adjacent non-cardiomyocytes. Stretching induced in cultured cardiomyocytes, fibroblasts, endothelial cells and smooth muscle cells (SMCs) to secrete factors which cause cardiomyocyte hypertrophy. We hypothesized that cardiac SMCs promote hypertensive cardiac hypertrophy through molecular signals controlled by the transcription factor Sox6. Methods: We used a SMCs tamoxifen inducible Sox6 knock out mice (Myh11 CreERT2 /Sox6 fl/fl -Sox6KO) to define if Sox6 was involved in hypertensive cardiomyopathy. Hypertension was induced by Angiotensin II (Ang II-1000 ng/kg/min x 28 days) infusion after tamoxifen. Cardiac function was measured by ultrasound; cardiomyocyte shape was defined by staining tissue sections with cardiac troponin-T and wheat germ agglutinin; and blood pressure was determined by tail cuff. Results: Ang II induced hypertension in Sox6KO and the Myh11 CreERT2 /Sox6 wt/wt (Myh11 CreERT2 -wild type for Sox6) (SBP mm Hg, 150 vs. 153, SEM= 11 n=3-4). The Myh11 CreERT2 developed cardiac hypertrophy with decreased ejection fraction (65 vs 58, SEM= 2, n=7, p&lt;0.001) and increased systolic (1.33 mm vs 1.8 mm, SEM= 0.1, n=7, p&lt;0.01) and diastolic LVD (1.33 mm vs 1.52 mm, SEM= 0.08, n=7, p&lt; 0.01). Cardiomyocyte area was increased in the Myh11 CreERT2 mice compared to the Sox6KO animals (area - square microns, 300 vs 100, SEM= 36, n=3, p&lt;.001). The Sox6KO mice had a higher base line LVD in both diastole and systole. However, the cardiomyocytes area was similar to normotensive Myh11 CreERT2 mice. Conclusion: Hypertension in control Myh11 CreERT2 animals was associated with impaired cardiac function. In contrast, there was no decrease in cardiac function in hypertensive Sox6KO mice. While in Myh11 CreERT2 mice, Ang II induced significant cardiomyocyte hypertrophy, in Sox6KO mice, Ang II did not induce cardiomyocytes hypertrophy. These results suggest that Sox6 signaling in SMCs is a critical mediator of hypertension induced cardiomyocyte hypertrophy.
The 15 Year Long-Term Survival of Patients with Chronic Myeloid Leukaemia from 35 Regions of Russian Federation: A Follow up of a Multicenter Observation Study Eutos Osp Initiated By European Leukemia NET
Authors: Olga V. Lazareva, Ekaterina Yu. Chelysheva, Olga Vinogradova, Anton Kulikovsky, Varvara I. Bakhtina, Eva Burnasheva, Tatiana Chagorova, Dolgorzhap Dasheeva, Elena Fedorova, Lubov Gavrilova, Nataliya Glonina, Anatoly Golenkov, Tatiana Klitochenko, Tatiana S. Konstantinova, Marina Kosinova, Marina Kozmina, Alexandr Korobkin, Galina Kuchma, Elza Lomaia, Alexander S. Luchinin, Anna Lyamkina, Ludmila Napso, Andrew Proidakov, Gysual Safuanova, Olga Senderova, Vasilisa Skatova, Anton Shutilev, Svetlana Volkova, Sergey Voloshin, Elena Volodicheva, Vera Yablokova, Andrew Zhuravkov, Andrey Zaritsky, Sergei M. Kulikov, Anna G. Turkina
Journal: Blood (2021)
How my Achilles tendon rupture drives my academic career
Authors: Joris Chapon
Journal: British Journal of Sports Medicine (2021)

<h3>Abstract</h3> Social belonging is an important human drive that influences mood and behavior. Neural responses to social exclusion are well-characterized, but the specificity of these responses to processing rejection-related affective distress is unknown. The present study compares neural responses to exclusion and over-inclusion, a condition that similarly violates fairness expectations but does not involve rejection, with a focus on implications for models of dorsal anterior cingulate cortex (dACC) and anterior insula (AI) function. In an fMRI adaptation of the Cyberball paradigm with adolescents 11.1-17.7 years of age (N=69), we employed parametric modulators to examine scaling of neural signal with cumulative exclusion and inclusion events, an approach that overcomes arbitrary definitions of condition onsets/offsets imposed on fluid, continuous gameplay. We identified positive scaling of dACC and posterior insula response with cumulative exclusion events, but these same regions exhibited trending signal <i>decreases</i> with cumulative inclusion events. Furthermore, areas within the dACC and insula also responded to context incongruency (throws to the participant in the exclusion run; throws between computer players in the over-inclusion run). Taken together, these findings caution against interpretations that responses in these regions uniquely reflect aspects of affective distress within social rejection paradigms. We further identified that the left ventrolateral PFC, rostromedial PFC, and left intraparietal sulcus responded similarly to cumulative exclusion and inclusion. These findings shed light on which neural regions exhibit patterns of differential sensitivity to exclusion or over-inclusion, as well as those that are more broadly engaged by both types of social interaction.
A Nobel Prize for Sensational Research
Authors: Mark J. Zylka
Journal: New England Journal of Medicine (2021)

This year's Nobel Prize in Physiology or Medicine was awarded to David Julius and Ardem Patapoutian for identifying molecules that relay sensation of capsaicin pepper, temperature, and physical force. They thus provided the first insights into how animals sense hot and cold temperatures, mechanical force, and the pungent chemicals in spices.
Abstract 9365: Psip1a is Critical for Vascular Development in Zebrafish
Authors: Chang-Ying Chiang, Chih-wen Ni
Journal: Circulation (2021)

Transcription coactivators function in variety ways which effectively facilitate the process of transcription and play an essential role in gene regulation. Among them, Psip1, the gene codes LEDGF/p75, has been implicated in cell survival, cancer, autoimmune diseases and HIV pathogenesis. Especially for its role in HIV replication, psip1 tethers and targets HIV integrase to the bodies of active genes, which makes it a novel target for anti-HIV treatment. However, the basic biology of psip1 is not fully elucidated, and such antiviral drugs may have unexpected side effect. Here, we show that psip1a is essential for vascular development in zebrafish. Knockdown or knockout of psip1a caused the structure disruption in the caudal vein plexus suggesting the cell death of endothelial cells. Interestingly, RNA-seq data suggested that psip1a is the master regulator for p53 signal pathway. Indeed, our data showed that psip1a directly associates to the alternative p53 promoter and potentially regulates Δ113p53 expression to antagonize p53 pathway and exhibited an anti-apoptotic effect. Such function of psip1a is medicated by IBD domain which is important for recruiting its binding partners for different functions of psip1. Zebrafish embryos treated with non-catalytic integrase inhibitors (NCINIs) showed the same vascular defects as the knockdown of psip1a, which was also mediated by the IBD domain. This unexpectedly side effect suggests a unforeseen risk of using NCINIs in antiviral treatment. Our results demonstrate the importance of psip1 in vascular development and how it regulates the p53 pathway to inhibit apoptosis. We anticipate our study to provide a new insight into the role of psip1 in vascular development. Better understanding the mechanism of psip1 function would also help to prevent unexpectedly side effects of new antiviral drug in HIV treatment.
BIOM-39. METHYLATION AND MUTATION PROFILES IN MENINGIOMA CELL-DERIVED EXTRACELLULAR VESICLE DNA REFLECT EPIGENETIC AND GENOMIC ALTERATIONS IN ORIGINAL TUMORS
Authors: Franz Ricklefs, Cecile Maire, Kathrin Wollmann, Lasse Dührsen, Krystian Fita, Felix Sahm, Christel Herold-Mende, Andreas von Deimling, Marceline Fuh, Harmut Schlüter, Markus Glatzel, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2021)

Abstract The majority of meningiomas are benign but approximately 20% of display an aggressive behavior, resulting in significant patient morbidity and mortality. Standard monitoring after meningioma resection relies on serial MRI examinations, which are time-consuming, expensive and provide no information on molecular alterations that may indicate progression towards a more aggressive tumor. Extracellular vesicles (EVs) are released by tumor cells and contain high molecular weight DNA, rendering circulating EVs a potential biomarker source for non-invasive disease monitoring and for obtaining information on genetic and epigenetic alterations. We quantified EVs in plasma of 46 meningioma patients (n = 29 M1, 12 M2, 5 M3) by nanoparticle tracking analysis and detected significantly higher levels compared to age-matched healthy donors (n = 18). EV concentrations correlated with malignancy grade (p = 0.0049) and with the extent of peritumoral edema (p = 0.0031). Comparisons between paired pre- and postoperative samples revealed that EV levels counts dropped significantly the day after tumor resection and were reduced to normal levels after about one week. Completely resected patients (Simpson grade I) displayed a greater reduction of postoperative EV concentrations than incompletely resected patients. DNA methylation profiling was performed on EVs secreted by cultured meningioma cells, as well as matched cells and original tumors using 850k arrays (n = 7 M1, 5 M2, 3 M3). All EV samples were correctly identified as meningiomas by the Heidelberg classifier, and methylation subclasses were also correctly assigned in almost all cases. t-SNE analysis showed that EVs mapped in close proximity to their corresponding parental cells and tumor tissue. Tumor specific mutations and copy number variations were detected in EV-DNA with high accuracy. Differential quantitative proteomic analysis of EVs, cells and tumors identified shared proteins that could potentially be useful for enriching tumor-derived circulating EVs from biofluids.
Abstract 13342: Transcriptional Profiling of Surgical Myectomy Tissue in Patients With Hypertrophic Cardiomyopathy Reveals Genotype Independent Counterregulatory Alterations in Hypertrophy Pathways
Authors: Ramin Garmany, Johan Bos, David J Tester, Cristobal Dos Remedios, Joseph J Maleszewski, Joseph A Dearani, Michael J Ackerman
Journal: Circulation (2021)

Introduction: Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases characterized by asymmetric left ventricular hypertrophy (LVH) and vast clinical and genetic heterogeneity. Several transcriptional studies in HCM heart tissues have shown severe alterations in gene expression. However, these earlier studies relied on microarray technology or were limited by small sample size or lack of genotype-specific analyses. Methods: We obtained flash-frozen cardiac tissue from patients with HCM undergoing surgical myectomy/septal reduction therapy for relief of left ventricular outflow tract obstruction. RNA-sequencing (RNAseq) was performed using paired-end index reading on 97 myectomy tissues (44 female [45%]; mean age at surgery of 47 ± 18 years) and 23 control tissues (10 female [43%]; mean age at death of 43 ± 12 years) to identify differentially expressed genes (DEGs) using edgeR and pathways in HCM using Ingenuity Pathway Analysis. Additionally, genome sequencing (GS) was performed and HCM patients were divided into genotype-based subgroups to compare the transcriptional profile across different genotypes. Results: Overall, 43% had a pathogenic, HCM-associated variant including 23% with MYBPC3-HCM and 15% with MYH7-HCM. Among the 15,634 genes expressed in the cardiac tissue,1,246 genes (8%) were upregulated and 738 genes (3%) were downregulated significantly in HCM vs. controls. Pathway analysis showed alterations in 126 pathways with downregulation of 44 pathways and upregulation of 1 pathway. There were notable transcriptional alterations of most canonical, pro-hypertrophic pathways, including statistically and biologically significant downregulation of five pathways [-log (BH p-value)≥ 1.3; Z-score≤ -2]: ERK/MAPK, p38 MAPK, ERK5, IL6, and NF-κB signaling. Far less DEGs were observed between genotypic subgroups, with only 37 DEGSs identified between sarcomere positive- and genotype negative-HCM. Conclusions: At the time of surgical myectomy, the ventricular myocardium’s transcriptome, independent of genotype, reveals widespread downregulation of pro-hypertrophic pathways. Whether these counter regulatory measures can be targeted therapeutically warrants further investigation.
Insights into the role of gut and intratumor microbiota in pancreatic ductal adenocarcinoma as new key players in preventive, diagnostic and therapeutic perspective
Authors: Concetta Panebianco, Davide Ciardiello, Annacandida Villani, Brigida Anna Maiorano, Tiziana Pia Latiano, Evaristo Maiello, Francesco Perri, Valerio Pazienza
Journal: Seminars in Cancer Biology (2021)
Abstract 12239: Improvement in Measures of Disease Progression With Tafamidis in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT)
Authors: Mazen A Hanna, Nowell Fine, Balarama Gundapaneni, Marla B Sultan, Ronald Witteles
Journal: Circulation (2021)

Introduction: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience a progressive decline in health and quality of life. Tafamidis is an effective treatment for patients with ATTR-CM, and was shown to reduce mortality and CV-related hospitalization in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). As ATTR-CM is a progressive disease, either stabilization or improvement signifies an efficacious treatment. Methods: This was a post-hoc analysis of the proportion of patients in ATTR-ACT who stabilized or improved in clinical parameters. In ATTR-ACT, 441 adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or placebo for 30 months, with pooled tafamidis (n=264) compared with placebo (n=177). Change from baseline was assessed at each study visit to determine patients who improved/did not change in: 6MWT distance; KCCQ-OS score; NT-proBNP concentration; PGA scale; and NYHA class. Any patient with missing data was considered not improved. Results: A significantly greater proportion of patients improved/did not change with tafamidis compared with placebo for each outcome at Month 30 ( Table ). Of patients who started treatment with tafamidis, 20-27% improved in 6MWT distance, KCCQ-OS score, and NT-proBNP concentration at Month 30, compared with 5-10% of patients with placebo. There were greater proportions who improved in these measures at earlier timepoints (32-42% with tafamidis vs 19-24% with placebo at Month 12; P &lt;0.01 for all). Conclusions: While patients with ATTR-CM are expected to experience a progressive decline over time, a significant proportion of tafamidis-treated patients in ATTR-ACT had improvements in measures of functional capacity, health-related quality of life, and cardiac biomarkers within 12 months and through the study. These data provide further evidence of the clinical benefits with tafamidis in patients with ATTR-CM.
PATH-45. APOLLO: RAMAN-BASED PATHOLOGY OF MALIGNANT GLIOMA
Authors: Adrian Lita, Joel Sjöberg, Stefan Filipescu, Orieta Celiku, Luigia Petre, Mark Gilbert, Houtan Noushmehr, Ion Petre, Mioara Larion
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND DNA methylation is an essential component for integrative diagnosis in glioma. Methylation subtype prediction of gliomas is currently done via sample extraction of high-quality of reasonable amount of DNA (~1ug), methylome profiling, followed by probe identification, curation and subsequent analysis via different random forest classifiers. However, the DNA methylation classification is not always available for all the samples. METHODS Raman Spectroscopy performed of the regions of interest using 1mm2 FFPE tissue spots from 45 patient samples with LGm1 to LGm6 methylation subtypes. Spectral information was then used to train a convolutional neural network (CNN) and develop a prediction algorithm. 70 % of dataset - model training while the remaining 30% for validation. Supervised wrapper methods and random forests were used to identify the top 109 most discriminatory Raman frequencies out of 1738. RESULTS We identified the most discriminatory features from these analyses and demonstrated that these frequencies show differential spectral intensities for these frequencies depending upon the glioma subtypes across the larger areas of the tissue. We compared the results of the Ward linkage clustering with the separation induced by the “frequency criterion”, an empirical observation that Raman spectra of tumor spots are characterized by intensities higher than 5000 on some of the frequencies from 1463 to 1473. For each of the 45 samples we ran Ward linkage clustering with a variable number of clusters (from 2 to 7), with the majority cluster corresponding to tumor spots and the others corresponding to (various types of) non-tumor spots. We found that the majority cluster matches very well the tumor spots characterized by the frequency criterion, The average accuracy over all samples was 90:3%, the average precision was 99:6% and the average recall was 90:2%. For most samples, two clusters were sufficient to distinguish between tumor and non-tumor spots with accuracy.
Abstract 10074: Cardiovascular Outcomes in Patients with Concurrent Atrial Fibrillation and Myeloproliferative Neoplasms
Authors: Orly Leiva, Andrew Jenkins, Rachel P Rosovsky, Rebecca Karp-Leaf, Katayoon Goodarzi, Gabriela Hobbs
Journal: Circulation (2021)

Introduction: Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET) and myelofibrosis (MF), are clonal stem cell neoplasms. Therapy is instituted to prevent thrombosis, a leading cause of morbidity/mortality in this population. Atrial fibrillation (AF) is also associated with increased risk of thromboembolism. Risk scores, including CHA 2 DS 2 VASC, are used to determine benefit of anticoagulation (AC) but have not been validated in patients with MPN. Methods: This is a single-center, retrospective cohort study of patients with concurrent MPN and AF from 2000 to 2020 (n = 142; 62 ET, 54 PV, 26 MF). Outcomes included composite of arterial thrombotic events (ATE; MI, ischemic stroke, or peripheral arterial embolism) and cardiovascular (CV) death, bleeding requiring hospitalization, and all-cause mortality (ACM). Results: AC was used in 69% of all MPN patients (73% of ET/ PV, 50% of MF). CHA 2 DS 2 VASC scores were significantly higher in patients with ET/PV compared with MF (4 ± 2 vs 3 ± 1, p = 0.0019). After median follow-up (FU) of 49 months (IQR 18, 86) the composite outcome occurred in 39% of patients with MPN (ET/PV 36%, MF 50%). Bleeding occurred in 30% of patients (ET/PV 29%, MF 30%) and ACM in 45% of all patients (ET/PV 40%, MF 83%). Patients with MF had worse composite-free survival (log-rank p = 0.0043, Fig-A) and no difference in bleed-free survival (Fig-B) compared with ET/PV patients. After multivariable logistic regression including CHA 2 DS 2 VASC, age, sex, MF, AC, CAD, hypertension, diabetes, prior stroke, aspirin use, MPN treatment and FU time as co-variables, MF was associated with the composite (aOR 4.1, 95% CI 1.2-14.9), CHA 2 DS 2 VASC was not (aOR 1.3, 95% CI 0.8-2.1). Conclusions: Patients with MPN and AF have high rates of adverse outcomes with MF having worse composite-free survival compared to ET/PV. Traditional risk scores may underperform in this patient population underscoring the need for further investigation.
Whole Genome Sequencing Uncovers a Rare Germline Variant in ATM Associated with Familial Myeloproliferative Neoplasms
Authors: Shiyu Wang, Hang Chen, Eddie Imada, Jack Ghannam, Clifton L. Dalgard, Camille Alba, Christopher S. Hourigan, Luigi Marchionni, Alison R. Moliterno, Lukasz P. Gondek, Evan M. Braunstein
Journal: Blood (2021)