tbuckley/cabot-search huggingface dataset:
Abstract P408: Cardiovascular Health And Recovery From Mobility Limitation in Middle Aged African Americans: The Jackson Heart Study
Authors: Michelle C Odden, Kendra D Sims, Roland Thorpe, Nancy Min, Mandip S Dhamoon, Mario Sims, Adolfo Correa
Journal: Circulation (2020)

Despite a well-established literature demonstrating that African Americans shoulder a high burden of mobility limitation, little is known about factors associated with recovery. Although poor cardiovascular health is a risk factor for mobility limitation, its role in recovery is less clear. The present study investigated demographic and cardiovascular factors associated with recovery from incident mobility limitation within one year in the Jackson Heart Study, a cohort study of African Americans in Jackson, MS. Participants underwent three in-person interviews and exams from 2000-2013, and mobility limitations were assessed by self-reported limitations in walking half a mile or climbing stairs during annual phone calls. The outcome of interest, recovery from mobility limitation, was defined as no mobility limitation the following year. Candidate predictor variables were assessed in logistic regression models and included sociodemographic factors, behaviors, cardiovascular health measures, and chronic conditions. Multiple imputation using chained equations was used to address missing data. Among 5,276 participants [mean (SD) age = 55.4 (12.9) years], 1,759 (33%) had an incident mobility limitation over 12 years of follow-up, and 953 (54%) reported recovery from mobility limitation by one year later. Young women were more likely to recover from mobility limitation than young men. However, with increasing age, women were less likely to recovery from mobility limitation compared with men (p-value for age and gender interaction = 0.03). In adjusted models, being married was associated with a greater likelihood of recovering (OR: 1.26; 95% CI: 1.02, 1.55), whereas a history of heart failure and current statin use were associated with a lower likelihood of recovering (OR = 0.57; 95% CI: 0.34, 0.98 and 0.77; 95% CI: 0.61, 0.98, respectively). In conclusion, the majority of incident mobility limitations in this population of middle-aged African Americans was transient. Being married may support recovery from limitations by providing a form of structural social support. Cardiovascular health status appears to be an important factor in recovery.
Defining and Managing High-Risk Multiple Myeloma: Current Concepts
Authors: Luciano J. Costa, Saad Z. Usmani
Journal: Journal of the National Comprehensive Cancer Network (2020)

Multiple myeloma is a very heterogeneous disease. Despite advances in diagnostics and therapeutics, a subset of patients still experiences abbreviated responses to therapy, frequent relapses, and short survival and is considered to have high-risk multiple myeloma (HRMM). Stage III diagnosis according to the International Staging System; the presence of del(17p), t(4;14), or t(14;16) by fluorescence in situ hybridization; certain gene expression patterns; high serum lactic dehydrogenase level; and the presence of extramedullary disease at diagnosis are all considered indicators of HRMM. More recent evidence shows that patients who experience response to therapy but with a high burden of measurable residual disease or persistence of abnormal FDG uptake on PET/CT scan after initial therapy also have unfavorable outcomes, shaping the concept of dynamic risk assessment. Triplet therapy with proteasome inhibitors, immunomodulatory agents, and corticosteroids and autologous hematopoietic cell transplantation remain the pillars of HRMM therapy. Recent evidence indicates a benefit of immunotherapy with anti-CD38 monoclonal antibodies in HRMM. Future trials will inform the impact of novel immunotherapeutic approaches, including T-cell engagers, CAR T cells, and nonimmunotherapeutic approaches in HRMM. Those agents are likely to be deployed early in the disease course in the setting of risk- and response-adapted trials.
Abstract 15715: Dna Methylation of Genes Involved in Inflammation Correlates With Cardiometabolic Function in Morbidly Obese Adults
Authors: Mohamed M Ali, Chandra Hassan, Mario Masrur, Francesco Bianco, Patrice Frederick, Giulianotti P Cristoforo, Antonio Gangemi, Shane A Phillips, Abeer M Mahmoud
Journal: Circulation (2020)

Obesity is a major risk factor for cardiovascular disease. We previously demonstrated impaired vascular function that correlated with global DNA hypomethylation in adipose tissue (AT) isolated from obese adults (OB). Blood-detected epigenetic profiles may serve as non-invasive clinically relevant biomarkers and stand as an unexploited precision medicine reserve. Hypothesis: We hypothesized a contributing role of DNA methylation to systemic inflammation in OB subjects compared to lean controls (CON). We also explored the correlation between these methylation profiles and cardiometabolic measurements. Methods: We obtained blood and AT samples from bariatric patients (n=24; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and CON adults (n=24; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for flow-induced dilation (FID), nitric oxide (NO) and reactive oxygen species (ROS) production. Brachial artery flow-mediated dilation (FMD) was measured via Doppler ultrasound. Promoter methylation of 94 genes involved in inflammation and autoimmunity (EpiTect Methyl II PCR Arrays) were analyzed in whole-blood DNA in relation to vascular function and cardiometabolic risk factors. Results: 70% of genes had a higher methylated fraction in CON compare to only 28% in OB subjects. After correction for multiple testing, 28 genes were significantly hypermethylated in CON compared to OB; on top of these genes are CXCL1, CXCL12, CXCL6, EGR1, HDAC4, IGF2BP2, IL12A, IL12B, and IL17RA. Ten of these genes had significantly higher mRNA in OB compared to CON indicating the functional impact of such signals on gene transcription; on top of these genes are CXCL6, TLR5, IL6ST, IL15RA, and HDAC4. Methylation % of differentially methylated genes inversely correlated with BMI, total fat %, visceral fat%, blood pressure, fasting plasma insulin, serum IL6 and CRP (C-reactive protein), arteriolar ROS, and alcohol consumption and positive correlations with lean %, HDL, plasma folate and vitamin B12, arteriolar FID and NO production, and brachial FMD. Conclusions: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation. A downstream target for this pathway could reside in endothelial cells resulting in vascular dysfunction
Cisplatin prevents breast cancer metastasis through blocking early EMT and retards cancer growth together with paclitaxel
Authors: Haitao Wang, Sen Guo, Seung-Jin Kim, Fangyuan Shao, Joshua Wing Kei Ho, Kuan Un Wong, Zhengqiang Miao, Dapeng Hao, Ming Zhao, Jun Xu, Jianming Zeng, Koon Ho Wong, Lijun Di, Ada Hang-Heng Wong, Xiaoling Xu, Chu-Xia Deng
Journal: Theranostics (2020)

Cancer growth is usually accompanied by metastasis which kills most cancer patients. Here we aim to study the effect of cisplatin at different doses on breast cancer growth and metastasis. Methods: We used cisplatin to treat breast cancer cells, then detected the migration of cells and the changes of epithelial-mesenchymal transition (EMT) markers by migration assay, Western blot, and immunofluorescent staining. Next, we analyzed the changes of RNA expression of genes by RNA-seq and confirmed the binding of activating transcription factor 3 (ATF3) to cytoskeleton related genes by ChIP-seq. Thereafter, we combined cisplatin and paclitaxel in a neoadjuvant setting to treat xenograft mouse models. Furthermore, we analyzed the association of disease prognosis with cytoskeletal genes and ATF3 by clinical data analysis. Results: When administered at a higher dose (6 mg/kg), cisplatin inhibits both cancer growth and metastasis, yet with strong side effects, whereas a lower dose (2 mg/kg) cisplatin blocks cancer metastasis without obvious killing effects. Cisplatin inhibits cancer metastasis through blocking early steps of EMT. It antagonizes transforming growth factor beta (TGFβ) signaling through suppressing transcription of many genes involved in cytoskeleton reorganization and filopodia formation which occur early in EMT and are responsible for cancer metastasis. Mechanistically, TGFβ and fibronectin-1 (FN1) constitute a positive reciprocal regulation loop that is critical for activating TGFβ/SMAD3 signaling, which is repressed by cisplatin induced expression of ATF3. Furthermore, neoadjuvant administration of cisplatin at 2 mg/kg in conjunction with paclitaxel inhibits cancer growth and blocks metastasis without causing obvious side effects by inhibiting colonization of cancer cells in the target organs. Conclusion: Thus, cisplatin prevents breast cancer metastasis through blocking early EMT, and the combination of cisplatin and paclitaxel represents a promising therapy for killing breast cancer and blocking tumor metastasis.
Paradoxes of cancer: Survival at the brink
Authors: Jekaterina Erenpreisa, Kristine Salmina, Olga Anatskaya, Mark S. Cragg
Journal: Seminars in Cancer Biology (2020)

The fundamental understanding of how Cancer initiates, persists and then progresses is evolving. High-resolution technologies, including single-cell mutation and gene expression measurements, are now attainable, providing an ever-increasing insight into the molecular details. However, this higher resolution has shown that somatic mutation theory itself cannot explain the extraordinary resistance of cancer to extinction. There is a need for a more Systems-based framework of understanding cancer complexity, which in particular explains the regulation of gene expression during cell-fate decisions. Cancer displays a series of paradoxes. Here we attempt to approach them from the view-point of adaptive exploration of gene regulatory networks at the edge of order and chaos, where cell-fate is changed by oscillations between alternative regulators of cellular senescence and reprogramming operating through self-organisation. On this background, the role of polyploidy in accessing the phylogenetically pre-programmed "oncofetal attractor" state, related to unicellularity, and the de-selection of unsuitable variants at the brink of cell survival is highlighted. The concepts of the embryological and atavistic theory of cancer, cancer cell "life-cycle", and cancer aneuploidy paradox are dissected under this lense. Finally, we challenge researchers to consider that cancer "defects" are mostly the adaptation tools of survival programs that have arisen during evolution and are intrinsic of cancer. Recognition of these features should help in the development of more successful anti-cancer treatments.
Inspirations and silver linings in a pandemic year
Authors: Sophie Cook
Journal: BMJ (2020)

Inspirations and silver linings in a pandemic year Sophie Cook head of scholarly commentChallenging, unprecedented, turbulent, extraordinary: this year was the toughest that most health professionals have ever known.It's hard to imagine anyone missing 2020 when it's over.In times of darkness, we yearn for inspiration, and this year's
SARS-CoV-2 antibody seroprevalence in the general population and high-risk occupational groups across 18 cities in Iran: a population-based cross-sectional study
Authors: Hossein Poustchi, Maryam Darvishian, Zahra Mohammadi, Amaneh Shayanrad, Alireza Delavari, Ayad Bahadorimonfared, Saeid Eslami, Shaghayegh Haghjooy Javanmard, Ebrahim Shakiba, Mohammad Hossein Somi, Amir Emami, Nader Saki, Ahmad Hormati, Alireza Ansari-Moghaddam, Majid Saeedi, Fatemeh Ghasemi-Kebria, Iraj Mohebbi, Fariborz Mansour-Ghanaei, Manoochehr Karami, Hamid Sharifi, Farhad Pourfarzi, Nasrollah Veisi, Reza Ghadimi, Sareh Eghtesad, Ahmadreza Niavarani, Ali Ali Asgari, Anahita Sadeghi, Majid Sorouri, Amir Anushiravani, Mohammad Amani, Soudeh Kaveh, Akbar Feizesani, Payam Tabarsi, Hossein Keyvani, Melineh Markarian, Fatemeh Shafighian, Alireza Sima, Alireza Sadjadi, Amir Reza Radmard, Ali H Mokdad, Maryam Sharafkhah, Reza Malekzadeh
Journal: The Lancet Infectious Diseases (2020)
QOL-55. INTEGRATED MULTI-SCALE MODEL FOR PEDIATRIC BRAIN TUMOR SURVIVAL PREDICTION
Authors: Yeping Lina Qiu, Amaury Sabran, Hong Zheng, Olivier Gevaert
Journal: Neuro-Oncology (2020)

Abstract Brain tumors are the most common solid tumors affecting children, and its prognosis has been a great challenge for physicians and researchers. With the advances in high-throughput sequencing technology and digital pathology, more quantitative data is now becoming available and more information may potentially be discovered in whole slide images (WSIs) and molecular tumor characteristics to determine survival and treatment. Imaging and genomic data, though very different in nature, both may contain different aspects of disease characteristics that are important for survival prediction. Hence our work aims to build a framework to integrate two data modules, whole-slide histopathology image data, and RNA sequencing data, for a unified model to improve pediatric brain tumor survival outcome prediction. The imaging data and genomic data are both of high dimensions and on different scales. We use two independent modules, each of which consists of a deep neural network, to extract lower dimensional features from imaging and genomic data respectively. We concatenate the extracted features and use a third neural network to train a Cox regression model using the merged feature as input. Each module is first pre-trained with TCGA adult brain tumor data, and subsequently fine-tuned with pediatric brain tumor data. The entire pipeline is tested on the holdout pediatric brain tumor dataset. Preliminary results suggest that the integrated framework achieves improved prediction performance than using each single data module alone. The concordance index (C-index) of integrated model is 0.68, compared to 0.62 with imaging data only, and 0.66 with genomic data only.
NIMG-39. UTILITY OF PHYSIOLOGIC MR METRICS IN DISTINGUISHING TRUE-PROGRESSION FROM PSEUDOPROGRESSION IN GLIOBLASTOMAS STRATIFIED BY MGMT PROMOTER METHYLATION
Authors: Sanjeev Chawla, Sumei Wang, Amir Nazem, Morgan Burke, Nasrallah MacLean, Stephen Bagley, Steven Brem, Suyash Mohan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Methylation of O6-methyl-guanine-methyl transferase MGMT gene promoter is associated with favorable prognosis in glioblastoma (GBM) patients treated with surgery and chemoradiation therapy (CRT). OBJECTIVE To investigate potential of diffusion and perfusion MR imaging in distinguishing TP from PsP in GBM patients stratified by MGMT status. METHODS A cohort of 92 patients demonstrating new/increasing enhancing lesions within six months of completion of CRT underwent 3T MR imaging. Median values of mean diffusivity (MD), fractional anisotropy (FA), anisotropy coefﬁcients [linear(CL), planar (CP), and spherical (CS)] and maximum relative cerebral blood volume (rCBVmax) were computed from enhancing lesions. Patients were classified as TP (n=65) and PsP (n=27) based on histopathology or follow-up MRI scans. Mann-Whitney, independent-sample T-tests and receiver operating characteristic (ROC) curve analyses were performed to distinguish TP from PsP. Of 92 patients, MGMT status was available from 60 patients [MGMT-methylated (n=23) and MGMT-unmethylated (n=37)]. Statistical analyses were also performed in distinguishing TP (n=15) and PsP (n=8) from MGMT-methylated and MGMT-unmethylated subgroups (TP=28; PsP=9). A p-value of 0.05 was considered significant. RESULTS Significantly higher rCBVmax and FA and a trend towards higher CP were observed in TP compared to PsP. Among these parameters, rCBVmax had the best sensitivity=62%, specificity=68% and accuracy=67% in distinguishing TP from PsP. ROC analysis revealed sensitivity=54%, specificity=78% and accuracy=68% after combination of these parameters. In MGMT methylated patients, only rCBVmax was significantly higher in TP than in PsP with sensitivity=79%, specificity=67% and accuracy=74% at a threshold rCBVmax value of 2.23. In MGMT unmethylated group, a trend towards higher rCBVmax was observed in TP than in PsP with sensitivity=67%, specificity=77%, accuracy=69%, threshold value=2.89. CONCLUSION Physiologic imaging parameters demonstrate variable diagnostic values for detecting PsP in GBM patients stratified by MGMT status. The best parameter in distinguishing TP from PsP was rCBVmax in patients demonstrating MGMT promoter methylation.
Abstract 18764: Glycocalyx Shedding is Markedly Increased in New Onset Atrial Fibrillation
Authors: Thanh H Nguyen, Nathan Procter, Olivia Tonnu, Irene Stafford, Simon Stewart, Yuliy Chirkov, John D Horowitz
Journal: Circulation (2017)

Background: Atrial fibrillation (AF) is associated with increased thromboembolic risk. More importantly, new onset AF (NAF) has been linked to inflammatory activation, impairment of nitric oxide (N...
IMMU-10. INTERIM ANALYSIS OF THE HIT-HGG REZ IMMUNVAC STUDY - DENDRITIC CELL VACCINATION WITH PARTIAL TREG DEPLETION IN CHILDREN, ADOLESCENTS, AND ADULTS WITH RELAPSED HIGH-GRADE GLIOMAS
Authors: Matthias Eyrich, Jürgen Krauss, Johannes Rachor, Camelia Monoranu, Brigitte Bison, Mario Löhr, Stefan Rückriegel, Matthias Wölfl, Elisabeth Miller, Paul G Schlegel, Christof Kramm
Journal: Neuro-Oncology (2020)

Abstract Efficacy of therapeutic dendritic cell vaccines (DCV) can be limited by immunosuppressive mechanisms in the micromilieu of high-grade gliomas. In the HIT-HGG-Rez Immunovac trial (Eudra-CT 2013-000419-26), we investigate whether a reduction of Treg with metronomic cyclophosphamide (metrCyc) might be a feasible option to improve vaccine efficacy. 10 pediatric (mean age 11.4±4.2y) and 5 adult patients (mean age 39.5±19.9y) with relapsed glioblastoma were treated according to the HIT-HGG-Rez Immunovac protocol so far. 2 children were treated within the trial, the other 13 in the pilot phase. Patients received upfront oral metrCyc for 2–4 weeks. After reoperation and monocyte-apheresis, patients received 4 weekly intradermal doses of autologous, TNFa/IL-1ß matured DCs pulsed with tumor lysate in imiquimod-prepared skin. Thereafter, tumor lysate boosts were given. All patients received at least 5 vaccines (4xDCs, 1xlysate boosts). MetrCyc was well tolerated and led to a reduction in Treg-frequency of 35.6±17.8% followed by a rebound after cessation of metrCyc. Importantly, 13/14 analyzed patients showed a positive IFNg-T-cell response against autologous tumor lysate with a tendency to decrease over time. 6-month overall survival was 100%, compared to 65% in a historical control. Mean PFS and OS were 5.7 and 21.1 months with no difference between adults and children. We conclude that DCV in combination with partial Treg depletion is feasible, safe, and related with a high rate of tumor-specific IFNg-responses. As the clinically and immunologically beneficial effects seem to diminish over time, we aim to combine our approach with checkpoint inhibition in the next amendment.
TAMI-23. NEUTROPHIL-TRIGGERED FERROPTOSIS PROMOTES TUMOR NECROSIS IN GLIOBLASTOMA PROGRESSION
Authors: Patricia Yee, Yiju Wei, Soo Yeon Kim, Tong Lu, Cynthia Lawson, Miaolu Tang, Zhijun Liu, Benjamin Anderson, Megan Young, Krishnamoorthy Thamburaj, Dawit Aregawi, Michael Glantz, Brad Zacharia, Charles Specht, Hong-Gang Wang, Wei Li
Journal: Neuro-Oncology (2020)

Abstract Tumor necrosis indicates poor prognoses in many cancers, including glioblastomas (GBMs). Although thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscured by lack of animal models recapitulating the extent of necrosis in human GBMs. The molecular and clinical heterogeneity of GBMs adds further complexity. Not all GBMs contain necrosis. Mesenchymal (MES)-GBM, the subtype correlated with worst prognosis and highest treatment resistance, is most closely associated with necrosis. MES-GBM exhibits hyperactivity of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in human GBMs predicts short survival. To elucidate mechanisms driving GBM necrosis, we devised a novel orthotopic mouse model recapitulating human MES-GBM phenotypically and histopathologically by expressing a constitutively-active TAZ mutant (TAZ4SA) in three human GBM cell lines (LN229, U87, and LN18) lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter than mice implanted with GBMvector or mutant TAZ unable to bind its downstream effector, TEAD (GBM4SA-S51A). Extensive (≥30% of tumor volume) necrosis was present in GBM4SA mice but not GBMvector or GBM4SA-S51A. In GBM4SA tumors, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse tumors killed co-cultured tumor cells. Neutrophils induce iron-dependent accumulation of lipid hydroperoxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibiting myeloperoxidase suppresses neutrophil-induced tumor cytotoxicity. Intratumoral glutathione peroxidase 4 (GPX4) overexpression or acyl-CoA synthetase 4 (ACSL4) depletion diminishes necrosis and aggressiveness of tumors. Human GBM analysis indicates neutrophils and ferroptosis are associated with necrosis and predict poor survival. Together, we propose that certain tumor damage(s) during early tumor progression (i.e. ischemia) recruits neutrophils to damaged tissue and results in a positive feedback loop, amplifying GBM necrosis development. We show GBM necrosis involves neutrophil-triggered ferroptosis and reveal an unprecedented pro-tumorigenic role of ferroptosis.
RADT-18. LONG-TERM FOLLOW-UP OF PATIENTS TREATED WITH GAMMA KNIFE® STEREOTACTIC RADIOSURGERY (GK-SRS) FOR VESTIBULAR SCHWANNOMA (VS)
Authors: Amber Retzlaff, Michael Straza, Joseph Bovi, Malika Siker, David Friedland, Michael Harris, Nathan Zwagerman, Katherine Albano, Ruizhe Wu, Anjishnu Banerjee, Christopher Schultz
Journal: Neuro-Oncology (2020)

Abstract PURPOSE GK-SRS is an accepted definitive treatment option for appropriately selected patients with VS. To assess long-term outcomes in VS patients treated with GK-SRS, we retrospectively evaluated all patients treated at our institution from 2007-2019. METHODS For VS patients treated with GK-SRS from 2007-2019, clinical data (symptoms, physical exams, audiograms, and imaging) was collected via retrospective chart review at pre-treatment and standard follow-up intervals (6 weeks, 6 months, 12 months, then annually). Descriptive analyses, including the proportions of patients in different grades of clinical parameters, are reported. For each clinical parameter, only patients with both pre- and post-treatment data were included in the evaluation set used for analysis. RESULTS Of 177 patients identified, 46 were excluded from the evaluable set (age &amp;lt; 18 years, prior resection, NF-2, or no follow-up). Among the remaining 131, median follow-up was 42 months (6 weeks to 11 years), and 36.6% completed 5+ years of follow-up. At time of treatment, median age was 61 years, and median Karnofsky Performance Score was 90. 58.0% of lesions were left-sided, and 42.0% were right-sided. The majority were Koos grade II (37.4%) or III (38.2%); the remainder were grade I (13.0%) or IV (11.5%). Pre-treatment central necrosis and ventriculomegaly were present in 39.7% and 4.6%, respectively. Following treatment, audiogram analysis with Gardner-Robertson Hearing Score demonstrated no change in 48.9%, some level of decline in 47.8%, and improvement in 3.3% at last follow-up. 97.7% had House-Brackmann scores of I at diagnosis; the remainder were House-Brackmann II. House-Brackmann scores remained unchanged at last follow-up for 96.9%, improved for 1.6%, and worsened for 1.6%. Salvage therapy in the form of surgery (n=5) or repeat GK-SRS (n=2) was necessary in 5.3% (n=6 for progression; n=1 for trigeminal symptoms). CONCLUSION Long-term follow-up demonstrates that GK-SRS remains a well-tolerated, primary definitive treatment for VS.