tbuckley/cabot-search huggingface dataset:
Predictive accuracy of the low erythropoietin level for the diagnosis of polycythemia vera.
Authors: Oleksandra Lupak, Xiaoxia Han, Peter Xie, Sharmeen Mahmood, Hadi Mohammed, Vijayalakshmi Donthireddy
Journal: Journal of Clinical Oncology (2019)

7060 Background: A low erythropoietin (EPO) level is a minor diagnostic criterion for Polycythemia Vera (PV) based on the updated 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms. The diagnostic value of EPO has been debated due to the increasing availability of advanced molecular testing. We hypothesized that EPO level below the normal range may not provide additional diagnostic information if JAK2 mutation status is positive. Methods: In this retrospective review we used Logistic regression to build a predictive model for the diagnosis of PV based on EPO value and JAK2V617F mutation status. 415 patient records were reviewed. 162 were used in the final statistical analysis. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the predictive accuracy. All statistical analysis was performed with R version 3.5.1. A p-value less than 0.05 was considered statistically significant. Results: EPO level below the normal range as a standalone diagnostic modality is significantly associated with PV (odds ratio (OR) 0.857; p-value &lt; 0.001). When JAK2V617F mutation status is included in the prediction model, the association of the low erythropoietin level is not statistically significant (OR 0.962 and p-value 0.269). Positive JAK2V617F demonstrates a strong predictive value for PV (OR 670.5, p-value 0.006) either alone or in combination with other variables. Moreover, 34.2% of patients with the diagnosis of PV had EPO level within the normal range, which reflects it’s physiological variability. Conclusions: Results show that erythropoietin level below the normal range does not bring additional diagnostic value when JAK2V617F mutation status is positive. Additionally, erythropoietin level has a negative correlation with increased BMI and smoking status, making it not a reliable diagnostic marker.
Abstract 4577: Anti-tumor immunity is a key determinant of small cell lung cancer survivorship
Authors: Farhad Kosari, Prasuna Muppa, Simone Terra, Anurag Sharma, Aaron Mansfield, Marie Christine Aubry, Nafiseh Janaki, Aqsa Nasir, Tobias Peikert
Journal: Cancer Research (2019)

Abstract Introduction: While most small cell lung cancer (SCLC) patients die within a few months, a sub-group of patients survive for many years. Factors determining long-term survivorship remain largely unknown. We present the first comprehensive comparative genomic and tumor microenvironment analyses of small cell lung cancer (SCLC) between patients with long term (LTS) and expected (EXS) survival times. Methods: We compared surgically resected tumors of 23 LTS (survival &amp;gt; 4 years) and 18 EXS (survival ≤ 2 years). There were no differences in clinical variables including TNM staging and curative versus non-curative intend surgery between the groups. Gene expression profiling was performed by microarrays and tumor microenvironment analyses were by IHC of prominent immune related markers. Results: Immune related genes and pathways represented the majority of the differentially overexpressed genes in LTS compared to the EXS. The differences in the immunological tumor-microenvironment were confirmed by quantitative immuno-staining. Increased numbers of tumor infiltrating and associated lymphocytes were present throughout tumors of LTS. Several differentiating patterns of enhanced anti-tumor immunity were identified. While some areas of LTS tumors also harbored higher numbers of suppressive immune cells (monocytes, regulatory lymphocytes, and macrophages), ratios of these suppressive cells to CD3+ lymphocytes were generally lower in LTS tumors indicating a more tumor suppressive microenvironment. Conclusions: Our data demonstrate that long-term survivorship of SCLC patients is strongly influenced by the presence of anti-tumor immune cells in the tumor microenvironment. Characterization of the anti-tumor immune responses may identify opportunities for individualized immunotherapies for SCLC. Citation Format: Farhad Kosari, Prasuna Muppa, Simone Terra, Anurag Sharma, Aaron Mansfield, Marie Christine Aubry, Nafiseh Janaki, Aqsa Nasir, Tobias Peikert. Anti-tumor immunity is a key determinant of small cell lung cancer survivorship [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4577.
Abstract P009: Association of MRI Signs With Development of Mild Cognitive Impairment and Dementia: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Aozhou Wu, A. R Sharrett, Rebecca F Gottesman, Melinda C Power, Thomas Mosley, Clifford R Jack, David S Knopman, B. G Windham, Alden L Gross, Josef Coresh
Journal: Circulation (2018)

Background: Brain infarcts, white matter hyperintensities (WMH), and brain atrophy appear to contribute to the development of mild cognitive impairment (MCI) and dementia in selected populations, but few prospective studies are available in general populations. Methods: The study included 732 black and white participants, sampled from the original ARIC cohort, who had 3T brain Magnetic Resonance Imaging (MRI) scans, were free of MCI and dementia during 2011-13 (Visit 5), and were evaluated for cognitive impairment during 2016-17 (Visit 6, about 90% complete). We assessed the associations of brain infarcts, WMH, and brain volumes measured on MRI from 2011-2013 with incident MCI and dementia (combined), diagnosed using a computer algorithm based on specified criteria and comprehensive assessment at Visit 6. We used logistic regression, incorporating sampling weights, to evaluate the risk for incident MCI/dementia with adjustment for demographic covariates, major dementia risk factors, and history of cardiovascular diseases. Results: Participants had a median age of 75 (IQR: 71, 79) at Visit 5 (baseline); 62% (453) were female and 33% (242) were African American. There were 156 newly identified cases of MCI or dementia during a median follow-up time of 4.9 (IQR: 3.4, 5.2) years. The presence of any brain infarct was associated with a nonsignificantly higher risk of MCI/dementia (OR: 1.50; 95%CI: 0.87 to 2.58), but the only significant individual association was with cortical infarcts (OR: 1.99; 95%CI: 1.03 to 3.85). WMH volume above the median value was nonsignificantly associated with conversion to MCI/dementia. Smaller Alzheimer’s disease (AD) signature region was an independent predictor for greater risk of MCI/dementia (OR: 1.49; 95%CI: 1.00 to 2.22). A similar but nonsignificant association was observed for total brain volume. Conclusions: Brain infarcts (cortical infarcts) and lower brain volume (AD signature region), measured in community-based older residents, are risk factors for MCI and dementia incidence.
Abstract 1895: Identification of therapeutic targets in peritumoral microenvironment by single-cell assays using impedance spectroscopy
Authors: Christian Maercker
Journal: Cancer Research (2019)

Abstract Metastasis and tumor growth are very much dependent on the peritumoral microenvironment. Cells in the peripheral cortex send out growth factors and generate an extracellular matrix which is decisive for infiltration of neoplastic cells and, finally, the formation of a functioning tumor tissue. To figure out specific functions of different cell types and their various interactions in in vitro or in vivo assays, which are possibly relevant for the identification of new drug targets, is a challenge, because we deal with a very complex multifactorial network. Therefore, our goal is to develop test systems with a limited complexity, but which still are informative in terms of molecular tumor development. To reach this, we first have to singularize cells from tumor tissue. Within surgical tissue, tumor core tissue has to be discriminated from surrounding tissue by MRI or immunohistochemistry. Afterwards, microdissected tissue samples have to be dissociated by protease digest. In a next step, the mixture of cells has to be separated into the different cell types by immunopanning and/or FACS sorting. RNAseq helps to identify gene expression profiles specific for individual cells within the tumor compared to the tumor microenvironment. For us the most important parameters are the adhesion and migration activities of the various cell types of different origin on different matrices. To establish a test system as a starting point for a more sophisticated experimental setup to characterize tumorigenic tissues, we firstly isolated mesenchymal stem cells (MSC) from fat tissue or bone marrow, before transfer to microwells covered with electrodes to monitor cell adhesion by electrochemical impedance sensing. We found that pre-coating of the microwells with either collagen type I or IV induced different impedance profiles, corresponding to distinct differentiation pathways which was confirmed by histochemical staining as well as protein and gene expression analyses. In another approach, we used impedance sensing to measure prostate or breast cancer cell migration towards the secretome of mesenchymal stem cells. MSC cell culture supernatant was fractionated by size exclusion and ion exchange chromatography. We identified type I and III collagen, fibronectin and Laminin 421 as extracellular matrix proteins to be the main drivers of rapid cancer cell migration requiring as little as two hours for a full migration response. The challenge now is to adjust this experimental approach to individual cell types isolated from different tumor types and also to different matrices simulating the tumor microenvironment. Citation Format: Christian Maercker. Identification of therapeutic targets in peritumoral microenvironment by single-cell assays using impedance spectroscopy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1895.
Abstract 3843: LSD1 modulation by allosteric ligands
Authors: Wei B. Emond, Matthis Geitmann, Malin Jarvius, Konrad Koehler, Per Källblad, Mia Niklasson, Vendela Parrow, Rajiv Sawant, Maria Sjöberg, Johan Winquist, Anna Segerman, Ulf Bremberg
Journal: Cancer Research (2019)

Abstract LSD1 has emerged as a potential therapeutic target for a number of cancer types (e.g. AML, SCLC, colorectal, breast, liver, prostate, glioblastoma, Ewing sarcoma), as well as sickle cell anaemia and Alzheimer’s disease. Irreversible LSD1 catalytic inhibitors have shown limited clinical efficacy in AML and SCLC, while solid tumours are largely unaddressed. This is in contrast to LSD1 knockdown with impact on a wide range of cancers, indicating that LSD1 functions other than enzymatic should be targeted. We have developed novel small molecules that modulate LSD1 via an allosteric site - without inhibiting its enzymatic function - inducing a 60% reduction of nuclear LSD1 levels. The sensitivity profile in a cancer cell line panel is unique and dissimilar to &amp;gt;300 diverse reference compounds. In vitro efficacy is observed in glioma-initiating clones that are highly resistant to standard-of-care temozolimide as well as catalytic LSD1 inhibitors. Efficacy in the sub-µM range is observed with other solid tumour models, e.g. prostate cancer. The compounds exhibit synergy (Bliss independence &amp;gt;40%) with HDAC inhibitors as evaluated by viability in cellular cancer models, including lung, liver and glioblastoma. Pharmacokinetic studies show good blood-brain-barrier penetration and oral availability of the allosteric LSD1 modulator BEA-17. A repeat dose of 25 mg/kg was well tolerated by NOD SCID mice, leading to µM level accumulation in the brain. Results from orthotopic glioblastoma PDX models, and in vivo hollow-fiber models of other solid tumours will be presented, as well as mechanistic insights from biophysical assays and gene expression analysis. Citation Format: Wei B. Emond, Matthis Geitmann, Malin Jarvius, Konrad Koehler, Per Källblad, Mia Niklasson, Vendela Parrow, Rajiv Sawant, Maria Sjöberg, Johan Winquist, Anna Segerman, Ulf Bremberg. LSD1 modulation by allosteric ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3843.
Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies
Authors: Roheena Z. Panni, John M. Herndon, Chong Zuo, Samarth Hegde, Graham D. Hogg, Brett L. Knolhoff, Marcus A. Breden, Xiaobo Li, Varintra E. Krisnawan, Samia Q. Khan, Julie K. Schwarz, Buck E. Rogers, Ryan C. Fields, William G. Hawkins, Vineet Gupta, David G. DeNardo
Journal: Science Translational Medicine (2019)

Agonism of CD11b overcomes myeloid cell–induced immunosuppression to render pancreatic cancer models responsive to checkpoint immunotherapy.
PET/CT alone versus PET/CT and MRI-guided therapy in patients with upper aerodigestive tract natural killer/T-cell lymphoma, nasal type: A prospective study.
Authors: Tongyu Lin, Quanguang Ren, He Huang, Xue Ying Li, Huangming Hong, Zhao Wang, Xiaojie Fang, Cheng-cheng Guo, Fangfang Li, Limei Zhang, Ying Huang, Zhi-Ming Li, Qingqing Cai, Ying Tian, Hanyu Wang, Xiaoping Lin, Wei Fan, Lie Zheng, Suxia Lin, Qing Liu
Journal: Journal of Clinical Oncology (2019)

7537 Background: Radiotherapy is extremely important in extranodal natural killer/T-cell lymphoma (ENKTL). [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a routine pretreatment imaging technique used in ENKTL, while magnetic resonance imaging (MRI) plays a key role in head and neck (HN) cancer. The purpose of this study was to investigate the value of pretreatment HN-MRI and PET/CT-guided therapy in improving survival in upper aerodigestive tract ENKTL (UADT-ENKTL). Methods: We prospectively conducted a single center study on untreated patients with pathologically diagnosed UADT-ENKTL. Patients undergoing PET/CT with/without HN-MRI were decided by clinicians for staging and restaging. The patients were treated with L-asparaginase/Pegaspargase and non-anthracycline-based chemotherapy with intensity-modulated radiation therapy (IMRT). Results: We enrolled 171 patients (median age, 44 years; range, 18-75 years; 118 (69%) males) from April 2011 to March 2018. Overall, 71 patients underwent PET/CT and HN-MRI (PET/CT-MRI) and 100 patients underwent PET/CT alone. HN-MRI upgraded the clinical stages in 8 patients (8/71) undergoing PET/CT based on the Ann Arbor staging system and in 10 patients (10/71) based on the TNM staging system by detecting additional local lesions ( P=0.011 and P=0.019, respectively). With a median follow-up of 54 months, the 5-year overall survival (OS), local recurrence-free survival (LRFS) and progression-free survival (PFS) rates were 72.7%, 68.6% and 68.2%, respectively, for all patients. The 5-year LRFS rate was 100% in the PET/CT-MRI group and 64.3% in the PET/CT group ( P&lt;0.001). Similarly, the 5-year OS and PFS were longer in the PET/CT-MRI group than in the PET/CT group (84.5% vs. 67.8% and 78.3% vs. 65.6%; P=0.04 and P=0.03, respectively). Conclusions: HN-MRI and PET/CT-guided therapy could assist in decreasing local recurrence, which improved prognosis in UADT-ENKTL patients. Therefore, HN-MRI and PET/CT should be incorporated into routine pretreatment imaging examinations in patients with UADT-ENKTL. Clinical trial information: NCT01788137.
Abstract 13542: Five-Year Outcomes in Patients Hospitalized With Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction in the Medicare Population
Authors: Kevin S Shah, Haolin Xu, Roland A Matsouaka, Deepak L Bhatt, Paul A Heidenreich, Adran F Hernandez, Adam D Devore, Clyde W Yancy, Gregg C Fonarow
Journal: Circulation (2017)

Introduction: We sought to characterize differences in outcomes in patients hospitalized with heart failure (HF) with preserved left ventricular ejection fraction (HFpEF), borderline LVEF (HFbEF) a...
Abstract 2614: CCAR2 acetylation establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition
Authors: Gavin S. Johnson, Praveen Rajendran, Li Li, Ying-Shiuan Chen, W. Mohaiza Dashwood, Nhung Nguyen, Ahmet M. Ulusan, Furkan Ertem, Mutian Zhang, Deqiang Sun, Yun Huang, Shan Wang, Hon-Chiu E. Leung, David Lieberman, Laura M. Beaver, Emily Ho, Mark T. Bedford, Kyle Chang, Eduardo Vilar, Roderick H. Dashwood
Journal: Cancer Research (2019)

Abstract There continues to be interest in targeting epigenetic ‘readers, writers and erasers’ for the treatment of cancer and other pathologies. A mechanistic understanding is frequently lacking, however, for the synergy observed when combining deacetylase and bromodomain inhibitors. We identified cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane (SFN). N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 (HDAC3) and β-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl ‘reader’ proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. The BET inhibitor JQ1 synergized with SFN in colon cancer cells, and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with SFN+JQ1 in combination implicated a BET/BRD9 acetyl switch, and a shift in the pool of acetyl ‘reader’ proteins in favor of BRD9 regulated target genes. These results highlight the competition that exists among the ‘readers’ of acetylated histone and non-histone proteins, and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments. Citation Format: Gavin S. Johnson, Praveen Rajendran, Li Li, Ying-Shiuan Chen, W. Mohaiza Dashwood, Nhung Nguyen, Ahmet M. Ulusan, Furkan Ertem, Mutian Zhang, Deqiang Sun, Yun Huang, Shan Wang, Hon-Chiu E. Leung, David Lieberman, Laura M. Beaver, Emily Ho, Mark T. Bedford, Kyle Chang, Eduardo Vilar, Roderick H. Dashwood. CCAR2 acetylation establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2614.
Comparative effectiveness of front-line agents in the treatment of metastatic clear cell renal cell carcinoma.
Authors: Benjamin Haaland, Akhil Chopra, Gilberto de Lima Lopes
Journal: Journal of Clinical Oncology (2012)

e15045 Background: Based on improved clinical outcomes in randomized controlled clinical trials (RCT) the FDA has approved 4 drugs in the front line treatment of good to intermediate risk metastatic clear cell renal cell carcinoma (RCC). However, there is little if any comparative data to help choose the most effective drug among these agents. Methods: We performed an indirect comparative effectiveness analysis of the pivotal RCTs (Escudier JCO 2009 and 2010, Rini JCO 2010, Motzer JCO 2009, Sternberg JCO 2010, MRCRCC Lancet 1999, Steineck Acta Oncologica 1990, Pyrhonen JCO 1999, Kriegmair Urology 1995) evaluating outcomes with sunitinib (SU), sorafenib (SO), bevacizumab plus interferon alpha (B+I), pazopanib (P), interferon alone (I) and other controls. Progression-free-survival (PFS) was the main endpoint. Other endpoints included response rate (RR) and overall survival (OS). Estimates, confidence intervals, and p-values from analyses that are stratified by risk factors were used throughout if available. A linear mixed effects model with a random effect for each study and known error variances was fit by restricted maximum likelihood and used to obtain indirect estimates. Results: The indirect estimate of the hazard ratio (95% confidence interval; p-value) for PFS for SU vs. B+I is 0.813 (0.624-1.059; p=0.125); for B+I vs. SO is 0.753 (0.497-1.141; p=0.181); for P vs. B+I is 0.963 (0.612-1.518; p=0.874); for SU vs. SO is 0.613 (0.392-0.956; p=0.0311); for SU vs. P is 0.844 (0.521-1.366; p=0.49; for P vs. SO is 0.726 (0.407-1.295; p=0.278)(Figure 1). SU, P, B+I had better PFS than I alone and than other controls, while SO did not. SU had statistically significantly better RR when compared to P, SO and B+I with HR of 0.254, 0.215 and 0.419 (all p&lt;0.05). OS data was not available to compare all agents and may be confounded by cross-over in the trials. Conclusions: Based on PFS, SU, B+I and P are adequate front line options in the treatment of advanced clear cell RCC. As SU had better RR it may be a preferred option for patients with symptoms or large disease burden. SO should not be considered an optimal front line treatment.
Non-viral delivery of chemically modified mRNA to the retina: Subretinal versus intravitreal administration
Authors: Joke Devoldere, Karen Peynshaert, Heleen Dewitte, Christian Vanhove, Lies De Groef, Lieve Moons, Sinem Yilmaz Özcan, Deniz Dalkara, Stefaan C. De Smedt, Katrien Remaut
Journal: Journal of Controlled Release (2019)
Educational attainment and cardiovascular disease in the United States: A quasi-experimental instrumental variables analysis
Authors: Rita Hamad, Thu T. Nguyen, Jay Bhattacharya, M. Maria Glymour, David H. Rehkopf
Journal: PLoS Medicine (2019)

There is ongoing debate about whether education or socioeconomic status (SES) should be inputs into cardiovascular disease (CVD) prediction algorithms and clinical risk adjustment models. It is also unclear whether intervening on education will affect CVD, in part because there is controversy regarding whether education is a determinant of CVD or merely correlated due to confounding or reverse causation. We took advantage of a natural experiment to estimate the population-level effects of educational attainment on CVD and related risk factors.
Скринінгове дослідження захворювань кишечника у населення Західного регіону України
Authors: Ya.V. Nahurna
Journal: GASTROENTEROLOGY (2020)

Мета роботи: проаналізувати та визначити кількість органічних та функціональних захворювань кишечника в Західному регіоні України.Матеріали і методи: анкетування, аналіз калу на кальпротектин, приховану кров, яйця глистів, фіброколоноскопія.Висновки. Як показали дослідження, частота виявлення синдрому подразненого кишечника (СПК) становить 881 випадок у загальної популяції: СПК iз діареєю — 478, iз запорами — 403. Щодо неспецифічного виразкового коліту і хвороби Крона, то частота їх виявлення в досліджуваному регіоні дорівнює 19 випадкам на 10 000 населення, що значно нижче порівняно зі світовими даними і потребує подальшого вивчення. Кількість виявлених хворих на рак кишечника становить 35 осіб на 10 000 населення, що відповідає європейським і світовим тенденціям. Поширенiсть глистової інвазії у досліджуваному регіоні — 598 випадків (як дитяче, так і доросле населення). Наведені дані є точними і відповідають даним світових скринінгових досліджень вищевказаних захворювань.