tbuckley/cabot-search huggingface dataset:
Protection against pressure overload-induced right heart failure by uncoupling protein 2 silencing
Authors: Azadeh Esfandiary, Hanna S Kutsche, Rolf Schreckenberg, Martin Weber, Oleg Pak, Baktybek Kojonazarov, Akylbek Sydykov, Christine Hirschhäuser, Annemarie Wolf, Daniela Haag, Matthias Hecker, Ludger Fink, Werner Seeger, Hossein A Ghofrani, Ralph T Schermuly, Norbert Weißmann, Rainer Schulz, Susanne Rohrbach, Ling Li, Natascha Sommer, Klaus-Dieter Schlüter
Journal: Cardiovascular Research (2019)

The role of uncoupling protein 2 (UCP2) in cardiac adaptation to pressure overload remains unclear. In a classical model of left ventricular pressure overload genetic deletion of UCP2 (UCP2−/−) protected against cardiac hypertrophy and failure. However, in UCP2−/− mice increased proliferation of pulmonary arterial smooth muscle cells induces mild pulmonary hypertension, right ventricular (RV) hypertrophy, and reduced cardiac output. This suggests a different role for UCP2 in RV and left ventricular adaptation to pressure overload. To clarify this situation in more detail UCP2−/− and wild-type mice were exposed to pulmonary arterial banding (PAB). Mice were analysed (haemodynamics, morphometry, and echocardiography) 3 weeks after PAB or sham surgery. Myocytes and non-myocytes were isolated and analysed separately. Cell shortening of myocytes and fura-2 loading of cardiomyocytes were used to characterize their function. Brd assay was performed to study fibroblast proliferation. Isolated mitochondria were analysed to investigate the role of UCP2 for reactive oxygen species (ROS) production. UCP2 mRNA was 2.7-fold stronger expressed in RV myocytes than in left ventricular myocytes and stronger expressed in non-myocytes compared with myocytes. Three weeks after PAB, cardiac output was reduced in wild type but preserved in UCP2−/− mice. UCP2−/− had increased RV wall thickness, but lower RV internal diameters and displayed a significant stronger fibrosis. Cardiac fibroblasts from UCP2−/− had reduced proliferation rates but higher collagen-1 expression. Myocytes isolated from mice after PAB banding showed preserved function that was further improved by UCP2−/−. Mitochondrial ROS production and respiration was similar between UCP2−/− or wild-type hearts. Despite a mild pulmonary hypertension in UCP2−/− mice, hearts from these mice are well preserved against additional pressure overload (severe pulmonary hypertension). This—at least in part—depends on different behaviour of non-myocytes (fibroblasts).
Developing and adopting safe and effective digital biomarkers to improve patient outcomes
Authors: Andrea Coravos, Sean Khozin, Kenneth D. Mandl
Journal: npj Digital Medicine (2019)

Biomarkers are physiologic, pathologic, or anatomic characteristics that are objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to therapeutic interventions. Recent advances in the development of mobile digitally connected technologies have led to the emergence of a new class of biomarkers measured across multiple layers of hardware and software. Quantified in ones and zeros, these "digital" biomarkers can support continuous measurements outside the physical confines of the clinical environment. The modular software-hardware combination of these products has created new opportunities for patient care and biomedical research, enabling remote monitoring and decentralized clinical trial designs. However, a systematic approach to assessing the quality and utility of digital biomarkers to ensure an appropriate balance between their safety and effectiveness is needed. This paper outlines key considerations for the development and evaluation of digital biomarkers, examining their role in clinical research and routine patient care.
Abstract P182: Prescribing Blood Creatinine and Urine Protein Tests Lowered the Risk of Cardiovascular Disease in Patients With Hypertension: a Follow-up of 66,362 People Who Started Antihypertensive Treatment
Authors: Hyeon Chang Kim, Hokyou Lee, Sung Ha Park
Journal: Circulation (2019)

Introduction: Hypertension treatment guidelines recommend the routine evaluation of target organ damage for better management of hypertension. However, many of the hypertension patients in Korea are not tested for their kidney complications. Hypothesis: We hypothesized that prescribing blood creatinine or urine protein tests is associated with the future risk of cardiovascular disease (CVD) in patients with hypertension. Methods: The National Health Insurance Service-Health Screening (NHIS-HEALS) cohort comprised a 10% random sample of Korean adults who were aged 40-79 years and completed national adult health screening in year 2002-2003 (n= 514866). From the NHIS-HEALS cohort, we identified 66,362 patients who were diagnosed with hypertension and started antihypertensive treatment in 2003-2008. Exposures were prescriptions for blood creatinine test and urine protein test within one year of starting antihypertensive treatment. CVD outcomes were hospitalization for myocardial infarction or stroke until the end of 2013. Cox proportional hazard models were used to calculate hazard ratio (HR) for CVD, after adjusting for sex, age, employment status, household income, Charlson comorbidity index, antihypertensive drug class, medication adherence, smoking, alcohol consumption, exercise, body mass index, systolic blood pressure before treatment, fasting glucose, and total cholesterol. Results: Among the 66362 patients, 37913 (57.1%) and 40361 (60.8%) were tested for blood creatinine and urine protein, respectively. Compared to patients who were tested, those who were not tested had significantly higher risk of CVD: adjusted HR was 1.15 (95% CI 1.05-1.28) for blood creatinine test and 1.19 (95% CI 1.07-1.31) for urine protein test. Compared to those who had both blood and urine tests, the risk of patient who had only one test was not different (adjusted HR 1.00, 95% CI 0.88-1.15) but the risk of patients who did neither of the tests was significantly higher (adjusted HR 1.22, 95% CI 1.10-1.37). Similar findings were observed in sex-specific analysis, but the association was more prominent in women than in men. Conclusion: These nationally representative data confirmed the importance of testing kidney complications in hypertension management and CVD prevention.
Sequential use of bevacizumab and cetuximab in patients with K-RAS wild type advanced colorectal cancer.
Authors: Hakan Akbulut, Onay Gercik, Fikri Icli, Dilsa Mizrak, Ahmet Demirkazik, Handan Onur, Filiz Cay Senler, Gungor Utkan
Journal: Journal of Clinical Oncology (2015)

e14681 Background: Monoclonal antibodies targeting either VEGF or EGFR have improved the treatment outcomes in patients with advanced colorectal cancer (CRC). Although cetuximab or panitumumab are widely used as the first choice of MoAb in patients with K-RAS wild type tumors, the superiority of those over bevacizumab is still controversial. The primary aim of the study was to evaluate the efficacy of the sequential administration of bevacizumab and cetuximab in patients with K-RAS wild type CRC. Methods: Patients with advanced CRC who were K-RAS wild type and completed at least 2 cycles of MoAb added to doublet chemotherapy back bone were included. The chemotherapy regimens were either FOLFIRI or FOLFOX. Bevacizumab was given at the dose of 5 mg/kg q2w or cetuximab 500 mg/m2 q2w following a loading dose of 800mg/m2. Treatment was continued until disease progression or further 2 cycles after disease stabilization. The patients in bevacizumab group were given cetuximab sequentially following the cessation of bevacizumab. Results: Seventy-three patients (33 bevacizumab and 40 cetuximab groups) were recruited between 2009 and 2013. The chemotherapy backbone was mainly FOLFIRI in both groups. The patient characteristics were similar in both groups. The median age was 56 years, and visceral disease was present in all patients. Median number of cycles of MoAbs were 8 (2-16) in both groups. Objective response rates were 30% in bevacizumab and 44% in cetuximab groups (p = 0.170). Five patients were lost to follow-up (3 in bevacizumab and 2 in cetuximab groups). Median PFS was similar (7.1 vs 7.0 mos., respectively). Though not significant, median overall survival was longer in bevacizumab group compared to cetuximab group (33,4 vs 24,5 months, respectively). The 3-year overall survival rate was significantly higher in the bevacizumab group compared to cetuximab group (45,5% vs 17,2%; p = 0.018, respectively). Both MoAbs were well tolerated with manageable toxicity profile. Conclusions: In conclusion, the sequential use of bevacizumab and cetuximab seems better than cetuximab in patients with K-RAS wild type advanced colorectal cancer. However, the results of the current study need to be further tested in a phase III trial.
Automatic identification of family cancer risk.
Authors: Eduardo L. Morgenfeld, Natasha Gercovich, Angela Gomez, Ernesto Gil Deza, Gaston Martin Reinas, Daniela Gercovich, Juan Pollola, Edgardo G. J. Rivarola, Felipe G. Gercovich
Journal: Journal of Clinical Oncology (2015)

e12571 Background: In the last 15 years at least 17 ASCO publications, 2 NCNN guidelines y 2 INC (Instituto Nacional del Cancer-Argentine) publications evaluated the necessity of genetic counseling while demonstrating the difficulty of implementing these recommendations. The following paper’s objective is to evaluate the feasibility of an automatic identification of high-risk patients (Pts) in order to refer them to genetic counseling. Methods: As of August 2012, all new IOHM Pts completed a Past Medical History Form (PMHF) with their personal and family medical history, The PMHF database was searched from its inception until August 1st 2014 with an algorithm designed to find at least one of the following criteria for genetic counseling: a) cancer diagnosis younger than 35, b) diagnosis of the same cancer in two first degree relatives or any cancer diagnosis in more than three first or second degree relatives. The algorithm was tested by trying to identify between 5 and 10% breast/ovarian cancer Pts and 2 to 5% colon/rectum cancer Pts who might theoretically need genetic counseling. Results: 4875 Pts filled out the PMHF in the studied time frame. Population characteristics: Sex F = 2635, M = 2240. Age: median 61 years old (range 17- 98). There were 503 (10.3%) Pts with two or more first degree relatives with cancer and 273 (5.6%) Pts younger than 35. The clinical records of 141 out of 1422 (10%) breast/ovarian cancer Pts and 32 (6%) out of 587 colon/rectum cancer Pts that met at least one of the criteria for genetic counseling were identified which validates the search algorithm used. Conclusions: Automatic family risk detection can be a tool to offer a better Pts genetic counseling. The next step would be direct communication with Pts and doctors, informing them about the option of genetic counseling.
NHS and Vertex remain deadlocked over price of cystic fibrosis drug
Authors: Jacqui Wise
Journal: BMJ (2019)

Both sides of the stalled negotiations on the provision of the cystic fibrosis (CF) drug Orkambi (lumacaftor/ivacaftor) accused the other of inflexibility while giving evidence to the Health and Social Care Committee’s inquiry this week.

Vertex Pharmaceuticals has been in dispute with NHS England over the high price the company wants for Orkambi—£105 000 (€123 000; $138 000) per patient per year. There has been mounting frustration from patients over the impasse. The committee received 334 written submissions to the inquiry, mostly from patients.1 After the hearing there was a demonstration by relatives of patients with CF and campaigners in Parliament Square.

Jeff Leiden, chief executive officer of Vertex Pharmaceuticals, told the committee he is meeting the health secretary Matt Hancock on Monday 11 March and would put forward some …
A Novel iPSC Model Reveals a Role for RUNX1 in the Maintenance of AML Leukemia Stem Cells
Authors: Josephine Wesely, Andriana G. Kotini, Maria Georgomanoli, Hanzhi Luo, Han Yuan, Franco Izzo, Dan A. Landau, Christina Leslie, Michael G. Kharas, Eirini P. Papapetrou
Journal: Blood (2018)
Genomic characterization of pulmonary-metastatic prostate cancer: A unique molecular subtype.
Authors: Eugene Shenderov, Pedro Isaacsson Velho, Anas Hamid Awan, Nooshin Mirkheshti, Mario A. Eisenberger, Drew M. Pardoll, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2019)

210 Background: Metastatic prostate cancer (mPC) rarely spreads to the lungs and lung-only metastatic disease has not been clearly defined. This study investigated the clinical and molecular features of lung-only mPC. Methods: This is a retrospective single-institution study. Medical records of 40 metastatic prostate patients with lung-only (N=25) or lung-predominant (N=15) disease were analyzed. Germline and/or somatic DNA sequencing results, when available, were recorded. Results: 25 lung-only mPC patients were identified, of which 14 underwent germline/somatic DNA analysis. Nine (64%) had a driver mutation in either: the WNT pathway (29%), PI3K/PTEN pathway (21%), homologous recombination DNA repair (HRD) (36%) or mismatch repair (MMR) (29%). 15 lung-predominant mPC patients were also analyzed, of which 10 underwent genomic analysis. Seven (70%) had a driver mutation in either: WNT (10%), PI3K/PTEN (40%), HRD (40%), or MMR (21%). Representative driver mutations for both cohorts summarized in Table. In comparison, in our genomic database, 52.1% had a driver mutation (in WNT 15%, PI3K/PTEN 33%, HRD 22% or MMR 4%). The lung-only and lung-predominant cohorts did not differ by age (p=0.41), race, PSA (p=0.16), Gleason sum (p=0.77), intraductal/ductal histology (p=0.71), lymphovascular invasion (p=0.64), perineural invasion (p=0.73), or having relatives with cancer (p=0.22). Our results are limited by the small sample size and retrospective nature of the analysis. Conclusions: In this exploratory study, the overall prevalence of DNA repair gene alterations was higher than anticipated (35%), suggesting a potential enrichment (esp. in MMR mutations) in men with lung-only or lung-predominant mPC. This finding may have important therapeutic implications. These results require prospective validation of the hypothesis that pulmonary-tropic mPC biology may be fundamentally different from non-pulmonary mPC, and that these patients may benefit from PARP inhibitor or anti–PD-1 treatments. Clinical outcomes data will also be presented. [Table: see text]
Abstract P013: Serum Uric Acid is Not Associated With Incident Dementia in the ARIC-NCS Cohort
Authors: Aniqa B Alam, Aozhou Wu, Melinda C Power, Nancy West, Alvaro Alonso
Journal: Circulation (2019)

Background: Recent studies have investigated the involvement of serum uric acid (SUA) in the progression of cognitive decline and dementia with conflicting results. SUA is known to be associated with hypertension, inflammation, and other cardiovascular risk factors, which often contribute to dementia and dementia-like morbidity, yet several cross-sectional studies have suggested that its antioxidant properties may be protective against cognitive decline. Hypothesis: We hypothesized lower levels of serum uric acid at baseline would be associated with an increased risk of incident dementia. Methods: The ARIC study is an ongoing, biracial, community-based cohort study in the US with longitudinal data first collected in 1987. Participants were examined during follow-up throughout 6 visits (last one 2016-17). Serum uric acid measurements were collected through fasting blood samples in 1990-92 (age range 47-70 years), baseline for this analysis. Incident dementia was determined based on examiner assessments at visits 5 (2011-13) and 6 (2016-17), dementia surveillance based on dementia screeners conducted over telephone interviews starting from visit 5, hospitalization discharge codes, and death certificates prior to visit 6. We estimated the association of SUA, categorized into quartiles, with incidence of dementia by calculating hazard ratios (HR) using Cox regression models adjusting for potential confounders. Results: Our analysis included 11,452 participants free of dementia, prevalent coronary heart disease, or stroke, and with available SUA followed for a median of 24.1 years. Baseline SUA in the highest quartile was associated with incident dementia [HR (95% CI): 1.22 (1.07, 1.38)] when adjusted for age, race, gender, and education level. However, after full adjustment including cardiovascular risk factors, this relationship disappeared (Table). Conclusion: Within a large community-based cohort, we found no evidence of SUA’s influence on incident dementia independent of cardiovascular risk factors.
Abstract P257: Acute Type A Aortic Dissection: Post-Repair Quality of Life and Its Association With Post-Traumatic Stress Disorder, Exercise and Sexual Activity
Authors: Selena R Pasadyn, Eric Roselli, Amanda Artis, Karen Hurley, Eugene Blackstone
Journal: Circulation (2019)

Introduction: Aortic dissection (AD) classically presents with abrupt onset of symptoms immediately followed by major emergency surgery. This can be physically and mentally traumatic. Little is known about the post-repair Quality of Life (QOL) of patients and its association with exercise, post-traumatic stress disorder (PTSD), and sexual activity. Our objective was to describe these associations. Methods: There were 295 identified patients who survived acute type A aortic dissection repair. All were surveyed and 132 responded. Included was the Veterans RAND 12-item Health Survey (VR-12). Also included was a validated screening tool to identify PTSD (PC-PTSD) and questions about exercise and sexual activity. The VR-12 produces physical and mental health QOL summary scores (PCS and MCS) that are standardized using a T-score metric with mean of 50±10. Wilcoxon signed rank tests were used to test if median PCS and MCS scores were equal to 50. Kruskal-Wallis tests were used to test for associations between QOL and PTSD, post-AD exercise status, and limited sexual activity. Hodges-Lehmann (HL) estimates of the location shifts between the two groups and their 95% CIs are also provided as (HL [lower CI, upper CI]). Skewed distributions are presented as median [15 th , 85 th ] percentiles. Results: Median PCS (40.1 [25.9, 51.2]) was significantly lower than 50 (P&lt;.0001). There was no statistical difference between median MCS (54.6 [33.9, 61.4]) and 50 (P=0.2454). The median PCS QOL score was significantly lower in AD patients who screened positive for PTSD than those who did not (HL: -9.3 [-14.0,-4.1], p=0.0008). The same was true for the median MCS score (HL: -17.0 [-23.1,-10.0], p&lt;.0001). The median PCS QOL score was significantly higher in AD patients who were exercisers than those who were not (HL: 6.8 [2.4, 11.1], p=.0015). The same was true for the median MCS score (HL: 4.2 [1.0, 7.8], p=.0095). The median PCS QOL score was significantly lower in AD patients experiencing limited sexual activity after their dissection than those who did not (HL: -8.0 [-12.6, -4.3], p=.0002). The same was true for the median MCS score (HL: -5.5 [-10.5,-1.8], p=.0026). Conclusions: The traumatic and debilitating nature of AD and its emergency repair results in lower physical, but not mental, QOL scores than the general population. Lower physical and mental scores are also associated with PTSD, non-exercisers and limited sexual activity in this population. To promote physical and mental QOL in these patients, physicians should investigate and treat PTSD, encourage exercise, and promote resumption of sexual activity when safe.
The NIH Genetic Testing Registry and content tailored for oncologists.
Authors: Wendy S. Rubinstein, Mark Benson, Shanmuga Chitipiralla, Jeffrey Hoover, Brandi L. Kattman, Kenneth S. Katz, Donna R. Maglott, Adriana J. Malheiro, Radhika Tekumalla, Jennifer M. Lee
Journal: Journal of Clinical Oncology (2015)

e12543 Background: Oncology professionals have no centralized resource to locate the specific set of genetic tests relevant to their practice. Instead they rely on education, marketing, and word of mouth to find genetic tests in scattered locations with non-uniform content and formats. Access to standardized test information at the point of care fuels efficient adoption of targeted therapies into practice. Methods: The Genetic Testing Registry (GTR; http://www. ncbi.nlm.nih.gov/gtr/) is a repository of detailed genetic test information voluntarily submitted by test providers. GTR has over 25,000 registered tests for 5200 conditions and is the only resource with somatic/tumor tests. We leveraged MedGen (http://www.ncbi.nlm.nih.gov/medgen/) to enable application developers to serve only content germane to testable conditions in oncology: neoplasms, hereditary cancer syndromes, and pharmacogenetics. NCBI developed an open application programming interface (API), accessible via E-utilities to encourage creation of many diverse applications. Results: Over 2200 tests for over 550 conditions of interest to oncologists are searchable. These are comprised of ~700 tests for 200 neoplasms, 1550 tests for 175 hereditary cancer syndromes, and all 250 tests for 150 pharmacogenetic responses. Searches are supported for genes, conditions, labs and tests with several filters (e.g., lab location, certifications). Practical test details including methodology, what is tested (genes/chromosomes/analytes) and ordering instructions as well as high-value content (e.g., practice guidelines, dosing recommendations, GeneReviews, ClinicalTrials.gov) are integrated into GTR. An ‘OncoGTR’ website will be developed at NCBI to serve oncology professionals. Conclusions: We have enabled a large breadth and depth of oncology genetic testing information to be used at the point of care based on the GTR API. All laboratories are encouraged to register genetic tests they offer to bring full value to ordering oncologists. Feedback on design is welcome and we hope to see many applications.
New Molecular and Therapeutic Insights into Canine Diffuse Large B Cell Lymphoma Elucidates the Role of the Dog As a Model for Human Disease
Authors: Luca Aresu, Serena Ferraresso, Laura Marconato, Luciano Cascione, Sara Napoli, Eugenio Gaudio, Ivo Kwee, Chiara Tarantelli, Andrea Testa, Chiara Maniaci, Alessio Ciulli, Petra Hillmann, Thomas Bohnacker, Peter Wymann, Stefano Comazzi, Massimo Milan, Fulvio Riondato, Giulia Dalla Rovere, Mery Giantin, Diana Giannuzzi, Francesco Bertoni
Journal: Blood (2018)