tbuckley/cabot-search huggingface dataset:
Abstract MP58: Intermuscular Fat Density: Novel Risk Factor for Cardiometabolic Risk Factors in African-Ancestry Men
Authors: Curtis Tilves, Allison L Kuipers, Joseph M Zmuda, J J Carr, James G Terry, Sangeeta Nair, Akira Sekikawa, Clareann H Bunker, Victor Wheeler, Iva Miljkovic
Journal: Circulation (2019)

Background: While overall obesity remains a major risk factor for cardiometabolic diseases, the location of stored fat is also thought to play a role. In addition to fat storage in ectopic sites, the density of fat, a marker of fat quality, is emerging as a novel risk factor for cardiometabolic diseases. Previous studies have focused primarily on visceral (VAT) and abdominal subcutaneous (SAT) adipose tissue density and in predominantly white cohorts; however, studies in populations of African ancestry who are at higher risk of cardiometabolic diseases are lacking. Additionally, information is lacking on associations of density of other relevant ectopic fat depots, such as intermuscular adipose tissue (IMAT), with cardiometabolic risk factors. Methods: We investigated whether VAT, SAT, or thigh IMAT densities were associated with cardiometabolic measures in 648 black men aged 50-91 years (mean age 63.6 years, mean BMI 27.7 kg/m 2 ). Adipose tissue volume (cm 3 ) and density (Hounsfield units, HU) was measured in the abdomen (between L4 and L5) and mid-thigh from computed tomography scans. Cardiometabolic measures, including blood pressure, fasting serum glucose and insulin homeostasis, and serum lipids (N=476), were transformed as needed and used as outcomes in multiple linear regression models adjusting for age, lifestyle factors, medication use (antihypertensive, antidiabetic, or lipid-lowering), and corresponding fat depot volume. Results: After adjustment (Table), VAT, SAT, and IMAT densities were significantly associated with fasting insulin, insulin resistance, and lipids. Results remain similar after adjustment for BMI instead of fat volume and in a sensitivity analysis excluding those taking relevant medications. Conclusion: As reported in other studies, in our study among African ancestry individuals VAT and SAT were associated with several cardio-metabolic risk factors. Importantly, our findings suggest that thigh IMAT density may be a novel predictor of cardiometabolic risk in African ancestry men.
Lgr5 Functions As Negative Regulator of Wnt Signaling in B Cells and Is Critical for Self-Renewal of Normal and Transformed B Cells
Authors: Kadriye Nehir Nehir Cosgun, Anna Hecht, Xin Yang, Maurizio Mangolini, Ali Aghajanirefah, Zhengshan Chen, Gang Xiao, Lars Klemm, Chao Hong, Huimin Geng, Hassan Jumaa, Hans Clevers, Markus Muschen
Journal: Blood (2017)
PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma
Authors: Elaine Y. Chung, Yun Mai, Urvi A. Shah, Yongqiang Wei, Elise Ishida, Keisuke Kataoka, Xiaoxin Ren, Kith Pradhan, Boris Bartholdy, Xiaolei Wei, Yiyu Zou, Jinghang Zhang, Seishi Ogawa, Ulrich Steidl, Xingxing Zang, Amit Verma, Murali Janakiram, B. Hilda Ye
Journal: Clinical Cancer Research (2019)

To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models.Frequency and prognostic impact of PAK2 amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and in vivo xenograft models were developed using primary ATLL cells from North American patients. Two PAK inhibitors were used to block PAK kinase activity pharmacologically. siRNA-based gene silencing approach was used to genetically knockdown (KD) PAK1 and PAK2 in ATLL cell lines.PAK1/2/4 are the three most abundantly expressed PAK family members in ATLL. PAK2 amplifications are seen in 24% of ATLLs and are associated with worse prognosis in a large patient cohort. The pan-PAK inhibitor PF-3758309 (PF) has strong in vitro and in vivo activity in a variety of ATLL preclinical models. These activities of PF are likely attributed to its ability to target several PAK isoforms simultaneously because genetic silencing of either PAK1 or PAK2 produced more modest effects. PAK2 plays a major role in CADM1-mediated stromal interaction, which is an important step in systemic dissemination of the disease. This finding is consistent with the observation that PAK2 amplification is more frequent in aggressive ATLLs and correlates with inferior outcome.PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Taken together, PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs.
MRI targeted biopsy dramatically increases detection of clinically significant prostate cancer while reducing the risk of indolent cancer detection.
Authors: Michael Ahdoot, Amir H Lebastchi, Sandeep Gharam, Patrick H Gomella, John Dibianco, Jonathan Bloom, Graham Hale, Samuel A Gold, Baris Turkbey, Peter A. Pinto, Thomas Sanford, Peter L. Choyke, Howard L. Parnes
Journal: Journal of Clinical Oncology (2019)

108 Background: MRI fusion prostate biopsy has been shown to improve detection of clinically significant prostate cancer, however the degree of this benefit is poorly characterized in large clinical trials. Methods: 1750 MRI targeted plus sextant biopsies were performed in 1742 male patients from 2007 to 2017. Patient demographics, PSA, prostate volume, primary and secondary Gleason scores, Johns Hopkins Grade Groups, number of MRI targeted lesions, number of cores obtained, and biopsy yield were recorded. Results: The patient population consisted of men averaging 62.9-year-old (36-86) with a mean PSA 9.6ng/mL, and prostate volume of 59.2 ml. A total of 804 cancers were detected on sextant biopsy and 839 were detected on MRI targeted biopsy. Relative to targeted biopsy, sextant biopsy detected only significantly more Gleason 6 disease (14% vs 21.5%, p &lt; 0.0001) than targeted biopsy. Targeted biopsy detected more Gleason 7 (21% vs 16.6%, p = 0.0009) and Gleason 8-10 (13.4% vs 9.4%). Additionally, Gleason 7 sub-stratification demonstrated substantially more Gleason 4+3 detection in targeted group vs sextant biopsy (4% vs 0.5%, p &lt; 0.0001). When stratified by Grade Group targeted biopsy detected 76% more Grade Group 3-5 cancers (p &lt; 0.0001) and 17.7% less Gleason Group 1-2 cancers (p &lt; 0.0001). Only 1.7% of Grade Group 3-5 cancers were detected on sextant biopsy alone, where as 15.7% of Grade Group 3-5 cancers were detected on targeted biopsy alone. Conclusions: MRI targeted biopsy significantly increases the likelihood of detecting clinically significant cancer and decreases the risk of indolent cancer detection. These finding strongly support the use of MRI targeted biopsy when possible.
Newly Diagnosed Pernicious Anemia Can be Treated with a Single Megadose of Cobalamin. Results of a Pilot Trial
Authors: Cesar O Pezina Cantú, Perla R. Colunga Pedraza, Andres Gomez De Leon, Diana E Garcia-Camarillo, Oscar Marquez-Pinedo, Paola Santana-Hernandez, Olga Cantu Rodriguez, Cesar Homero Gutierrez Aguirre, Luz del Carmen Tarín Arzaga, David Gomez-Almaguer
Journal: Blood (2018)
Exploring the Lipid Paradox Theory in Rheumatoid Arthritis: Associations of Low Circulating Low‐Density Lipoprotein Concentration With Subclinical Coronary Atherosclerosis
Authors: Jon T. Giles, Mary Chester M. Wasko, Cecilia P. Chung, Moyses Szklo, Roger S. Blumenthal, Amy Kao, Sabahat Bokhari, Afshin Zartoshti, C. Michael Stein, Joan M. Bathon
Journal: Arthritis & Rheumatology (2019)

Objective Rheumatoid arthritis ( RA ) patients with the lowest circulating low‐density lipoprotein ( LDL ) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown. Methods RA patients pooled from 4 cohort studies of cardiovascular disease ( CVD ; n = 546) were compared with non‐ RA controls from the Multi‐Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid‐lowering medications were excluded. Differences in cardiac computed tomography–derived Agatston coronary artery calcium ( CAC ) scores between the RA and control groups were compared across strata of LDL concentration. Results Among those with low LDL concentrations (&lt;70 mg/dl), mean adjusted CAC scores were &gt;4‐fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P &lt; 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P &lt; 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations. Conclusion RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.
Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults
Authors: Luanluan Sun, Robert Clarke, Derrick Bennett, Yu Guo, Robin G. Walters, Michael Hill, Sarah Parish, Iona Y. Millwood, Zheng Bian, Yiping Chen, Canqing Yu, Jun Lv, Rory Collins, Junshi Chen, Richard Peto, Liming Li, Zhengming Chen
Journal: Nature Medicine (2019)
Methylation levels of MGMT and RASSF1 genes in testicular cancer as potential biomarkers for the success of chemotherapy.
Authors: Marija Gamulin, Vlatka Zoldos, Ivana Beceheli, Dora Markulin, Ivana Samarzija, Aleksandar Vojta, Mislav Grgic, Irena Jukic, Cedomir Maglov, Renata Zunec, Aleksandra Fucic
Journal: Journal of Clinical Oncology (2015)

e15560 Background: Since testicular cancer shows different disease progress depending on etiology and the neoplastic tissue profile, with epigenetic changes being a likely underlying mechanism, we investigated CpG methylation of MGMT and RASSF1, which had been identified as promising candidate biomarkers for disease progression, chemotherapy success and prognosis. Methods: Genomic DNA was isolated from blood of 32 healthy individuals and 32 patients with testicular cancer before and after the chemotherapy: etoposide, cisplatin, bleomycin (BEP). Eighteen samples were seminomas and 14 were nonseminomas. For quantitative measurement of DNA methylation levels in MGMT and RASSF1A, bisulfite-converted DNA was amplified by PCR and then sequenced using a pyrosequencing technology. Results: Methylation levels were not significantly different for MGMT before and after chemotherapy; however, methylation of the tested CpG sites in RASSF1 was significantly higher in patients before treatment compared with controls at 5 of 9 sites, two sites remaining significant even after the Bonferroni correction. Methylation of RASSF1 approached that of the controls after treatment. In addition, we found indications that additional stratification by histopathological profile might add value to MGMT and RASSF1 methylation as a prognostic marker. The methylation of LINE1 elements was similar in patients before and after chemotherapy. Conclusions: Increasing statistical power by studying larger cohorts has a potential to further confirm RASSF1 methylation as a chemotherapy success biomarker, while additional stratification by histopahological characteristics could give further insight leading to more accurate prognosis using both RASSF1 and MGMT, thereby enabling better risk-adapted management of testicular cancer.
Prostate cancer in young men: Our experience.
Authors: Joao Vasco Barreira, Gil Falcão, Anuraj Parmanande, Ana Sofia Spencer, Diana Simão, Patricia Winckler, Ricardo Luz
Journal: Journal of Clinical Oncology (2019)

133 Background: Prostate cancer (PCa) diagnosis is not uncommon in younger men. The three recognized risk factors for PCa are increasing age, african-american race and a family history (FH). Data about PCa treatment outcomes are controversial, younger men may have more aggressive disease and worse prognosis. On the other hand, more recent studies suggest higher rates of indolent PCa with more favorable outcomes in young men after radical prostatectomy (RP). We aimed to compare younger (G1, ≤ 55 yo) vs. older adults (G2, &gt; 56 yo) who underwent RP for PCa between 2010-2016 in terms of FH, race and tumor aggressiveness. Secondly, to determine if the PCa in G1 is more aggressive when there is a PCa familiar background. Methods: Between 2010-2016, 419 men underwent RP for clinically localized PCa at Central Lisbon Hospitals, of which 49 were aged ≤55 years at the time of RP. Clinical characteristics such as race, FH, PSA level, clinical stage, and biopsy Gleason score (BGS) were recorded before RP. Pathological parameters (pathological stage, GS and PSA) were collected after surgery. Results: In G1, 31% had PCa FH vs. 10% in G2 (p &lt; 0.001). Before RP, the average PSA in G1 was 7.47 vs. 8.08 in G2 (p = 0.371). In BGS, 44,3% had Gleason (G) 6, 37,4% G7, 6.9% G≥8, not significantly different between both groups (p = 0.651). Albeit, G1 had more aggressive tumors after RP: 27% G6, 45% G7 e 29% G≥8 vs. 37%, 53% e 11% respectively in G2 (p = 0.002). The pathological stage (pT) was not significantly different between groups (p = 0.243). Biochemical recurrence (BCR) was higher in G1 20% vs. 9% (p = 0.010). In a multivariate logistic regression model, the G1 had more BCR (p = 0.047) and higher PCa FH incidence (p = 0.002). When comparing african vs. caucasian men, the first group had more aggressive tumor histology (p = 0.021). Conclusions: Our study demonstrated that the youngest had superior pathological grades with higher BCR rates. Also, we found a strong relationship between G1 and FH of PCa. Data regarding pathological findings after RP in young men are still controversial. Recent studies confirm that pathological PCa characteristics in young men are not more aggressive than in older men. The present intends to add to the scientific debate around the impact of patients’ age in PCa aggressiveness and prognosis.
Selective internal radiation therapy (SIRT/Y90) in the management of unresectable hepatic malignancies.
Authors: Emily Harrold, Derek Gerard Power, Patrick Nicholson, David Tuite, Connor Gerard O'Leary
Journal: Journal of Clinical Oncology (2015)

e14702 Background: Hepatic malignancies present therapeutic challenges.35-60% of colorectal cancer patients develop liver metastases and untreated median survival is 4-6 months. Average survival rates for untreated primary hepatic malignancies (HCC) are comparable. Increasingly liver directed therapies are being used in unresectable and in chemo-refractory disease. Selective internal Radiation Therapy (SIRT/Y90) is one such therapy. Previously identified independent predictors of survival post SIRT include ≤ 2 cytotoxic agents, no exposure to biologics, ECOG 0, tumour burden < 25 %, lack of extra-hepatic disease and albumin > 3 g/dL. Methods: Cork University Hospital is the only Irish site offering SIRT. Using a prospectively maintained institutional database we identified all patients referred for consideration of SIRT between January 2010 and December 2014. We retrospectively examined baseline clinical characteristics, nature of previous treatment modalities and time to progression post procedure. We assessed toxicities post procedure using CTCAE criteria. Results: 38 patients were referred for consideration of SIRT over this period; 5 HCC, 32 with metastatic colorectal cancer (mCRC) and one with carcinoid tumour. In the mCRC cohort average number of lines of previous chemotherapy was 2.8. Seven mCRC patients were eligible. Time to progression (TTP) ranged from 1.5 to 11 months. Notably the patient with the longest TTP had received two previous lines of chemotherapy and tumour was KRAS mutated. In the HCC cohort one patient was eligible. TTP is 16months to date. Median stay was 3.5 days. One grade 3 GI toxicity was observed necessitating six days of parenteral nutrition and longer inpatient stay. Conclusions: In a selected patient population SIRT is a tolerable treatment modality in management of unresectable hepatic malignancies. This review reflects the only Irish experience of SIRT to date. Although it comprises small patient numbers there is a suggestion that SIRT should be considered earlier and can be associated with prolonged progression free survival. Multicentre phase three trials data is eagerly anticipated and may alter current treatment paradigms particularly in setting of mCRC.
Sarcopenia is independently associated with decreased overall survival after surgery for inferior vena cava tumor thrombus patients.
Authors: Milton Williams, Reza Nabavizadeh, Amir Ishaq Khan, Dattatraya H Patil, Sarah P. Psutka, Aarti Sekhar, Kenneth Ogan, Mehmet Asim Bilen, Viraj A. Master
Journal: Journal of Clinical Oncology (2019)

674 Background: The presence of sarcopenia, a lean muscle mass deficiency is independently associated with inferior survival following the surgical treatment of localized renal cell carcinoma (RCC). This association has not yet been studied in more advanced disease such as patients with RCC and concomitant IVC thrombus tumors. In this study we retrospectively examined the association between preoperative sarcopenia and overall survival following definitive surgery for IVC tumor thrombus patients. Methods: Baseline lumbar skeletal muscle index (SMI) for patients who underwent surgical treatment for known IVC thrombus tumors between 2006 and 2018 by a single surgeon were quantified at the 3 rd lumbar vertebra from preoperative computerized tomography (CT) or magnetic resonance imaging (MRI). The SMI thresholds used to define sarcopenia were developed using ROC analysis of our data and had the most significant relation to overall survival. Overall survival was compared between patients with and without sarcopenia using the Kaplan-Meier method as well as univariate and multivariate cox proportional hazards regression models. Results: The cohort consisted of 194 patients of whom 128 (65%) were male and 146 (75%) were non-Hispanic white. There were 143 (74%) clear cell renal cell carcinoma cases. 110 patients (57%) were sarcopenic. Patients with sarcopenia had significantly decreased overall survival, log-rank p=0.009 (Figure). The presence of sarcopenia was also associated with decreased overall survival in univariate analysis, (hazard ratio (HR)=1.80, 95% CI 1.15-2.83; p=0.010). In multivariable analysis controlled for age, number of comorbidities, and AJCC Stage, sarcopenia maintained significance as a predictor of decreased overall survival (HR= 1.66, 95% CI 1.05-2.61; p=0.030). Conclusions: Preoperative sarcopenia is independently associated with mortality in patients with IVC thrombus tumors.
Comprehensive radiogenomics analysis of qualitative and quantitative features of cross-sectional imaging in the TCGA project in MIBC.
Authors: Seth P. Lerner, Vinay Duddalwar, Erich Huang, Ersan Altun, Tharakeswara Bathala, Steven Kennish, Juan Ibarra, Fabiano Lucchesi, Valdair Francisco Muglia, Stephen Thomas, Raghu Vikram, Hebert Alberto Vargas, Steven Yong Cen, Darryl Hwang, Kevin George King, Bino Varghese, Brenda Fevrier-Sullivan, Justin Kirby, Carl Jaffe, John Freymann
Journal: Journal of Clinical Oncology (2019)

482 Background: Quantitative imaging descriptors derived from CT and MRI can be integrated with genomic data that may be used as non-invasive prognostic or predictive biomarkers. We report an integrated radiogenomics project designed to develop subjective and objective parameters extracted from cross-sectional imaging of MIBC from studies archived in the TCIA and linked to the TCGA project. Methods: We reported comprehensive integrated genomic analysis of 412 tumors (Cell 2017). 7 of 33 tissue source sites submitted CT scans to the TCIA (n=106). We developed 17 features describing tumor size/location, metastases sites, and tumor morphology; 9 GU radiologists reviewed the scans in a blinded manner. EH analyzed the data independent of the radiologists. We computed kappa statistics for categorical features and coverage probabilities for quantitative features (Lin et al 2002). The tumor was segmented on an axial image and the segmented image analyzed using a radiomics panel (radiomicslab.usc.edu). Associations between individual features and subtypes were assessed (Fisher’s Exact Test) for categorical features and Kruskal-Wallis Test for quantitative features. Results: Substantial agreement (k≥ 0.6) was observed in 4 features: tumor laterality, tumor within bladder diverticulum, right and left UVJ involvement and hydroureter. We observed weak agreement (95% CI &lt;0.4) for bladder neck, posterior bladder, dome, and trigone involvement, tumor margin, internal architecture, radiographic stage, left upper tract involvement, and metastases. The coverage probability for lesion size was 0.59 (0.544-0.638) (Figure). Tumor morphology was associated with microRNA cluster, with diffuse wall thickening having a higher tendency toward Clusters 3 and 4 (p &lt; .001). Radiomic analysis identified statistically significant associations of mutations in FGFR3, CREBBP, CASP8 and EP300 with multiple radiomic features. Conclusions: This blinded comprehensive assessment of features extracted from CT images highlights many of the ongoing challenges in staging patients with MIBC. Preliminary analysis shows promise in analyzing associations between radiomic features and mutations.
Substrate mechanics controls adipogenesis through YAP phosphorylation by dictating cell spreading
Authors: Jorge Oliver-De La Cruz, Giorgia Nardone, Jan Vrbsky, Antonio Pompeiano, Ana Rubina Perestrelo, Francesco Capradossi, Katarína Melajová, Petr Filipensky, Giancarlo Forte
Journal: Biomaterials (2019)

The mechanoregulated proteins YAP/TAZ are involved in the adipogenic/osteogenic switch of mesenchymal stem cells (MSCs). MSC fate decision can be unbalanced by controlling substrate mechanics, in turn altering the transmission of tension through cell cytoskeleton. MSCs have been proposed for orthopedic and reconstructive surgery applications. Thus, a tight control of their adipogenic potential is required in order to avoid their drifting towards fat tissue. Substrate mechanics has been shown to drive MSC commitment and to regulate YAP/TAZ protein shuttling and turnover. The mechanism by which YAP/TAZ co-transcriptional activity is mechanically regulated during MSC fate acquisition is still debated. Here, we design few bioengineering tools suited to disentangle the contribution of mechanical from biological stimuli to MSC adipogenesis. We demonstrate that the mechanical repression of YAP happens through its phosphorylation, is purely mediated by cell spreading downstream of substrate mechanics as dictated by dimensionality. YAP repression is sufficient to prompt MSC adipogenesis, regardless of a permissive biological environment, TEAD nuclear presence or focal adhesion stabilization. Finally, by harnessing the potential of YAP mechanical regulation, we propose a practical example of the exploitation of adipogenic transdifferentiation in tumors.
Physical activity and quality of life in patients with pulmonary hypertension
Authors: Thomas M. Cascino, Vallerie V. McLaughlin, Caroline R. Richardson, Nilofar Behbahani-Nejad, Victor M. Moles, Scott H. Visovatti, Elizabeth A. Jackson
Journal: European Respiratory Journal (2019)

<b>In a longitudinal study of stable pulmonary hypertension patients, there was a nonlinear association between 6MWD and step counts at higher levels of exercise capacity and average step counts were associated with disease-specific and global HRQoL</b>http://bit.ly/2JiCvRX