tbuckley/cabot-search huggingface dataset:
Abstract 16708: Socioeconomic Status and the Incidence of Atrial Fibrillation in Whites and African Americans: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Jeffrey R Misialek, Kathryn M Rose, Susan A Everson-Rose, Elsayed Z Soliman, Cari J Clark, Faye L Lopez, Alvaro Alonso
Journal: Circulation (2011)

Background: Lower socioeconomic status (SES) has been associated with a higher risk of cardiovascular disease (CVD) overall. However, the association of SES and atrial fibrillation (AF) has not been investigated to date. Methods: We studied 14,352 men and women (75% white, 55% women, mean age 54) free of AF participating in the Atherosclerosis Risk in Communities (ARIC) study. SES was assessed at baseline (1987-89) through educational level and family income. Incident AF cases through 2008 were ascertained from electrocardiograms, hospital discharge codes, and death certificates. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals of AF for education and family income separately. Models were initially adjusted for age, sex, and race. Additional models further adjusted for study site, diabetes, systolic blood pressure, use of antihypertensive medications, smoking status, alcohol consumption, body mass index, and a history of other CVD (heart failure, myocardial infarction, or stroke). Interactions were tested between the measures of SES and race and sex. Results: Over a median follow-up time of 19.6 years, 1,648 AF cases were identified. Low income was associated with higher AF risk in the entire cohort (table), with no evidence of significant interactions between family income and sex or race. A significant multiplicative interaction was present between sex and education (p&lt;0.0001). Low education was associated with higher AF risk in women but not in men (table). No interaction was found between education and race. Adjustment for cardiovascular risk factors and other CVD strongly attenuated all associations (table, model 2). Conclusion: Lower SES was associated with a higher AF risk. This association was not different between whites and African Americans; however, the impact of education on risk of AF may be more prominent for women. Cardiovascular risk factors and other CVD likely mediate this association.
Targeting Rac and Cdc42 GTPases in Cancer
Authors: María del Mar Maldonado, Suranganie Dharmawardhane
Journal: Cancer Research (2018)

Abstract Rac and Cdc42 are small GTPases that have been linked to multiple human cancers and are implicated in epithelial to mesenchymal transition, cell-cycle progression, migration/invasion, tumor growth, angiogenesis, and oncogenic transformation. With the exception of the P29S driver mutation in melanoma, Rac and Cdc42 are not generally mutated in cancer, but are overexpressed (gene amplification and mRNA upregulation) or hyperactivated. Rac and Cdc42 are hyperactivated via signaling through oncogenic cell surface receptors, such as growth factor receptors, which converge on the guanine nucleotide exchange factors that regulate their GDP/GTP exchange. Hence, targeting Rac and Cdc42 represents a promising strategy for precise cancer therapy, as well as for inhibition of bypass signaling that promotes resistance to cell surface receptor-targeted therapies. Therefore, an understanding of the regulatory mechanisms of these pivotal signaling intermediates is key for the development of effective inhibitors. In this review, we focus on the role of Rac and Cdc42 in cancer and summarize the regulatory mechanisms, inhibitory efficacy, and the anticancer potential of Rac- and Cdc42-targeting agents. Cancer Res; 78(12); 3101–11. ©2018 AACR.
Co-delivery of LOX-1 siRNA and statin to endothelial cells and macrophages in the atherosclerotic lesions by a dual-targeting core-shell nanoplatform: A dual cell therapy to regress plaques
Authors: Yi Zhao, Hai Gao, Jianhua He, Cuiping Jiang, Jing Lu, Wenli Zhang, Hu Yang, Jianping Liu
Journal: Journal of Controlled Release (2018)
Relationship between changes in left ventricular ejection and use of angiotensin-converting enzyme inhibitors and/or betablockers during adjuvant trastuzumab chemotherapy in early breast cancer: Data from the real world.
Authors: Francesco Giotta, Stefano Oliva, Lidia Boccardi, Silvia Frattini, Agnese Maria Fioretti, Edda Simoncini, Giovanni Pulignano, Gianni Cioffi, Chiara Lestuzzi, Nicola Maurea, Luigi Tarantini
Journal: Journal of Clinical Oncology (2012)

645 Background: Adjuvant trastuzumab chemotherapy (aTrastC) improves DFS of pts with breast cancer and overexpression of HER-2. However, cardiovascular complication (CV) such as heart failure (HF) or significant left ventricular ejection fraction (LVEF) reduction may appear especially in those pts at increased CV risk. Methods: 253 women treated with aTrastC for EBC in 7 italian oncologic centers during the period 2008-2009 entered in a multicenter registry and were retrospectively studied in 4 subgroups according to the treatment with ACEi and/or BB. Occurrence of symptoms of HF and/or decrease in 10 points % of LVEF were recorded during the follow up. LVEF was measured at baseline and 3-6-9-12 months. Results: Symptoms of HF occurred in 2% of pts who did not take either ACEi/ARB or BB. HF event-rate was similarly increased in pts receiving one or both medications, partially justified by the increased CV risk in these subgroups. Prevalence of decrease in LVEF &gt; 10 points% was similar in all study subgroups. Trends in LVEF were characteristics for each study subgroup: at 3-month evaluation a significant decrease in LVEF was detected in ACEi/ARB and ACEi/ARB + BB group. Multiple logistic regression analysis showed that combined ACEi/ARB + BB therapy depended on history of hypertension (OR 36.7, CI 4.3-315.5) and reduction of LVEF from baseline to 3-month evaluation (OR 0.88, CI 0.78-0.97) (best prediction – 3.5 points %, AUC 0.78, IC 0.65-0.91). Conversely, no association was found between changes in LVEF and ACEi/ARB or BB therapy alone. LVEF recovery from 3 to 12-month evaluation was inversely related to the changes in LVEF from baseline to 3-month evaluation and did not depend on any pharmacological treatment. Conclusions: In clinical practice, a history of hypertension and changes in LVEF during the first 3 months of aTrastC for early breast cancer influence the use of ACEi/ARB and BB. This behaviour may explain the characteristic trend in LVEF showed in the subgroups of patient receiving or receiving not ACEi/ARB or BB. Subsequent recovery of LVEF does not seem to be related to any medical treatment.
LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study
Authors: Marialuisa Quadri, Wim Mandemakers, Martyna M Grochowska, Roy Masius, Hanneke Geut, Edito Fabrizio, Guido J Breedveld, Demy Kuipers, Michelle Minneboo, Leonie J M Vergouw, Ana Carreras Mascaro, Ekaterina Yonova-Doing, Erik Simons, Tianna Zhao, Alessio B Di Fonzo, Hsiu-Chen Chang, Piero Parchi, Marta Melis, Leonor Correia Guedes, Chiara Criscuolo, Astrid Thomas, Rutger W W Brouwer, Daphne Heijsman, Angela M T Ingrassia, Giovanna Calandra Buonaura, Janneke P Rood, Sabina Capellari, Annemieke J Rozemuller, Marianna Sarchioto, Hsin Fen Chien, Nicola Vanacore, Simone Olgiati, Yah-Huei Wu-Chou, Tu-Hsueh Yeh, Agnita J W Boon, Susanne E Hoogers, Mehrnaz Ghazvini, Arne S IJpma, Wilfred F J van IJcken, Marco Onofrj, Paolo Barone, David J Nicholl, Andreas Puschmann, Michele De Mari, Anneke J Kievit, Egberto Barbosa, Giuseppe De Michele, Danielle Majoor-Krakauer, John C van Swieten, Frank J de Jong, Joaquim J Ferreira, Giovanni Cossu, Chin-Song Lu, Giuseppe Meco, Pietro Cortelli, Wilma D J van de Berg, Vincenzo Bonifati, Vincenzo Bonifati, Marialuisa Quadri, Wim Mandemakers, Anneke J.A. Kievit, Agnita J.W. Boon, Janneke P.A Rood, Leonie J.M. Vergouw, Frank J. de Jong, John C. van Swieten, Francesco U.S. Mattace-Raso, Klaus L. Leenders, Joaquim J. Ferreira, Leonor Correia Guedes, Andreas Puschmann, Emil Ygland, Christer Nilsson, Hsin F. Chien, Egberto Barbosa, Laura Bannach Jardim, Carlos R.M. Rieder, Hsiu-Chen Chang, Chin-Song Lu, Yah-Huei Wu-Chou, Tu-Hsueh Yeh, Leonardo Lopiano, Cristina Tassorelli, Claudio Pacchetti, Giulio Riboldazzi, Giorgio Bono, Cristoforo Comi, Alessandro Padovani, Barbara Borroni, Francesco Raudino, Emiliana Fincati, Michele Tinazzi, Alberto Bonizzato, Carlo Ferracci, Alessio Dalla Libera, Giovanni Abbruzzese, Pietro Cortelli, Sabina Capellari, Roberto Marconi, Marco Guidi, Marco Onofrj, Astrid Thomas, Nicola Vanacore, Giuseppe Meco, Edito Fabrizio, Giovanni Fabbrini, Alfredo Berardelli, Fabrizio Stocchi, Laura Vacca, Paolo Barone, Marina Picillo, Giuseppe De Michele, Chiara Criscuolo, Michele De Mari, Claudia Dell'Aquila, Gianni Iliceto, Vincenzo Toni, Giorgio Trianni, Monica Gagliardi, Grazia Annesi, Aldo Quattrone, Valeria Saddi, Gianni Cossu, Maurizio Melis
Journal: The Lancet Neurology (2018)
Morbid obesity is related with adverse outcomes in triple negative breast cancer: A single institution experience.
Authors: Zeeshan Ali Jawa, Chad Glisch, Talha Badar, Lubna Chaudhary, Sailaja Kamaraju, John D. Burfeind, John A. Charlson, Christopher R. Chitambar, Irene Aguilera-Barrantes, Julie Jorns, Valentina Lagunova, Yee Chung Cheng
Journal: Journal of Clinical Oncology (2018)

e12663 Background: Obesity has been suggested as a risk factor for development of triple negative breast cancer (TNBC) in a meta-analysis. However, the impact of obesity on TNBC outcomes is still undefined. The aim of our study was to evaluate the prognostic significance of morbid obesity in patients with TNBC treated with neoadjuvant chemotherapy (NAC). Methods: 107 patients with non-metastatic TNBC, treated with neoadjuvant chemotherapy between June 2006 and March 2016 were retrospectively evaluated. Demographics and clinicopathological characteristics were studied. Results: Median age for the 107 patients was 49 years with a median follow up of 49 months. 46% of patients were premenopausal and 54% post-menopausal, 74% were Caucasians, 24% African Americans and 2% Hispanic. 50% patients had lymph node involvement. The average BMI was 29.9. Majority were grade III tumors (89%). Everyone received anthracycline based chemotherapy with 32% receiving an additional platinum chemotherapy. BRCA positivity was 11%. Overall pathologic complete response (pCR) rate was 46%. No association was observed between pCR and factors such as age, menopausal status, lymph node involvement, BMI, addition of platinum therapy, AR expression, tumor size and BRCA status. Patients with BMI ⩾40 (n = 9) had a median disease-free survival (DFS) of 20.6 months and overall Survival (OS) of 24.9 months vs not reached in patients with BMI < 40 (73% DFS [p = 0.015] and 74% OS [p = 0.008] at 60 months). There was no difference in DFS and OS comparing pre-menopausal and post-menopausal subgroups at 60 months (DFS 70% vs 65%, p = 0.39; OS 69% vs 66%, p = 0.492). Other factors associated with improved OS on multivariate analysis were pCR and negative lymph node status ( < 0.005). Conclusions: Our study shows that morbid obesity is an important adverse prognostic factor in patients with TNBC who received NAC.
Abstract 315: Mechanical Stretch Activates Biased AT1R Signaling and a Distinct β-arrestin Conformation
Authors: Clarice Gareri, Jialu Wang, Kenji Hanada, Alem W Kashai, Xinyu Xiong, Sudarshan Rajagopal, Howard A Rockman
Journal: Circulation Research (2017)

Introduction: Angiotensin II Type 1 receptor (AT1R) is a member of the G protein-coupled receptors (GPCRs) family, playing an important role in several cardiovascular diseases. Depending on the stimulus, AT1R activates a cascade of signaling pathways including those mediated by G proteins and the multifunctional proteins β-arrestins. AT1R is also mechanosensor and respond to membrane stretch by activating ligand-independent β-arrestin-biased signaling. Objective: The aim of this study is to investigate the precise molecular mechanism for mechanoactivation of the AT1R. Methods and Results: Our previous work demonstrated that mechanical stretch induced by hypotonicity (osmotic-stretch, OSM) allosterically activates the AT1R to mediate β-arrestin signaling. Using Proximity Ligation Assays (PLA) and co-IP we now demonstrate that OSM uniquely promotes Gαi recruitment to AT1R to initiate β-arrestin signaling. In sharp contrast to the β-arrestin-biased ligand TRV120023, the Gαi inhibitor Pertussis Toxin (PTX) blocked the OSM-induced β-arrestin recruitment, EGFR transactivation and ERK signaling. To determine whether the two biased stimuli (OSM and TRV120023) can activate different β-arrestin conformations, we used β-arrestin FLAsH constructs and monitored BRET following AT1R activation by either ligand or stretch stimulation. A FlAsH constructs located in the N-domain domain and two located in the C-domain domain showed a distinct BRET pattern indicating that in response to OSM, β-arrestin assumes a distinct conformation from either the balanced ligand Angiontensin II and the TRV120023 (N=7; p&lt;0.05). Current studies are underway using site-specific stable-isotope labeling strategies coupled with mass spectrometry-based quantitative analysis (CDSiL-MS) to obtain biophysical information regarding the precise AT1R conformations induced by these balanced and β-arrestin-biased stimuli. Conclusion: The principal driver for differential signaling is thought to be different receptor conformations stabilized by each ligand. Our data suggest that in response to two β-arrestin-biased stimuli, AT1R likely adopt distinct conformations indicating remarkable conformational heterogeneity in activating intracellular responses.
Impact of supplemental parenteral nutrition early during critical illness on invasive fungal infections: a secondary analysis of the EPaNIC randomized controlled trial
Authors: G. De Vlieger, C. Ingels, P.J. Wouters, Y. Debaveye, I. Vanhorebeek, J. Wauters, A. Wilmer, M.P. Casaer, G. Van den Berghe
Journal: Clinical Microbiology and Infection (2018)
Relationship of testicular cancer incidence and cellular phone use.
Authors: Robert A. Somer, Rakesh Surapaneni, Douglas Francis Beach
Journal: Journal of Clinical Oncology (2012)

e12008 Background: Because of the ubiquitous usage of cellphones, any health consequences, if found, would be of paramount importance. Many have questioned the relationship of cellphone radiofrequency waves and malignancies such as brain tumors. Because men usually store their phones in close proximately to the testicles, we analyzed the relationship between cell phone usage and testicular cancer. Methods: Testicular cancer data was obtained from SEER-9 United States Population Data Base of the National Cancer Institute. Cell phone subscription data was obtained from the World Health Organization publication. Initial data analysis was done from 1991 to 2008, with subsequent age specific and other analyses performed from 1999 to 2008. Trends over time were calculated as Annual Percentage Change of incidence rates (APC) by using log linear models. Results: Rates of United States mobile subscriptions increased exponentially since the late 1990’s reaching 88.87 percent of the population by 2008. There was no statistically significant change in incidence rates of all testicular tumors (APC 0.7; CI -0.2, 0.7), Seminoma (APC 0.2; CI 0.8, 1.1) and non-Seminoma (APC 1.4; CI -0.6, 3.4) from 1999 to 2008. In the age specific analysis, three groups showed an increase in incidence rates: all testicular cancer age 25-34 (APC 2; CI 0.6, 3.4), All testicular cancer age greater than 45 (APC 1.7; CI 0.1, 3.3) and Seminoma age 25-34 (APC 2.1; CI 0.6, 3.7). All these changes were only minor percentage increase when compared to mobile subscriptions. Conclusions: Based on incidence data, there is no convincing evidence of increased risk of testicular cancer from cell phone use. Given possible lag time incidence, continued monitoring is needed.
Randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC).
Authors: Sibylle Loibl, Michael Untch, Nicole Burchardi, Jens Bodo Huober, Jens U. Blohmer, Eva-Maria Grischke, Jenny Furlanetto, Hans Tesch, Claus Hanusch, Mahdi Rezai, Christian Jackisch, Wolfgang D Schmitt, Gunter Von Minckwitz, Jörg Thomalla, Sherko Kummel, Beate Rautenberg, Peter A. Fasching, Kerstin Rhiem, Carsten Denkert, Andreas Schneeweiss
Journal: Journal of Clinical Oncology (2018)

104 Background: Combining immune-checkpoint inhibitors with chemotherapy yielded high response rates in patients (pts) with metastatic TNBC. Therefore, we evaluated the addition of durvalumab, an anti-PD-L1 checkpoint inhibitor, to standard neoadjuvant chemotherapy in pts with primary TNBC. Methods: GeparNuevo randomized pts to durvalumab (D) 1.5 g i.v. or placebo every 4 weeks (wks). D/placebo monotherapy (0.75 g i.v.) was given for the first 2 wks (window phase), followed by a biopsy and D/placebo plus nab-paclitaxel (nP) 125 mg/m² weekly for 12 wks, followed by D/placebo plus epirubicin/cyclophosphamide (EC) q2 wks for 4 cycles. Randomization was stratified by stromal tumor infiltrating lymphocyte (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). Pts with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs status were included. Primary objective compares pCR (ypT0 ypN0) rates. Secondary objectives are pCR rates in stratified subpopulations and according to other pCR definitions; response rates; breast conservation rate; toxicity; compliance and survival. Sample size was planned assuming a pCR rate of 48% for placebo based on the GeparSepto results and 66% for D (as clinically meaningful benefit), requiring 158 pts to show superiority of D (2-sided α=0.2, 80% power). Assuming a 10% drop-out rate, randomization of 174 pts was planned. Results: A total of 174 pts were enrolled between June 2016 and September 2017 and all pts had completed treatment. Median age was 49.5 years [range 23.0-76.0]; 44.5% of pts had cT1, 49.7% cT2, 3.5% cT3, 2.3% cT4; 83.3% G3 and 31.4% cN-positive tumors assessed by sonography; sTILs categories were 37.9% low, 47.7% intermediate, and 14.4% high; median Ki67 was 49.0% [range 3.0%-96.0%]. A total of 86 SAEs and 65 immune related AEs of special interest (irAESI) were reported; 34.5% of pts had at least one SAE and 27.6% had at least one irAESI. Overall, 84 of 174 pts (48.3% 95%CI [40.7-56.0]) had a pCR. Conclusions: Combination of chemotherapy with durvalumab/placebo yielded a high pCR rate in TNBC. Treatment was feasible. Unblinded results will be presented at the meeting. Funding and drug was provided by AstraZeneca and Celgene. Clinical trial information: NCT02685059.
The role of HGF-MET pathway and CCDC66 cirRNA expression in EGFR resistance and epithelial-to-mesenchymal transition of lung adenocarcinoma cells
Authors: Nithila A. Joseph, Shiow-Her Chiou, Zoe Lung, Cheng-Lin Yang, Tze-Yi Lin, Hui-Wen Chang, H. Sunny Sun, Sachin Kumar Gupta, Laising Yen, Shulhn-Der Wang, Kuan-Chih Chow
Journal: Journal of Hematology & Oncology (2018)

Epithelial-to-mesenchymal transition (EMT) has, in recent years, emerged as an important tumor cell behavior associated with high metastatic potential and drug resistance. Interestingly, protein SUMOylation and hepatocyte growth factor could respectively reduce the effect of small molecule inhibitors on tyrosine kinase activity of mutated epidermal growth factor receptor of lung adenocarcinomas (LADC). The actual mechanism is yet to be resolved. Immunohistochemistry was used to stain proteins in LADC specimens. Protein expression was confirmed by Western blotting. In vitro, expression of proteins was determined by Western blotting and immunocytochemistry. Levels of circular RNA were determined by reverse transcription-polymerase chain reaction. SAE2 and cirRNA CCDC66 were highly expressed in LADC. Expression of SAE2 was mainly regulated by EGFR; however, expression of cirRNA CCDC66 was positively regulated by FAK and c-Met but negatively modulated by nAchR7α. EGFR-resistant H1975 also highly expressed cirRNA CCDC66. Immediate response of hypoxia increased phosphorylated c-Met, SAE2, and epithelial-to-mesenchymal transition. Either activation of FAK or silencing of nAchR7α increased cirRNA CCDC66. HGF/c-Met regulates expression of SAE2 and cirRNA CCDC66 to increase EMT and drug resistance of LADC cells. Multimodality drugs concurrently aiming at these targets would probably provide more benefits for cancer patients.
Association of a low-expression SLCO1B1 polymorphism with estrogen concentrations before and during aromatase inhibitor treatment for breast cancer.
Authors: Jacqueline M Dempsey, Kelley M. Kidwell, Christina L Gersch, Zeruesenay Desta, Anna Maria Storniolo, Vered Stearns, Todd C Skaar, Daniel F. Hayes, Norah Lynn Henry, James M. Rae, Daniel Louis Hertz
Journal: Journal of Clinical Oncology (2018)

543 Background: Three aromatase inhibitors (AI), the steroid exemestane, and the azoles anastrozole and letrozole, are effective in the treatment of estrogen receptor positive (ER+) breast cancer by preventing biosynthesis of estrogens including estradiol (E2), estrone (E1), and estrone-sulfate (E1S) in postmenopausal women. OATP1B1, encoded by SLCO1B1, transports E1S into the liver for desulfation to active E1. Women carrying the low-expression SLCO1B1 rs4149056 single nucleotide polymorphism (SNP) have higher E1-conjugate levels (Dudenkov Breast Cancer Res Treat 2017). We hypothesized that patients carrying this SNP would have increased E1S at baseline, and this E1S reserve could resupply E1 and E2 resulting in detectable estrogen levels during AI treatment. Methods: Five hundred postmenopausal women with ER+ breast cancer were randomized 1:1 to either exemestane 25 mg/day or letrozole 2.5 mg/day. Plasma estrogen concentrations were measured prior to and after 3 months of AI treatment using LC/MS/MS (LLOQ for E2 = 0.625 pg/mL, E1 = 1.56 pg/mL, E1S = 3.13 pg/mL). The additive genetic associations between rs4149056 and 1) log-transformed concentrations of E2, E1, and E1S at baseline and 2) detectable ( > LLOQ) concentrations of E2, E1, and E1S after 3 months of AI treatment, were tested using linear and logistic regression, respectively. Results: Patients carrying the low-expression rs4149056 (minor allele frequency = 0.18) SNP had 51% (per allele) higher baseline E1S concentrations (n = 438, 95% CI (29%-76%), p < 0.0001). After 3 months of AI treatment, 15% (58/378) of patients had detectable E1; carrying rs4149056 increased risk of maintaining detectable E1 by 84% (per allele) (odds ratio = 1.84, 95% CI (1.08-3.14), p = 0.025). Conclusions: Patients carrying a low-expression OATP1B1/SLCO1B1 SNP have higher pre-treatment E1S and greater risk of maintaining detectable E1 during AI treatment, possibly due to replenishment from E1S reserves. Further studies are needed to assess whether this common SNP is associated with increased risk of AI treatment failure.