tbuckley/cabot-search huggingface dataset:
Abstract 19900: Impact of Baseline Fitness in Young Adulthood and Age Related Fitness Changes on Cardiac Structure and Function in Middle Age: The CARDIA Study
Authors: Ambarish Pandey, Norrina Allen, Colby Ayers, Jared Reis, Henrique Moreira, Steve Sidney, David R Jacobs, Lisa Chow, Jamal Rana, James De Lemos, Mercedes Carnethon, Jarett D Berry
Journal: Circulation (2015)

Introduction: Low cardiorespiratory fitness (CRF) in mid-life is a significant risk factor for heart failure (HF) at a later age. However, the contribution of CRF in early adulthood to HF risk is not well understood. Because of the established association of subclinical abnormalities in left ventricular (LV) structure and function with HF risk, we studied the association between early life CRF levels and measures of LV structure and function in middle-age. Methods: We included the Coronary Artery Risk Development in Young Adults (CARDIA) study participants who had a maximal exercise treadmill test (modified Balke protocol) at year 0 and an echocardiogram at year 25. Percent change in CRF [ΔCRF (%)] was calculated in the subgroup of participants who had a repeat CRF test at year 20. Associations of baseline CRF and ΔCRF (%) with measures of LV structure [end-diastolic volume (LVEDV), relative wall thickness (RWT)] and function [global longitudinal strain (GLS), Septal &amp; Lateral E/e`] were assessed using multivariable linear regression. Results: We included 3,433 participants (baseline age: 25 years, 55% women) in the study. After adjustment for baseline characterstics, cumulative cardiovascular risk factor burden, and baseline and follow up body mass index (BMI), lower baseline CRF was associated with higher septal E/e`(β = -0.05, p = 0.01), higher lateral E/e` (β = -0.06, p = 0.008), and lower LVEDV (β = 0.07, p = 0.004). In contrast, CRF was not associated with GLS (p = 0.22) and RWT (p=0.27). Among participants with repeat CRF test (n =2,544), ΔCRF (%) was associated with LVEDV but not with measures of LV function. The association of baseline CRF with E/e` did not attenuate after additional adjustment for ΔCRF (%) (Table). Conclusions: Lower CRF in young adulthood is associated with subclinical abnormalities in diastolic function in middle age. These findings suggest that low CRF may identify young adults at increased risk of HF with preserved ejection fraction in later life.
DNA Repair Genes May Influence Cognitive Outcomes in Adult Patients with Hematologic Malignancies (HM) Treated with Blood or Marrow Transplantation (BMT)
Authors: Noha Sharafeldin, Alysia Bosworth, Yanjun Chen, Purnima Singh, Sunita Patel, Xuexia Wang, Emily Morse, Molly Mather, Can-Lan Sun, Liton F. Francisco, Stephen J Forman, F. Lennie Wong, Smita Bhatia
Journal: Blood (2018)
Novel mutations in mevalonate kinase cause disseminated superficial actinic porokeratosis
Authors: T. Zhu, D. Tian, L. Zhang, X. Xu, K. Xia, Z. Hu, Z. Xiong, J. Tan
Journal: British Journal of Dermatology (2018)

Disseminated superficial actinic porokeratosis (DSAP) is a rare autosomal dominant disease. In our previous research, we found that a linkage region of DSAP in a large family is located at 12q23·2-q24·1. Subsequently, the mevalonate kinase gene (MVK) was shown to be pathogenic in DSAP.To elucidate the mechanism by which MVK mutations lead to keratinocyte apoptosis and DSAP, and to report a new missense mutation, c.566 C>T (p.A189V), in MVK in a Chinese DSAP pedigree.The half-life of wild-type (WT) MVK protein and mutants was assessed using cycloheximide treatment of cells. Dimerization of MVK was analysed by coimmunoprecipitation and glutathione S transferase pull-down assay. MVK kinase activity, production of cell cholesterol, mitochondrial complex activity and apoptosis were detected, using the corresponding commercial kits, in cells overexpressing MVK WT and mutants.Mechanically, we demonstrated that both the pathogenic p.A189V mutant and a sporadic mutation p.H312R (c.935A>G), which we reported previously, have rapid degradation, decreased kinase activity and reduced production of cell cholesterol. Also, we found the p.H312R mutation confers on the MVK protein an inability to dimerize. Further, we demonstrated that the mutants are impaired in mitochondrial function and lead to increased apoptosis.Our results provide an important basis for elucidating the mechanism by which MVK missense mutations contribute to DSAP.
Prognostic factors in stage II colon cancer after radical resection.
Authors: Nieves Martinez Lago, Maria Vieito, Rafael Varela Ponte, Carmela Rodriguez, Sonia Candamio, Francisca Vazquez, Yolanda Vidal, Rafael Lopez
Journal: Journal of Clinical Oncology (2014)

e14604 Background: Stage II colon cancer has a 5 year survival over 80% that is only marginally improved by the use of adjuvant treatments, so the decision of starting an adjuvant treatment, especially in older adults, has to be individualized. Methods: 205 patients were included between January 2004 and December 2008. We assessed the clinical and pathological risk factors commonly used to indicate adjuvant treatment and their impact on survival, cancer specific DFS and DFS using a multivariate COX regression. We studied the adequacy of adjuvant treatment comparing the prevalence of risk factors between patients who received adjuvant chemotherapy and patient who didn’t receive it. Results: Baseline characteristics of the patients are listed in Table. There was a positive association between a high preoperatory CEA, an insufficient nº of excised lymph nodes and the presence of lymphovascular invasion and a higher risk of relapse. The median DFS, cancer specific DFS and OS was also worse. Patients who didn’t receive adjuvant treatment had a worse performance score, and a higher age. Patients who received adjuvant treatment had higher rate of risk factor. No differences in the median number of excised lymph nodes were found between these two groups but patients with a insufficient number of lymph nodes resected also received more adjuvant treatment. The 5 year survival was 77% (follow up 76 months). 30 deaths from other causes, 7 new colorectal cancers, 11 tumors of other origin and 42 recurrences were observed. Median overall survival was105 months, disease free survival 77 months and cancer specific DFS of 94 months. Patients who received adjuvant chemotherapy had a better OS, DFS and (74, vs 64 months), and cancer specific DFS(median 98 versus 83 months). In patients over 75 the OS, DFS, and cancer specific DFS was the same in adjuvant treatment and non adjuvant treatment group. Even with a higher percentage of higher risk patients the 5year survival for patient under 75 was better for patients who received adjuvant treatment. Conclusions: Although the use of molecular biomarkers (from the determination of microsatellite instability to molecular signatures) is increasing, they must be taken into consideration alongside the traditional pathological risk factors.
Comparison of prostate health index and PCA3 values in patients with clinical or biologic suspicion of prostate cancer.
Authors: Pierre-Jean Lamy, Benoit Leizour, Florence Castan, Frederic Montels, Anne-Claire Laberenne, Sylvie Roques, Didier Ayuso, Vincent Abd El Fattah, Samer Abdel-Hamid, Antoine Faix, Bruno Segui, David Azria, Xavier Rebillard
Journal: Journal of Clinical Oncology (2014)

5055 Background: The Prostate Health Index (PHI) and the Prostate CAncer gene 3 (PCA3) have shown to have predictive values for early detection of PCa. The aim of this prospective observational study was to compare the values of the both markers in patients consulting for a suspicion of PCa Methods: Samples of 573 consecutive patients presenting a suspicion of PCa were included in a biobank between 2010 and 2012. Total PSA (tPSA),Free PSA (fPSA) and -2proPSA (Beckman Coulter) were performed on serum to calculate the PHI ([-2proPSA/fPSA] X [tPSA]1/2). Urine samples were collected after digital rectal examination (DRE) by an urologist in order to calculate the PCA3 score ([PCA3 mRNA]/[PSA mRNA] X 1,000). Prostate biopsies were performed for 235 men according usual clinical practice. Correlation between PSA, PHI, PCA3 score and clinico-pathological factors were studied with the Kruskall-Wallis tests. ROC–derived area under the curve (AUC) was used to quantify the predictive accuracy of the tests predicting pathologic findings in biopsies specimens. Results: PCA3 score was only correlated with age (Spearman’s rho = 0.21; p=0.001) and PHI was only correlated with tPSA (Spearman’s rho = 0.35; p<0.0001). PHI and PCA3 were slightly correlated (Spearman’s rho = 0.16; p=0.01). Comparing biomarkers values in patients with positive (P+; n=60, 25.5%) and negative biopsy (P-; n=175, 74.5%), PHI and PCA 3 were statistically different according to patients status. Conclusions: In this large series of patients consulting for a suspicion of PCa, tPSA is hardly more effective than a coin toss to predict PCa. PHI, an independent biological marker, presented a higher predictive value for positive biopsy prediction than PCA3, a marker slightly correlated with age. Negative biopsies Positive biopsies p AUC AUC IC 235 men 74.5% 25.5% tPSA (median) 6.7 [0.6-36.6] 6.8 [2.5-43.0] p=0.19 0.56 95% [0.47; 0.64] fPSA (median) 1 [0.1-7.6] 0.8 [0.3-4.8] p=0.02 0.60 95% [0.52; 0.69] PHI (median) 37.0 [11.4-117.1] 49.3 [16.8-114.5] p<0.001 0.71 95% [0.63; 0.79] PCA3 (median) 30 [2-371] 47 [10-333] p<0.001 0.65 95% [0.57; 0.72]
Predictive analysis of microenvironment impact on clinical outcomes to drug agents using simulation of myeloproliferative neoplasms.
Authors: Peter P. Sayeski, Shireen Vali, Ansu Kumar, Neeraj Singh, Anuj Tyagi, Taher Abbasi, Susumu Kobayashi
Journal: Journal of Clinical Oncology (2014)

7110 Background: The Jak2-V617F mutation is frequently found in MPN. The bone marrow micro-environment of MPN patients constitutes high levels of TNFα, IFNγ and IL-6. Since resistance to drug agents is of great clinical relevance, we teased the impact of the individual cytokines on drug efficacy. Methods: To predict the response to the JAK2 inhibitor class of agents, we (1) employed predictive simulation to model JAK2 bearing cell lines (2) identified novel synergistic combinations of Bcl-2 and JAK2 inhibitors against this JAK2 driven pathogenesis, (3) simulated the impact of TNFα and IFNγ on growth and proliferation and (4) validated the outcomes on Jak2 mutant cells. We used a previously characterized JAK2 small molecule inhibitor, G6, which exhibits significant efficacy in Jak2-V617F-mediated MPN and ABT737 was the selected Bcl-2 agent. The predictive simulation approach from Cellworks provides a representation of disease physiology incorporating signaling and metabolic networks with an integrated phenotype view. We modeled the JAK2-V617F expressing HEL and SET-2 cell lines along with G6 and ABT737. We then screened prospectively these agents, both individually and in combination, and with and without the microenvironment inflammatory cytokines. Results: The simulation identified a dose response based synergistic impact of the combination of G6 and ABT737 on cell proliferation and viability.TNFα increased the sensitivity of the single drug agents and their combinations. IFNγ sensitized the drug action further beyond a certain dose threshold. IL-6 did not show any impact on the cells due to lack of IL-6 signaling within these cells. Simulation studies though have predicted IL-6 induced resistance to these drug agents and possibly cancelling out the positive impact of TNFα and IFNγ clinically. Conclusions: Thus, this study validates the impact of the micro-environment on drug response and the use of simulation based technology to predict patient responses to drug agents. By accurately predicting responses of a patient’s cells to targeted agents a priori, the in silico simulation model provides an innovative approach to precision medicine for Jak2-mediated MPN.
<i>Hscb</i>, a Mitochondrial Iron-Sulfur Cluster Assembly Co-Chaperone, Is a Novel Candidate Gene for Congenital Sideroblastic Anemia
Authors: Andrew Crispin, Paul Schmidt, Dean Campagna, Chang Cao, Daniel Lichtenstein, Anoop Sendamarai, Chaoshe Guo, Caiyong Chen, Gordon J Hildick-Smith, Nicolas C Huston, Jeanne Boudreaux, Sylvia S. Bottomley, Matthew M Heeney, Barry H. Paw, Mark D. Fleming, Sarah Ducamp
Journal: Blood (2017)
Downregulation of Mir-142 Promotes Leukemia Growth in Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL): A Possible Novel Therapeutic Target?
Authors: Huafeng Wang, Bin Zhang, Wei-Le Wang, Dandan Zhao, Ling Li, Herman Wu, Le Xuan Truong Nguyen, Weixu Meng, Tinisha McDonald, Flavia Pichiorri, Ya-Huei Kuo, Jianjun Chen, Nadia Carlesso, Ibrahim Aldoss, Vinod A. Pullarkat, Monzr Al Malki, Anthony S. Stein, Mark Boldin, Jie Jin, Guido Marcucci
Journal: Blood (2018)
Association of BCL2L12 overexpression with prolonged disease-free survival in breast cancer.
Authors: Alexandros Tzovaras, Athina Kladi, Ioannis Misitzis, Kleita Michaelidou, Sofia Stamatopoulou, Dimitra Stefanou, Marina Gkiaouraki, Maria Skondra, Alexandros Ardavanis, Andreas Scorilas
Journal: Journal of Clinical Oncology (2014)

e22202 Background: Deregulated apoptosis is a hallmark of breast cancer and plays an important role in the pathogenesis and progression of this malignancy. BCL2 gene family members are major regulators of programmed cell death. Increasing evidence suggest their aberrant expression in human breast cancer which in many cases is associated with disease prognosis and treatment response. BCL2L12 is a member of BCL2 family and recently and the expression levels of this gene have been studied in various cancer types. The results are auspicious regarding the potential use of BCL2L12 as a tumor biomarker. The objective of this study was the quantification of BCL2L12 mRNA expression in breast cancer tissues, and the determination of its clinical utility as a potential biomarker for this malignancy. Methods: A total of 182 samples (111 malignant and 71 matched normal adjacent tissues) were included. Total RNA was extracted from pulverized breast tissues and 2 μg of total RNA were reverse transcribed into first-strand cDNA. Gene expression study was conducted using a highly sensitive quantitative real-time polymerase chain reaction (qRT-PCR) method. Relative quantification analysis was performed using the comparative CT (2-ddCT) method. Results: Wilcoxon Test revealed a significant downregulation of BCL2L12 mRNA levels in breast cancer samples compared to non-cancerous counterparts (P=0.012). ROC curve analysis uncover a statistically significant power in discriminating cancerous from non-cancerous breast tissues (AUC=0.647, P=0.001). Besides, a statistically powerful relationship between BCL2L12 overexpression and small tumor size (P=0.010), as well as early TNM stages (P=0.007) was revealed by Jonckheere-Terpstra test and Mann-Whitney test respectively. Finally, survival analysis indicated that BCL2L12 overexpression is associated with longer disease free survival (DFS) (P=0.030), whereas according to multivariate analysis BCL2L12mRNA expression appears to be an independent prognostic marker for DFS in breast cancer (P=0.024). Conclusions: Regarding breast cancer, BCL2L12 was found to be an independent favorable marker, suggesting the possible application of BCL2L12 gene expression as a novel tumor marker.
Clinical dosimetry analysis of radiation-induced temporal lobe necrosis in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy.
Authors: Jin Yi Lang, Weidong Wang, Xigang Fan, Peng Xu, Yecai Huang, Yanmei Min, Zixuan Fan, Yangkun Luo
Journal: Journal of Clinical Oncology (2014)

6043 Background: Radiation induced temporal lobe necrosis(RITLN) is one of the late complications in nasopharyngeal carcinoma patients undergoing radiotherapy.This retrospective study aims to explore the clinical dosimetry characteristcs of radiation induced temporal lobe necrosis in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy. Methods: This study enrolled the patients in Sichuan cancer hospital from January,2004 to November, 2008; diagnosised as nasopharyngeal carcinoma and treated primarily with intensity-modulated radiotherapy (IMRT). Magnetic resonance imaging ( MRI) was taken for all these patients in follow-up, RITLN was diagnosised based on the T1-weight with contrast. Dosimetry parameters of bilateral temporal lobe D1cc(the 1 cubic centimeter temporal lobe received the max dose), D2cc, D3cc, D5cc, D10cc, D15cc, D20cc,Dmean, Dmax were analysised . Results: MRI were assessed in a total of 148 patients primarily diagnosised with nasopharyngeal carcinoma treated by IMRT, 59 cases of RITLN were found. Univariate analysis showed that all the parameters demonstrated statistically significant results (p<0.05). Multivariate analysis showed that D1cc (P= 0.026 <0.05) and Dmax (P=0.000 <0.05) had statistically significant. The 5 years incidence of RITLN for D1cc≤61Gy and Dmax≤70Gy is less than 5%, the RITLN incidence has 3.3% increasing per Gy of D1cc beyond 60Gy and 4.6% increasing per Gy of Dmax over 69Gy. Conclusions: The incidence of radiation induced temporal lobe necrosis has closely relationship between the dose of temporal lobe and corresponding volume, temporal lobe D1cc less than 61Gy and Dmax less than 70Gy may be the restrict dose of temporal lobe for IMRT patients.
Postoperative complications in nipple-sparing mastectomy.
Authors: Erin M Garvey, Jon A Nelson, Amylou C. Dueck, Richard J. Gray, Nabil Wasif, Barbara A. Pockaj
Journal: Journal of Clinical Oncology (2014)

1095 Background: Nipple-sparing mastectomy (NSM) has been accepted as a risk reducing procedure and for treatment of select breast cancers. The purpose of this study was to detail the types of postoperative complications experienced at a single center. Methods: A prospective breast cancer database was reviewed from June 2006 to November 2013. Patients who underwent NSM were identified and analyzed for postoperative complications. Results: Over the 7.5 year study period, a total of 1,630 breast cancer procedures were performed for 1,540 patients. 701 procedures were mastectomies, 392 of which included reconstruction. 160/392 procedures (41%) were attempted NSM and 147/160 (92%) were successful NSM. Most NSMs (87.8%) were followed by implant based reconstruction. The majority of patients were Caucasian (83.7%), average age was 51 years, average BMI was 25.5 and 50.3% were pre-menopausal. 5.4% were current and 30.6% were former smokers. 2.7% were prediabetic and 3.4% were diabetic. The average tumor size was 2 cm and the majority of patients either had DCIS (23.8%) or stage I cancer (40.8%). 29.9% underwent hormonal treatment, 17.7% cytotoxic treatment, 6.8% neoadjuvant treatment and 4.8% radiation treatment. 58.5% of procedures were associated with postoperative complications including a 1.4% rate of autogenous flap loss, 6.1% wound breakdown, 6.8% hematoma, 6.8% flap ischemia, 11.6% infection rate resulting in 12.4% expander/implant loss, 21.8% seroma and 33.3% nipple related complications. Repeat operative intervention was required for 7/9 wound breakdowns, 9/10 flap ischemia cases and 13/49 nipple related complications. No patient, disease or treatment characteristics were statistically associated with an increased risk of postoperative complications on univariate analysis; however, older age (p=0.09) and current or former tobacco use (p=0.08) trended toward an increase in postoperative complications. Conclusions: Nipple-related complications were the most common postoperative complications seen in NSM. Increased age and current or former tobacco use trended toward an increase in postoperative complications.
Joint cell-line and patient modeling of drug sensitivity reveals novel molecular biomarkers for targeted and conventional chemotherapy.
Authors: Charles Ferte, Elias Chaibub Neto, Frederic Commo, Olga Nikolova, in Sock Jang, Mehmet Gonen, Ludovic Lacroix, Valerie Koubi-Pick, Eric Angevin, Benjamin Besse, Michel Ducreux, Antoine Hollebecque, Christophe Massard, Adam Margolin, Stephen Henry Friend, Fabrice Andre, Jean-Charles Soria, Justin Guinney
Journal: Journal of Clinical Oncology (2014)

2565 Background: The unresponsiveness to anticancer drugs in patients outlines the need to identify novel and robust biomarkers of response to therapy. The recent release of large molecular cell line datasets labeled for drug sensitivity enables the development of such predictors. Cell line based models poorly reflect the extent of molecular heterogeneity existing at the patient level. We aimed to overcome this limitation by combining cell line with patient data to uncover novel molecular traits associated with drug response at the patient level. Methods: We used both patients and cell lines data from the following publicly available datasets: CCLE (1057 cell lines, 24 drugs), Sanger (790 cell lines, 130 drugs) and TCGA (patients: breast cancer, colorectal cancer, lung squamous carcinoma, lung adenocarcinoma, ovarian cancer, endometrial cancer and melanoma). A two-step Elastic Net approach was used to model the drug sensitivity using gene-expression, copy-number alteration, and somatic mutation data. As validation, we used the dataset of 420 cancer patients prospectively enrolled in the ongoing MOSCATO molecular screening program (Gustave Roussy, France). Results: As positive control, we were able to recover all of the recognized landmark biomarkers across drug - tissue combination (e.g. Erlotinib: EGFR mutation in lung adenocarcinoma; Lapatinib: ERBB2 amplification in breast cancer; Vemurafenib: BRAF mutation in melanoma, etc). We uncovered novel molecular traits (copy, number mutations) associated (FDR<20%) with drug response (e.g. erlotinib: CDKN2A deletion in lung adenocarcinoma, lapatinib: CDH1 deletion in breast cancer, etc.). The validation of our framework in the MOSCATO patients’ cohort will be presented. Conclusions: We provide a comprehensive annotation of mutations and copy-number events predicted to be associated with sensitivity and resistance in 142 anti-cancer drugs and across 7 tumor types. This approach is likely to exert a major impact on precision medicine programs in oncology.