tbuckley/cabot-search huggingface dataset:
Abstract #3945: Genetic variation in estrogen esterification pathway genes ACAA1, ACAA2, and LCAT and breast cancer risk
Authors: Sandra Deming, Yu-Tang Gao, Jirong Long, Xiao-Ou Shu, Alicia Beeghly-Fadiel, Qiuyin Cai, Wei Lu, Wei Zheng
Journal: Cancer Research (2009)

Estrogen esterification is catalyzed by acyl-CoA:acetyltransferase (ACAA1 and ACAA2) in tissue and lecithin/cholesterol acyltransferase (LCAT) in blood. Fat-rich mammary tissues can function as a reservoir for extremely lipophilic estrogen-fatty acid esters; these potent estrogen metabolites can then be released gradually with long-lasting hormone effects on the breast. Animal studies have consistently found that estrogen-fatty acid esters have much stronger effects than estrogens in promoting mammary epithelial cell proliferation. Thus, we hypothesized that variants in these genes may modify estrogen-fatty acid ester levels and thus modify breast cancer risk. We tested this hypothesis among participants in the Shanghai Breast Cancer Study (SBCS) utilizing a two-stage study design. A total of 39 polymorphisms were genotyped among 2,994 Chinese women participating in the Shanghai Breast Cancer Study (SBCS). Fourteen haplotype tagging SNPs (htSNPs) were genotyped among 2,131 Phase 1 participants. To increase the density of genetic markers and statistical power of our study, we included data for 25 additional SNPs genotyped among 2,167 Phase 1 and 827 Phase 2 participants from our recently completed genome-wide scan using Affymetrix 6.0. Polymorphisms were assessed for consistency with Hardy-Weinberg equilibrium, strength of association, significance level, and for possible interactions with known risk factors. Five ACAA1 SNPs were associated with a significant or borderline significant modification in breast cancer risk. Four out of the five polymorphisms produced consistent results in both phase I and phase II participants. In combined analysis, two polymorphisms in the 3\#8217;UTR and 3\#8217;flanking region were associated, in a dominant model, with a reduced risk of breast cancer (rs11129780, OR=0.65, 95% CI=0.43-1.00 and rs5875, OR=0.65, 95% CI=0.42-0.99). Two additional promoter polymorphisms, under dominant models, were associated with a borderline reduced risk of breast cancer (rs6767684, OR=0.64, 95% CI=0.40-1.00 and rs6853, OR=0.65, 95% CI=0.41-1.02). The fifth polymorphism (rs2128111), in intron 11, has not yet been genotyped in phase II participants to confirm phase I results (OR=0.62, 95% CI: 0.41-0.94). Together these data suggest a role for ACAA1 in breast cancer susceptibility.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3945.
Time-series of peripheral blood biomarkers as biomarkers for immunotherapy in advanced non-small cell lung cancer (aNSCLC) patients
Authors: A. Prelaj, S.E. Rebuzzi, P. Pizzutilo, M. Bilancia, M. Montrone, F. Pesola, V. Longo, G. Del Bene, V. Lapadula, F. Cassano, P. Petrillo, D. Bafunno, N. Varesano, V. Lamorgese, A. Mastranrdea, D. Ricci, A. Catino, D. Galetta
Journal: Annals of Oncology (2019)

Background: Immune-checkpoint inhibitors (ICIs) as second-line therapy showed an overall survival (OS) benefit, but only 18-20% of aNSCLC patients respond with a median progression-free survival (mPFS) of 2-4 months. The identification of biomarkers to select patients most likely to benefit from ICIs is still an unmet need in clinical practice. Methods: We conducted a retrospective monocentric analysis in 154 aNSCLC patients receiving single-agent nivolumab or pembrolizumab as second-line (68%) and >3rd line (32%) therapy. We recorded complete blood cell count at baseline (T0), before second (T1) and third cycle (T2), assessing neutrophil-lymphocyte ratio (NLR), derived-NLR (dNLR) and lymphocyte-monocyte ratio (LMR). Statistical analyses (univariate and multivariate analysis) were performed to evaluate the correlation between overall response rate (ORR), PFS and OS and the change from baseline of NLR, dNLR and LMR at second (T0-T1) and third cycle (T0-T2). We divided biomarker time-series into two groups of > 30% increase and <30% increase or decrease from baseline value. Results: The only biomarker statistically significantly associated with survival outcomes was NLR. An increase of > 30% of NLR from baseline to the second cycle (NLR T0-T1) was associated with a worse PFS (3.7 vs 4.9 months, HR 1.52 95% CI 1.02 – 2.24; p = 0.04). We also observed a statistically significant correlation between ORR and the >30% increase of LMR from baseline to the second (LMR T0-T1; p < 0.001) and the third cycle (LMR T0-T2; p = 0.001). Conclusions: According to the prognostic value of time-series of biomarkers at second and third cycle from baseline, patients who experienced an increase of > 30% of NLR after the first ICI cycle were associated with a worse PFS; also, an increase of > 30% of LMR after the first and second ICI administration lead to a better ORR. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: D. Galetta: Medical advisor: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
NSCLC stages IIa-IIIc: Tumor related IGRT yields better local control than kV-guidance to anatomic structures
Authors: F. Zehentmayr, J. Karner, K. Wurstbauer, R.E. Wass, G. Fastner, L. Rettenbacher, M. Studnicka, C. Pirich, F. Sedlmayer, P. Kopp
Journal: Annals of Oncology (2019)

Background: The prognosis for patients with LA-NSCLC (UICC stages IIa - IIIc) is still very limited with 5-year overall survival rates (OS) of approximately 20%. The meta-analysis published by Auperin et al. published in 2010 gives evidence that improved local control (LC) translates into better OS.Concurrent chemoradiotherapy – the standard of care treatment regimen – achieves LC around 65% at two years. The aim of the current single centre analysis was a comparison of LC after tumor related image guided radiotherapy (IGRT) versus kV-IGRT to central anatomic structures. Methods: 122 patients with LA-NSCLC treated between January 2010 and December 2014 were eligible. After induction chemotherapy patients were treated with dose-differentiated accelerated radiotherapy (DART-bid) with total doses ranging between 73.8 and 90.0 Gy. In group A (69 patients) image guidance was either performed by matching to the tumor (with cone beam CT or fiducials) whereas in group B (53 patients) two orthogonal kV-images were acquired for subsequent matching to central mediastinal structures. With respect to baseline characteristics patients in group B had a higher ECOG, more loss of weight and a higher probability of a centrally located tumor. KV-imaging was used more frequently in the years 2010 and 2011, with a shift towards tumor related IGRT thereafter. Irradiation techniques changed from 3D target splitting to IMRT by the end of 2013. Results: With a minimum follow-up of 3.5 years LC for all patients amounted to 73% and 59% at year 1 and 2 respectively. The difference between group A and B was insignificant (log-rank p-value = 0.080). Yet in the subgroup of 81 patients with peripheral lung cancer, tumor related IGRT led to a significantly better 1- and 2-year LC compared to kV-imaging: 84% and 72% versus 70% and 35% respectively (log-rank p-value: 0.010). Multivariate analysis (Cox regression, forward stepwise) showed that tumor related image guidance was the only significant prognosticator (p = 0.017, HR 0.279; 95%-CI 0.097 – 0.798) for LC. Conclusions: Tumor related image guidance is the IGRT method of choice for patients with peripherally located tumors in order to improve local control. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Atypical hyperplasia of bronchial epithelial cells induced by chronic exposure to PM 2.5 in mice
Authors: T.F. Hou, Q.H. Chen
Journal: Annals of Oncology (2019)

Background: Air pollution is still a major environmental problem affecting the health of the respiratory system. Studies have confirmed that air pollution is closely related to the occurrence of lung cancer. Air pollution (mainly PM2.5) has been classified as a carcinogen by the International Agency for Research on Cancer. Previous evidence of the relationship between PM2.5 and lung cancer mostly comes from countries with low PM2.5 exposure level. Exposure to fine particulate matter (PM2.5) may increase the risk of lung cancer, but the underlying mechanism is still unclear.There is no direct evidence that PM2.5 can directly induce lung cancer .The aim of our study was to investigate the atypical hyperplasia of bronchial epithelial cells induced by chronic exposure to PM2.5 in mice and the possible mechanism of PM2.5 in the pathogenesis of severe atypical hyperplasia. Methods: 30 BALB/c mice were treated with noninvasive tracheal instillation of PM2.5 suspension at different doses (2.5mg/kg, 5mg/kg, 10mg/kg) for 90 days (one time every 3 days), and the blank group and saline group were set as a control group. Tissue samples were taken at the end of the endotracheal infusion. Histopathological changes of lung tissue in mice and the expression of TTF-1, CK7 and Ki67 were detected by Hematoxylin-Eosin staining and immunohistochemical staining respectively. Results: Histopathological changes showed atypical hyperplasia of bronchiolo epithelia, part of glands papillary hyperplasia, some luminal glands crowded and disordered, glandular cavity back-to-back phenomenon, pulmonary septum widened, alveolar macrophages with engulfed particles and lymphocyte aggregation in bronchiole and alveolar, especially at high dose exposure group. Electron microscopic observation showed that normal structure of alveolar and bronchial epithelial cells disappeared and a large number of autophagic bodies were formed in the alveolar and bronchial epithelial cells of mice. The expression of TTF-1, CK7 and Ki67 in the lung tissue with 10mg/kg PM2.5 were positive. Conclusions: Chronic exposure to PM2.5 induced severe atypical hyperplasia of the bronchial epithelial cells in mice, it suggested that the model of severe atypical hyperplasia of lung in mice was established. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Abstract 14399: Endogenous Lats2 Mediates Ischemia/Reperfusion Injury by Promoting Foxo Degradation and Decreases in Antioxidants
Authors: Dan Shao, Peiyong Zhai, Junichi Sadoshima
Journal: Circulation (2012)

Lats2 is a tumor suppressor and a serine/threonine kinase, acting downstream of mammalian sterile 20 like kinase1 (Mst1), that stimulates apoptosis in cardiomyocytes (CMs). Lats2 is activated by ischemia/reperfusion (I/R) in the heart. In order to elucidate the role of Lats2 in mediating I/R injury, Lats2+/- mice were subjected to ischemia (20 min)/reperfusion (24 h). The size of myocardial infarction (MI)/area at risk was significantly smaller in Lats2+/- than in WT mice (27 and 59%, p<0.01). There were fewer TUNEL positive cells in Lats2+/- than in WT mice (0.05% and 0.15%, p<0.05). These results suggest that endogenous Lats2 mediates I/R injury and CM apoptosis. The level of oxidative DNA damage, as evaluated with 8-OHdG staining, was lower in Lats2+/- mice than in WT mice, suggesting that Lats2 mediates oxidative stress during I/R. In cultured CMs, transduction with adenovirus harboring short hairpin Lats2 (ad-sh-Lats2) significantly decreased H2O2-induced cell death, as evaluated with Cell Titer Blue...
Abstract 208: Out-of-Hospital Cardiac Arrests in High-Rise Buildings: Delays to Patient Care and Survival
Authors: Ian R Drennan, Ryan P Strum, Jason E Buick, Adam Byers, Steve Lin, Samantha R Hu, Sheldon Cheskes, Laurie J Morrison
Journal: Circulation (2014)

Background: In recent years, there has been a dramatic increase in the number of people living in high-rise buildings. This increase in vertical living presents unique barriers and response delays ...
The Prospective Epidemiologic Risk Factor (PERF I) Study: A serum biomarker reflecting collagen type I degradation as an early detection tool for cancer.
Authors: Cecilie Liv Bager, Stephanie Nina Kehlet, Nicholas Willumsen, Anne-Christine Bay-Jensen, Jesper Neergaard, Kathrine Dragsbaek, Diana Julie Leeming, Henrik Bo Hansen, Claus Christiansen, Morten Asser Karsdal
Journal: Journal of Clinical Oncology (2015)

11074 Background: Matrix metalloproteinase (MMP) mediated degradation of the extracellular matrix (ECM) play an important role in the development of cancer. One of the most abundant ECM proteins is type I collagen, which is commonly dysregulated and degraded in early stages of tumorigenesis. However, MMP mediated tissue destruction has not been quantified in larger prospective cancer outcome studies. The aim of this study was to investigate if a biomarker reflecting MMP-mediated degradation of type I collagen (C1M) could be used for early detection of cancer, in a large prospective study. Methods: From 1999-2001, 5,856 women aged 60-85 participated in the Prospective Epidemiologic Risk Factor (PERF I) stud, which addresses age-related diseases. Demographics and serum samples were collected at time of enrollment. Cancer diagnoses were collected from the Danish Cancer Registry ultimo 2014. Serum C1M levels were measured by ELISA and compared to time of diagnosis and to non-cancer diagnosed and non-diseased women (healthy). Women diagnosed with cancer prior to PERF1 enrollment were excluded from analysis. Data was analyzed using one way ANOVA on log transformed data and by Pearson’s correlation coefficient. Results: A total of 1,154 women were diagnosed with cancer following PERF I enrollment. C1M, at baseline, was significantly elevated in women diagnosed less than 6 months after blood draw compared to healthy women (p=0.016) and to women diagnosed more than 48 months (p=0.016) after blood draw (see table). Furthermore, C1M correlated with time to diagnosis up to 3 years after blood draw (r = -0.143, p=0.0146, n=289). Conclusions: The levels of MMP-degraded type I collagen (C1M) were significantly elevated in serum from women diagnosed up to 6 months after enrollment in PERF I and correlated with time to diagnosis up to 3 years after blood draw. Further investigations into C1M as an early detection tool for cancer could be highly relevant. Healthy (95% CL) n=3051 <6 months (95% CL) n=81 6-24 months (95% CL) n=121 24-48 months (95% CL) n=176 >48 months (95% CL) n=776 C1M (ng/ml) 50.1 (38.1-39.3) 63.6 (38.9-52.2) 51.0 ( 45.9-56.1) 53.0 ( 46.5-59.5) 49.4 (47.1-51.8)
SAT-279-Comparison of different and new types of non-invasive fibrosis tests in NAFLD
Authors: Paul Cales, Jerome Boursier, Maeva Guillaume, Valérie Moal, Cyrielle Delabaudière, Floraine Zuberbuhler, Marie-Angèle Robic, Lannes Adrien, METIVIER Sophie, Frédéric Oberti, Pierre Gourdy, Isabelle Fouchard Hubert, Jean Marie Peron, Bureau christophe
Journal: Journal of Hepatology (2019)
FRI-183-A phase 3 study comparing switching from tenofovir disoproxil fumarate to tenofovir alafenamide with continued TDF treatment in virologically-suppressed patients with chronic hepatitis B (CHB): week 48 efficacy and safety results
Authors: Pietro Lampertico, Maria Buti, Scott Fung, Sang Hoon Ahn, Wan-Long Chuang, Alnoor Ramji, Won Young Tak, Chiyi Chen, Edward Tam, Ho Bae, Xiaoli Ma, John F. Flaherty, Anuj Gaggar, Audrey Lau, Becket Feierbach, George Wu, Vithika Suri, Mani Subramanian, Huy N. Trinh, Seung Kew Yoon, Kosh Agarwal, Young-Suk Lim, Henry Chan
Journal: Journal of Hepatology (2019)
THU-234-High body-mass index is associated with increased risk of alanine aminotransferase elevation and hepatocellular carcinoma in chronic hepatitis B patients with sustained viral control
Authors: Jian Sun, Weiyin Lin, Kaifeng Wang, Rong Fan, Xieer Liang, Jie Peng, Yabing Guo, Jinjun Chen, Zhihong Liu, Xiaoyun Hu, Jinlin Hou
Journal: Journal of Hepatology (2019)
Comprehensive profiling of genomic and TCR repertoire in localized stage lung adenocarcinomas from a prospective cohort study
Authors: K. Chen, J. Bai, H. Zhao, F. Yang, C. Zhang, Y. Wang, L. Chang, Y. Guan, X. Yi, L. Feng, K. Zhang, S. Cheng, J. Wang
Journal: Annals of Oncology (2019)

Background: Recently, neoadjuvant targeted therapy and immunotherapy have presented a promising clinical effect for localized stage non-small cell lung cancer. However, the characteristics and relationship of genomic and immune profiling in surgical lung adenocarcinomas has been poorly delineated to date. Methods: We prospectively enrolled 100 consecutive patients with pulmonary nodule who intended to undergo curative lung resection during June 2017 to July 2018 (NCT03320044). We investigated the TCR repertoire using next-generation deep sequencing of the complementarity determining region 3 (CDR3) of the TCR β chain in the tissue and WBC samples. Target-capture deep sequencing of 1021 genes was used to detect genomic variations in both tissue and paired plasma samples. Results: EGFR (65.4%), TP53 (36.5%) and KRAS (11.5%) mutated most frequently. KRAS (84.6%) was enriched in mucinous adenocarcinoma. High invasive subtype and no ground-glass opacity status is more likely to be increasing tissue TMB (p = 0.0016, p = 0.0012), higher T-cell clonality (p = 0.05, p = 0.05), and more HLA-LOH event (p = 0.038, p = 0.035). A median of TNB was 2 neoantigens/Mb and showed positive relation with TMB (r = 0.97, p < 0.0001). EGFR-mutant co-occurring mutations were enriched TGF-beta, PI3K-Akt, hippo and Leukocyte trans-endothelial migration pathway (q < 0.05). Lower TCR clonality was shown in patients with EGFR mutation and co-occurring hippo or Leukocyte trans-endothelial migration pathway. Alterations in DNA damage response (DDR) pathways were observed in 15.8% patients, and these patients showed higher clonality (p = 0.03). 35.3%(24/68) ctDNA-positive were found in Stage I with a mean ctDNA abundance of 0.18% (ranged from 0.012 to 3.3%), which suggested the challenge of bTMB in biomarker study of early-stage LUAD. Analysis of TCR repertoire from available paired WBC showed no obvious characteristics. Conclusions: This is the first prospective study integrating the correlation of genomic alteration and T-cell receptor in localized surgical LUAD. Analysis of co-altered pathway of EGFR-mutant LUAD and immune microenviroment will provide a better understanding in choosing biomarkers and optimal benefit patients for neoadjuvant therapy. Clinical trial identification: NCT03320044. Legal entity responsible for the study: Jun Wang. Funding: National Natural Science Foundation of China (No.81602001). Disclosure: All authors have declared no conflicts of interest.
The Prehistory of the Mind. A Search for the Origins of Art, Religion and Science
Authors: Andy Conway Morris
Journal: BMJ (1999)

The nature of the human mind is a problem that has gripped many people's imagination since the earliest philosophers started to ponder our existence. It is a conundrum that has occupied the thinking careers of many of our finest minds. In an attempt to explain how the modern mind evolved Steven Mithen turns the spotlight of archaeological evidence on the problem.

Mithen has developed a theory that the hominid mind is concerned with social interaction, natural history (animal hunting …
THU-181-Safety and efficacy of glecaprevir/pibrentasvir for the treatment of HCV genotype 1-6: Results of the HCV-TARGET study
Authors: Richard Sterling, Stefan Zeuzem, Tania Welzel, Michael P. Manns, Rajender Reddy, Norah Terrault, Ziv Ben Ari, Irine Vodkin, Arifa Toor, Monika Vainorius, Lucy Akushevich, Michael W. Fried, David R. Nelson, Mark Sulkowski
Journal: Journal of Hepatology (2019)
FRI-248-Cost-effectiveness of elbasvir/grazoprevir (EBR/GZR) for treatment-naive (TN) patients with chronic hepatitis C virus (HCV) genotype 1b (GT1b) infection in Russia
Authors: Shelby Corman, Amy Puenpatom, Andrey Kulikov, Roza Yagudina
Journal: Journal of Hepatology (2019)
Association between radiation dose and outcomes with postoperative radiotherapy for N0-N1 non-small-cell-lung cancer.
Authors: Elyn H. Wang, Christopher D. Corso, Henry Soo-Min Park, Aileen B. Chen, Anthony W. Kim, Lynn D. Wilson, Roy H. Decker, James B. Yu
Journal: Journal of Clinical Oncology (2015)

7538 Background: To review trends in the use of postoperative radiation therapy (PORT) in the modern era for N0-N1 margin-negative non-small cell lung cancer (NSCLC) following surgical resection and evaluate the association between PORT dose and overall-survival (OS). Methods: We performed a retrospective study of non-metastatic stage II and III N0-N1 margin-negative NSCLC surgically-treated patients within the National Cancer Data Base from 2003-2011. Cox proportional hazards regression was performed for multivariable analyses of OS and PORT dose. Radiation modalities included non-conformal beam radiation, 3D-conformal radiation (3D-CRT), and intensity-modulated radiation therapy (IMRT). Results: We identified 2,167 (6.7%) and 30,269 (93.3%) patients with surgically-resected stage II or III N0-N1 margin-negative NSCLC who were treated with and without PORT, respectively. The proportion of patients treated with PORT (dose range: 45-74 Gy) decreased from 8.9% in 2003-2006 to 4.1% in 2010-2011. Among patients receiving PORT, the use of high-dose (60-74 Gy) PORT rose throughout the study period, starting at 34.8% in 2003-2006 and rising to 49.3% in 2010-2011. Overall, patients who received PORT had worse survival (HR = 1.30; 95% CI 1.20-1.40) compared to those not receiving PORT. This association was unchanged when limited to patients receiving modern treatment with 3-CRT or IMRT (HR = 1.35; 95% CI: 1.10-1.65]. Examining the association between dose and overall survival revealed that patients treated at doses < 50 Gy or ≥ 54 Gy had worse OS compared to no PORT while a trend showing decreased survival was observed among those receiving 50-53.9 Gy (HR = 1.14; 95% CI: 0.99-1.30). Limiting the analysis to patients receiving 3D-CRT or IMRT showed worse survival for patients receiving ≥ 60 Gy (HR = 1.43; 95% CI: 1.04-1.95) and similar survival between no PORT and the remaining dose groups. Conclusions: The use of PORT for N0-N1 margin-negative NSCLC decreased from 2003-2011. We found no evidence of benefit from PORT for resected N0-N1 margin-negative NSCLC, regardless of dose or technique. PORT should be approached with caution in this group of patients, regardless of radiotherapy technique.