tbuckley/cabot-search huggingface dataset:
Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14–mutant Non–small Cell Lung Cancer
Authors: Ken Suzawa, Michael Offin, Daniel Lu, Christopher Kurzatkowski, Morana Vojnic, Roger S. Smith, Joshua K. Sabari, Huichun Tai, Marissa Mattar, Inna Khodos, Elisa de Stanchina, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, William W. Lockwood, Alexander Drilon, Marc Ladanyi, Romel Somwar
Journal: Clinical Cancer Research (2018)

Abstract Purpose: MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear. Experimental Design: We examined clinical and genomic data from 113 patients with lung cancer with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models. Results: Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. Conclusions: KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.
Genetic Predisposition vs Individual-Specific Processes in the Association Between Psychotic-like Experiences and Cannabis Use
Authors: Nicole R. Karcher, Deanna M. Barch, Catherine H. Demers, David A. A. Baranger, Andrew C. Heath, Michael T. Lynskey, Arpana Agrawal
Journal: JAMA Psychiatry (2018)

Previous research indicates that cannabis use is associated with psychotic-like experiences (PLEs). However, it is unclear whether this association results from predispositional (ie, shared genetic) factors or individual-specific factors (eg, causal processes, such as cannabis use leading to PLEs).To estimate genetic and environmental correlations between cannabis use and PLEs, and to examine PLEs in twin and nontwin sibling pairs discordant for exposure to cannabis use to disentangle predispositional from individual-specific effects.In this cross-sectional analysis, diagnostic interviews and self-reported data were collected from 2 separate population-based samples of twin and nontwin sibling pairs. Data from the Human Connectome Project were collected between August 10, 2012, and September 29, 2015, and data from the Australian Twin Registry Cohort 3 (ATR3) were collected between August 1, 2005, and August 31, 2010. Data were analyzed between August 17, 2017, and July 6, 2018. The study included data from 1188 Human Connectome Project participants and 3486 ATR3 participants, totaling 4674 participants.Three cannabis-involvement variables were examined: frequent use (ie, ≥100 times), a DSM-IV lifetime cannabis use disorder diagnosis, and current cannabis use. Genetic and environmental correlations between cannabis involvement and PLEs were estimated. Generalized linear mixed models examined PLE differences in twin and nontwin sibling pairs discordant for cannabis use.Among the 4674 participants, the mean (SD) age was 30.5 (3.2) years, and 2923 (62.5%) were female. Data on race/ethnicity were not included as a covariate owing to lack of variability within the ATR3 sample; among the 1188 participants in the Human Connectome Project, 875 (73.7%) were white. Psychotic-like experiences were associated with frequent cannabis use (β = 0.11; 95% CI, 0.08-0.14), cannabis use disorder (β = 0.13; 95% CI, 0.09-0.16), and current cannabis use (β = 0.07; 95% CI, 0.04-0.10) even after adjustment for covariates. Correlated genetic factors explained between 69.2% and 84.1% of this observed association. Within discordant pairs of twins/siblings (Npairs, 308-324), Psychotic-like experiences were more common in cannabis-exposed individuals compared with their relative who used cannabis to a lesser degree (β ≥ .23, P < .05; eg, frequent and infrequent cannabis-using relatives significantly differed, z = -5.41; P < .001).Despite the strong contribution of shared genetic factors, frequent and problem cannabis use also appears to be associated with PLEs via person-specific pathways. This study's findings suggest that policy discussions surrounding legalization should consider the influence of escalations in cannabis use on traitlike indices of vulnerability, such as PLEs, which could contribute to pervasive psychological and interpersonal burden.
Sall2 transcription factor: a novel regulator of G1-S cyclins
Authors: Viviana E. Hermosilla, David E. Escobar, Matias I. Hepp, Elizabeth N. Riffo, Ginessa Salgado, Violeta Morin, Mario A. Galindo, Ariel F. Castro, Roxana Pincheira
Journal: Cancer Research (2018)
Towards optimal pancreatic cyst fluid management: the need for standardisation
Authors: Giacomo Puppa, Yann Christinat, Thomas Alexander McKee
Journal: Gut (2018)

We read with interest the paper by Singhi et al .1 The authors prospectively assessed using targeted next-generation sequencing (NGS) 626 pancreatic cyst fluid (PCF) samples from 595 patients. They found that compared with Sanger sequencing, cytology and CEA, preoperative NGS for KRAS/GNAS mutations is highly sensitive for intraductal papillary mucinous neoplasms (IPMNs) and specific for mucinous pancreatic cysts (PCs).

Moreover, alterations in TP53/PIK3/PTEN are significantly associated with advanced neoplasia facilitating decision-making for the management of these …
Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging
Authors: Chang-Jun Li, Ye Xiao, Mi Yang, Tian Su, Xi Sun, Qi Guo, Yan Huang, Xiang-Hang Luo
Journal: Journal of Clinical Investigation (2018)

Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-related lineage switch between osteogenic and adipogenic fates, which contributes to bone loss and adiposity. Here we identified a long noncoding RNA, Bmncr, which regulated the fate of BMSCs during aging. Mice depleted of Bmncr (Bmncr-KO) showed decreased bone mass and increased bone marrow adiposity, whereas transgenic overexpression of Bmncr (Bmncr-Tg) alleviated bone loss and bone marrow fat accumulation. Bmncr regulated the osteogenic niche of BMSCs by maintaining extracellular matrix protein fibromodulin (FMOD) and activation of the BMP2 pathway. Bmncr affected local 3D chromatin structure and transcription of Fmod. The absence of Fmod modified the bone phenotype of Bmncr-Tg mice. Further analysis revealed that Bmncr would serve as a scaffold to facilitate the interaction of TAZ and ABL, and thus facilitate the assembly of the TAZ and RUNX2/PPARG transcriptional complex, promoting osteogenesis and inhibiting adipogenesis. Adeno-associated viral-mediated overexpression of Taz in osteoprogenitors alleviated bone loss and marrow fat accumulation in Bmncr-KO mice. Furthermore, restoring BMNCR levels in human BMSCs reversed the age-related switch between osteoblast and adipocyte differentiation. Our findings indicate that Bmncr is a key regulator of the age-related osteogenic niche alteration and cell fate switch of BMSCs.
Letter by Murakami et al Regarding Article, “Risk of Dementia in Adults With Congenital Heart Disease: Population-Based Cohort Study”
Authors: Tomoaki Murakami, Masahiro Shiraishi, Taro Murakami
Journal: Circulation (2018)

We read with great interest the article by Bagge et al 1 that described an increased risk of dementia in adults with congenital heart disease.The article was highly informative; however, we would like to discuss the underlying mechanisms of the condition.In the article, the authors enumerated the possible mechanisms of the dementia: neurological malformations, the effects of the abnormal physiology, complex medical and surgical management strategies, chromosomal abnormalities, and acquired morbidities.In addition to them, we would like to nominate arteriosclerosis.Arteriosclerosis is degenerative change of the aorta in the aging process. 2 The progression of arteriosclerosis results in myocardial ischemia, end-stage heart failure, end-stage renal disease, and dementia. 3The augmentation index, which represents the degree of pressure wave reflection, is one of the biomarkers of the arteriosclerosis.We previously reported the elevation of the augmentation index in adults with congenital heart disease. 4Therefore, arteriosclerosis could be one of the causes of the dementia in adult patients with congenital heart disease.Because central blood pressure has been shown to relate more closely to dementia than brachial blood pressure, 5 we would like to know the information about the central hemodynamics (central blood pressure, augmentation index, etc) in the Bagge et al study.
Abstract P114: Metabolic Syndrome is Associated with Abnormal Ankle Brachial Index: Estimates From the National Health and Nutrition Examination Survey (1999-2004)
Authors: Sarah Singh, Courtney Pilkerton, Stephanie Frisbee
Journal: Circulation (2016)

Introduction: Metabolic syndrome (MetS) and low ankle-brachial index (ABI) share interrelated cardiovascular risk factors and are thus both strong indicators of an atherosclerotic process. However, few clinicians consider metabolic syndrome as a risk factor for abnormally low ABI and subsequent peripheral arterial disease. Therefore, it is necessary to highlight the relationship between abnormal ABI and MetS and the role of cardiovascular risk factors on this relationship. Hypothesis: We hypothesize that persons with MetS compared to those without, are more likely to experience abnormally low ABI even after accounting for additional cardiovascular risk factors not defined in the MetS. Methods: The eligible population consisted of 7,458 men and women aged 40 years and older, with and without cardiovascular disease (CVD) participating in The National Health and Nutrition Examination Survey from 1999-2004. Subjects were evaluated, according to the American Heart Association definitions, for abnormally low ABI &lt; 1.0 (which included borderline low and low ABI) and metabolic syndrome with ≥ 3 of the following 5 components; central obesity, hypertriglyceridemia, low HDL cholesterol, hyperglycemia and hypertension. Ordinal logistic regression models were used to identify relationships between abnormal ABI and MetS, with adjustments for additional cardiovascular risk factors in multivariate models. Results: Participants with metabolic syndrome, as compared to those without, were 1.51 (95% CI, 1.01-2.26) times more likely to experience abnormally lower values of ABI after adjusting for gender, race, education, smoking and CRP. The relationship between abnormal ABI and MetS was modified by age (p value 0.01) but not by gender (p value 0.10) or race (p value 0.09). Additionally, odds of a lower ABI was highest for those with 4-5 components of MetS compared to those with 0-2 components (OR, 2.22; 95% CI, 1.44 to 3.43). Examining individual MetS components in fully adjusted models revealed that hypertriglyceridemia (OR, 1.69; 95% CI, 1.16 to 2.46) and low HDL cholesterol (OR, 1.81; 95% CI, 1.15 to 2.87) were associated with higher odds of abnormal ABI. Conclusions: In conclusion, the presence of MetS in adults with and without CVD was associated with abnormally low ABI, even after accounting for additional cardiovascular risk factors not defined by the MetS. This study suggests that timely clinician awareness of abnormally low ABI in persons with at least three MetS components, hypertriglyceridemia or low HDL cholesterol, may be useful in preventing the debilitating effects of peripheral artery disease.
GW29-e1258 The Associations between Multiple Circulating Biomarkers and the Occurrence of Atrial Fibrillation in Hypertrophic Cardiomyopathy with or without Left Ventricular Outflow Tract Obstruction
Authors: Limin Liu, Lingmin Wu, Lihui Zheng, Ligang Ding, Gang Chen, Xiaohan Fan, Yan Yao
Journal: Journal of the American College of Cardiology (2018)
Atopic dermatitis, educational attainment and psychological functioning: a national cohort study
Authors: J. Smirnova, L.B. Kobyletzki, M. Lindberg, Å. Svensson, S.M. Langan, S. Montgomery
Journal: British Journal of Dermatology (2018)

Atopic dermatitis (AD) might adversely affect academic performance, possibly through influences on psychological functioning such as stress resilience. To investigate the association of atopic dermatitis with stress resilience, cognitive function and educational attainment. We used data from a national cohort of men who underwent a military conscription examination at ages 17–20 years in Sweden between 1969 and 1976. All potential conscripts met a physician who assessed current or previous history of AD. Stress resilience was measured by a psychologist using a semistructured interview. The conscription assessment included a written cognitive function test. The highest level of education achieved was identified through record linkage. The study population included 234 715 men, 1673 (0·7%) of whom had a diagnosis of AD. AD was associated with a greater risk of low stress resilience [adjusted relative risk ratio (RRR) 1·60, 95% confidence interval (CI) 1·38–1·86]. AD was associated with higher cognitive function (β‐coefficient 0·15, 95% CI 0·05–0·24) and higher educational level (RRR 1·29, 95% CI 1·13–1·47). However, adjustment for socioeconomic characteristics of the family of origin attenuated the magnitude of the associations and eliminated the statistical significance (β‐coefficient 0·06, 95% CI −0·03 to 0·15; RRR 1·16, 95% CI 1·00–1·35). Swedish men with AD had lower stress resilience in late adolescence but did not have lower cognitive function or poorer educational attainment. The lower stress resilience associated with AD is consistent with an increased risk of possible long‐term adverse health outcomes.
Immune checkpoint inhibitor efficacy and safety in elderly non-small cell lung cancer patients
Authors: T. Kubo, H. Watanabe, K. Ninomiya, K. Kudo, D. Minami, E. Murakami, N. Ochi, T. Ninomiya, D. Harada, M. Yasugi, E. Ichihara, K. Ohashi, K. Fujiwara, K. Hotta, M. Tabata, Y. Maeda, K. Kiura
Journal: Annals of Oncology (2018)
Abstract 17295: Metabolomics of Non-alcoholic Fatty Liver Disease in Young Adults Reveals Pronounced Metabolic Deviations Prior to Disease Onset
Authors: Peter Wurtz, Jari Kaikkonen, Antti J Kangas, Pasi Soininen, Mika Kahonen, Olli Raitakari, Mika Ala-Korpela
Journal: Circulation (2016)

Background: Nonalcoholic fatty liver is the most common liver disease worldwide. The disease is associated with obesity-related metabolic aberrations. Aim: We assessed how circulating metabolic bio...
P3.16-07 The Impact of Clinical and Molecular Profile of Resected EGFR-Mutant Non-Small Cell Lung Cancer on the Risk of Developing Brain Metastases
Authors: M. Moskovitz, M. Cabanero, J. Torchia, H. Sorotsky, J. Weiss, M. Pintilie, N. Leighl, P. Bradbury, G. Liu, G. Zadeh, M. Doherty, A. Kia, D. Torti, M. Tsao, T. Pugh, F. Shepherd
Journal: Journal of Thoracic Oncology (2018)
Introduction to the Liver Imaging Reporting and Data System for Hepatocellular Carcinoma
Authors: An Tang, Amit G. Singal, Donald G. Mitchell, Elizabeth M. Hecht, Kathryn J. Fowler, Laura Kulik, Neehar D. Parikh, Yuko Kono, Claude B. Sirlin
Journal: Clinical Gastroenterology and Hepatology (2018)
Impact of clinical, morphologic and molecular characteristics on response to neoadjuvant systemic therapy (NAST) in metaplastic breast cancer (MpBC)
Authors: C. Yam, S. Seth, K.R. Hess, E.A. Mittendorf, R.K. Murthy, S. Damodaran, T. Helgason, L. Huo, A.M. Thompson, M. Barton, M.L. Huang, E.M. Arribas, D.L. Lane, G.M. Rauch, B.E. Adrada, M.Z. Gilcrease, J.T. Chang, S.L. Moulder
Journal: Annals of Oncology (2018)
GW29-e0322 Role of interleukin-34 in predicting the aggravation of heart failure and long-term prognosis in patients with myocardial infarction
Authors: Qin Fan, Xiaoxiang Yan, Hang Zhang, Hongyang Xie, Rui Xi, Fang Wang, Rong Tao
Journal: Journal of the American College of Cardiology (2018)
P3.13-02 Lymphocytic Plevral Effusion Due to Crizotinib Usage: First Case in Literature
Authors: P. Akın Kabalak, Ü. Yılmaz, S. Kavurgacı, D. Kızılgöz, T. Inal Cengiz, Ş. Yaman
Journal: Journal of Thoracic Oncology (2018)
Evolution of novel, low cost, sustainable osteosarcoma care over two decades: Reducing ineﬃciencies &amp; improving outcomes
Authors: J. Bajpai, T. Mondal, V. Simha, A. Chandrashekharan, S. Hingmire, B. Rangarajan, N. Shetty, K. Shah, R. Dusane, B. Rekhi, T.S. Vora, J. Ghosh, S. Banavali, S. Gupta
Journal: Annals of Oncology (2018)
Abstract 13959: SIRT1 Deacetylase Mediates Klotho Gene Deficiency-induced Arterial Remodeling and Stiffness
Authors: Diansa Gao, Zhong Zuo, Jing Tian, Quaisar Ali, Yi Lin, Han Lei, Zhongjie Sun
Journal: Circulation (2016)

Objective: Arterial stiffness is an independent risk factor for stroke and myocardial infarction. This study was designed to investigate the potential role of SIRT1, an important deacetylase, and its relationship with Klotho, a kidney-derived aging-suppressor protein, in the pathogenesis of arterial stiffness and hypertension. Methods and Results: We found that the serum level of Klotho was decreased by nearly 45% in patients with arterial stiffness and hypertension. Interestingly, Klotho haplodeficiency caused arterial stiffening and hypertension, as evidenced by significant increases in pulse wave velocity (PWV) and blood pressure (BP) in Klotho-haplodeficient ( KL +/- ) mice. Notably, the expression and activity of SIRT1 were decreased significantly in aortic endothelial and smooth muscle cells in KL +/- mice, suggesting that Klotho deficiency downregulates SIRT1. Treatment with SRT1720 (15 mg/kg/day, IP), a specific SIRT1 activator, abolished Klotho deficiency-induced arterial stiffness and hypertension in KL +/- mice. Klotho deficiency was associated with significant decreases in activities of AMP-activated protein kinase alpha (AMPKα) and endothelial nitric oxide synthase (eNOS) in aortas, which were abolished by SRT1720. Furthermore, Klotho deficiency upregulated NADPH oxidase activity and superoxide production, increased collagen expression, and enhanced elastin fragmentation in the media of aortas. These Klotho deficiency-associated changes were blocked by SRT1720. Conclusion: This study provides the first evidence that Klotho deficiency downregulates SIRT1 activity in arterial endothelial and smooth muscle cells contributing to the pathogenesis of arterial remodeling and stiffening. Pharmacological activation of SIRT1 is likely to be an effective therapeutic approach for arterial stiffness and hypertension.
A phase III trial of Cape/5-FU+Bmab followed by CapeOX/mFOLFOX6+Bmab vs. CapeOX/mFOLFOX6+Bmab in mCRC: C-Cubed(C3) study
Authors: Keiichiro Ishibashi, Takeshi Nagasaka, Akira Sawaki, Hideyuki Mishima, Akihito Tsuji, Yasushi Tsuji, Yoshinori Munemoto, Shigeki Yamaguchi, Mototsugu Shimokawa, Masahiko Shibata, Yasuyuki Sugiyama, Hiroyuki Suzuki, Masazumi Okajima, Yoshiyuki Yamaguchi
Journal: Annals of Oncology (2018)
Not your usual tRNA synthetase: hWARS serves as an enterovirus entry factor
Authors: Stanley Perlman, Tom Gallagher
Journal: Journal of Clinical Investigation (2018)

Enteroviruses, including subtype EV-A71, infect the brain, liver, heart, and other organs, causing a myriad of human diseases. This spectrum of disease is thought to be due, in part, to differential binding to host cells, and additional knowledge of enterovirus cell entry is essential for therapeutic development. In this issue of the JCI, Yeung et al. provide evidence of a novel EV-A71 entry factor, a host-produced tryptophan tRNA synthetase (hWARS), that facilitates entry of multiple subtypes of enteroviruses. hWARS is a cytoplasmic enzyme that is essential for translation but also upregulated and secreted during inflammatory processes. The results of this study support the notion of secreted hWARS as an unconventional virus entry factor that raises interesting questions about mechanisms by which inflammation and a tRNA synthetase facilitate viral pathogenesis.
Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE—a global phase III study
Authors: T. Yoshino, D.C. Portnoy, R. Obermannová, G. Bodoky, J. Prausová, R. Garcia-Carbonero, T. Ciuleanu, P. García-Alfonso, A.L. Cohn, E. Van Cutsem, K. Yamazaki, S. Lonardi, K. Muro, T.W. Kim, K. Yamaguchi, A. Grothey, J. O’Connor, J. Taieb, S.R. Wijayawardana, R.R. Hozak, F. Nasroulah, J. Tabernero
Journal: Annals of Oncology (2018)

: Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters.Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum.RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276).In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant.NCT01183780.