tbuckley/cabot-search huggingface dataset:
Education and myopia: assessing the direction of causality by mendelian randomisation
Authors: Edward Mountjoy, Neil M Davies, Denis Plotnikov, George Davey Smith, Santiago Rodriguez, Cathy E Williams, Jeremy A Guggenheim, Denize Atan
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objectives</h3> To determine whether more years spent in education is a causal risk factor for myopia, or whether myopia is a causal risk factor for more years in education. <h3>Design</h3> Bidirectional, two sample mendelian randomisation study. <h3>Setting</h3> Publically available genetic data from two consortiums applied to a large, independent population cohort. Genetic variants used as proxies for myopia and years of education were derived from two large genome wide association studies: 23andMe and Social Science Genetic Association Consortium (SSGAC), respectively. <h3>Participants</h3> 67 798 men and women from England, Scotland, and Wales in the UK Biobank cohort with available information for years of completed education and refractive error. <h3>Main outcome measures</h3> Mendelian randomisation analyses were performed in two directions: the first exposure was the genetic predisposition to myopia, measured with 44 genetic variants strongly associated with myopia in 23andMe, and the outcome was years in education; and the second exposure was the genetic predisposition to higher levels of education, measured with 69 genetic variants from SSGAC, and the outcome was refractive error. <h3>Results</h3> Conventional regression analyses of the observational data suggested that every additional year of education was associated with a more myopic refractive error of −0.18 dioptres/y (95% confidence interval −0.19 to −0.17; P&lt;2e-16). Mendelian randomisation analyses suggested the true causal effect was even stronger: −0.27 dioptres/y (−0.37 to −0.17; P=4e-8). By contrast, there was little evidence to suggest myopia affected education (years in education per dioptre of refractive error −0.008 y/dioptre, 95% confidence interval −0.041 to 0.025, P=0.6). Thus, the cumulative effect of more years in education on refractive error means that a university graduate from the United Kingdom with 17 years of education would, on average, be at least −1 dioptre more myopic than someone who left school at age 16 (with 12 years of education). Myopia of this magnitude would be sufficient to necessitate the use of glasses for driving. Sensitivity analyses showed minimal evidence for genetic confounding that could have biased the causal effect estimates. <h3>Conclusions</h3> This study shows that exposure to more years in education contributes to the rising prevalence of myopia. Increasing the length of time spent in education may inadvertently increase the prevalence of myopia and potential future visual disability.
Concurrent genetic alterations identified by next-generation sequencing in pre-treatment, metastatic EGFR-mutant lung cancers.
Authors: Helena Alexandra Yu, Emmet Jordan, Ai Ni, Daniel Feldman, Christopher Rodriguez, Hyunjae Ryan Kim, Mark G. Kris, David B. Solit, Michael F. Berger, Marc Ladanyi, Maria E. Arcila, Gregory J. Riely
Journal: Journal of Clinical Oncology (2016)

9053 Background: Whether disease characteristics or outcomes for patients (pts) with EGFR-mutant lung cancers differ by co-mutations present is unknown. In order to understand the impact of co-mutations, we reviewed molecular results, disease course and clinical characteristics of pts with untreated, metastatic EGFR-mutant lung cancers. Methods: We identified all pts with untreated EGFR-mutant metastatic lung cancers who had targeted NGS performed from Jan 2014 to Sept 2015. Molecular alterations in 341 genes were assessed. Fisher's exact and log rank tests were used to identify associations between co-mutations and presence of central nervous system metastases, progression-free survival (PFS) on EGFR tyrosine kinase inhibitor (TKI) and overall survival (OS). Results: Activating kinase-domain mutations in EGFR were identified in 95 pts (exon 19 deletion = 43, L858R = 33, exon 20 insertion = 10, other = 9). The median depth of coverage was 654x; the median number of co-mutations was 5 (range 0-28). 242 unique co-mutations were identified. Median age: 63, women: 69%, never smokers: 58%, adenocarcinoma: 96%. The most frequent co-mutations were TP53 (62%), PIK3CA (14%), and RB1 (11%). The most frequent amplifications were seen in EGFR (26%) and NKX2.1/TTF-1 (13%). 1 sample had concurrent subclonal KRAS Q61H and EGFR L858R mutations. There were no concurrent ALK/ROS1/RET rearrangements. Co-mutations did not differ by EGFR mutation subtype. There was no association between co-mutations or EGFR mutation subtype and the presence of CNS metastases. EGFR amplification was associated with shorter overall survival after diagnosis of metastatic disease (HR 3.58, 95% CI 1.2-10.3, p = 0.012). 80 patients were subsequently treated with EGFR TKI (75 = erlotinib, 5 = other) with follow up available. Of those treated with erlotinib, there was a trend towards shorter PFS in patients with concurrent TP53 alterations (HR 2.45, p = 0.056). Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent genetic alterations with the most frequent being TP53, EGFR amplification, PIK3CA, TTF-1 amplification and RB1. Concurrent EGFR amplification was associated with shorter overall survival.
Another Step Toward Defining an Immune-Mediated Subtype of Autism Spectrum Disorder
Authors: Christopher J. McDougle
Journal: JAMA Network Open (2018)

Guifeng Xu, MD; Linda G. Snetselaar, PhD; Jin Jing, MD, PhD; Buyun Liu, MD, PhD; Lane Strathearn, MBBS, FRACP, PhD; Wei Bao, MD, PhD
The Burden of Opioid-Related Mortality in the United States
Authors: Tara Gomes, Mina Tadrous, Muhammad M. Mamdani, J. Michael Paterson, David N. Juurlink
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Opioid prescribing and overdose are leading public health problems in North America, yet the precise public health burden has not been quantified. <h3>Objective</h3> To examine the burden of opioid-related mortality across the United States over time. <h3>Design, Setting, and Participants</h3> This study used a serial cross-sectional design in which cross sections were examined at different time points to investigate deaths from opioid-related causes in the United States between January 1, 2001, and December 31, 2016. <h3>Main Outcomes and Measures</h3> Opioid-related deaths, defined as those in which a prescription or illicit opioid contributed substantially to an individual's cause of death as determined by death certificates. We compared the percentage of deaths attributable to opioids and the associated person-years of life lost by age group. <h3>Results</h3> Between 2001 and 2016, the number of opioid-related deaths in the United States increased by 345%, from 9489 to 42 245 deaths (33.3 to 130.7 deaths per million population). By 2016, men accounted for 67.5% of all opioid-related deaths, and the median (interquartile range) age at death was 40 (30-52) years. The percentage of deaths attributable to opioids increased in a similar fashion. In 2001, 0.4% of deaths (1 in 255) were opioid related, rising to 1.5% of deaths (1 in 65) by 2016, an increase of 292%. This burden was highest among adults aged 24 to 35 years. In this age group, 20.0% of deaths were attributable to opioids in 2016. Among those aged 15 to 24 years, 12.4% of deaths were attributable to opioids in 2016. Overall, opioid-related deaths resulted in 1 681 359 years of life lost (5.2 per 1000 population) in the United States in 2016, most of which (1 125 711 years of life lost) were among men. Adults aged 25 to 34 years had 12.9 years of life lost per 1000 population, and those aged 35 to 44 years had 9.9 years of life lost per 1000 population. <h3>Conclusions and Relevance</h3> Premature death from opioid-related causes imposes an enormous public health burden across the United States. The recent increase in deaths attributable to opioids among those aged 15 to 34 years highlights a need for targeted programs and policies that focus on improved addiction care and harm reduction measures in this high-risk population.
Epigenetic and Transcriptomic Profiling of Mammary Gland Development and Tumor Models Disclose Regulators of Cell State Plasticity
Authors: Christopher Dravis, Chi-Yeh Chung, Nikki K. Lytle, Jaslem Herrera-Valdez, Gidsela Luna, Christy L. Trejo, Tannishtha Reya, Geoffrey M. Wahl
Journal: Cancer Cell (2018)
Contessa: A multinational, multicenter, randomized, phase 3 registration study of tesetaxel in patients (Pts) with HER2-, hormone receptor + (HR+) locally advanced or metastatic breast cancer (MBC).
Authors: Joyce O'Shaughnessy, Martine J. Piccart-Gebhart, Lee Steven Schwartzberg, Javier Cortes, Nadia Harbeck, Seock-Ah Im, Hope S. Rugo, Michael Untch, Denise A. Yardley, Igor Bondarenko, Stephen Chan, Veronique Dieras, Luca Gianni, Mark D. Pegram, Stew Kroll, Joseph P. O'Connell, Jeffrey L. Vacirca, Thomas Wei, Kevin Tang, Andrew David Seidman
Journal: Journal of Clinical Oncology (2018)

TPS1106 Background: Chemotherapy treatments that offer improved quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing; no history of hypersensitivity reactions; and improved activity against chemotherapy-resistant tumors (Shionoya 2003; Chan 2006). 555 pts have been treated with T in clinical studies (492 monotherapy; 63 in combination with capecitabine (C)). In MBC, T had robust single-agent activity in 2 multicenter, Phase 2 studies. In TOB203, 38 pts with HER2-, HR+ MBC received single-agent T Q3W for MBC; the confirmed ORR per RECIST 1.1 in all 38 pts was 45% (95% CI: 29% - 62%); the median PFS was 5.7 mo (95% CI: 4.1 – 9.8 mo). In a Phase 1 study, the combination of T plus a reduced dose of C was associated with a tolerable AE profile with minimal overlapping toxicity. C is a preferred agent for pts with MBC. Combining the approved dose of C with currently available taxanes results in robust efficacy but significant toxicity, while preclinical and clinical studies suggest that reducing the dose of C in combination with a taxane may result in reduced toxicity without a reduction in efficacy. CONTESSA investigates T plus a reduced dose of C as an all-oral regimen in HER2-, HR+ MBC. Methods: CONTESSA is a 600-pt, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing T (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of C alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in pts with HER2-, HR+ MBC previously treated with a taxane in the (neo)adjuvant setting. Where indicated, pts must have received endocrine therapy with or without a CDK 4/6 inhibitor. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are OS, ORR assessed by IRC, disease control rate assessed by IRC and patient reported outcomes. Enrollment was initiated in Dec 2017. Clinical trial information: NCT03326674.
Evaluation of the OncoMasTR prognostic signature in postmenopausal women with primary ER-positive breast cancer.
Authors: Ivana Sestak, Richard Buus, Jack M. Cuzick, Stephen Barron, Tony Loughman, Bozena Fender, Cesar Lopez Ruiz, Peter Dynoodt, Chan-Ju Angel Wang, Desmond O'Leary, William M. Gallagher, Mitchell Dowsett
Journal: Journal of Clinical Oncology (2018)

553 Background: The assessment of distant recurrence (DR) risk in patients with early estrogen receptor (ER) positive breast cancer receiving adjuvant endocrine therapy is essential in making decisions on additional treatment. OncoMasTR (OM) is a continuous risk prediction model that provides a quantitative assessment of the likelihood of DR in patients with ER-positive breast cancer. The aim of this study was to assess the prognostic performance of OM in predicting DR for postmenopausal patients treated with anastrozole or tamoxifen. Methods: OM incorporates three genes and was developed in an endocrine treated population. OMclinical incorporates clinical parameters into the molecular OM. OM was evaluated for 648 ER-positive, HER2-negative patients with 0 to 3 involved lymph nodes in the TransATAC cohort. DR was the primary endpoint. Cox regression models were used to assess the prognostic performance. OM was evaluated for the overall time period and secondarily for late DR (years 5-10), and in node-negative and node-positive patients separately. Results: OM and OMclinical were highly prognostic for the prediction of DR in years 0-10 among all patients (LRχ2= 25.43 and LRχ2= 48.73, respectively, P < 0.001). OM/OMclinical provided significant additional prognostic value beyond standard clinicopathological variables. In women with node-negative disease, OM identified 37.8% of women as low risk with a 10-year DR risk of 3.5% (1.6-7.7), which was significantly lower compared to those categorised as high risk (10-year DR risk: 16.4% (12.4-21.5); HR = 4.8 (2.0-11.2)). Similar risk stratification and 10-year DR risks were observed for OMclinical in women with node-negative disease (HR = 6.5 (2.6-16.3)). Little prognostic information was provided for node-positive patients. OM and OMclinical were also highly prognostic for the prediction of late DR (LRχ2= 12.84 and LRχ2= 25.61, respectively, P < 0.001). Conclusions: OM and OMclinical were highly prognostic for early and late DR in women with early-stage (particularly node-negative) ER-positive breast cancer receiving 5 years of endocrine therapy and merit further evaluation as risk stratifiers to identify women who can safely forego chemotherapy.
International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets
Authors: F. Caraci, F. Calabrese, R. Molteni, L. Bartova, M. Dold, G. M. Leggio, C. Fabbri, J. Mendlewicz, G. Racagni, S. Kasper, M. A. Riva, F. Drago
Journal: Pharmacological Reviews (2018)

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.
Targeted Therapy for Premenopausal Women with HR+, HER2− Advanced Breast Cancer: Focus on Special Considerations and Latest Advances
Authors: Aditya Bardia, Sara Hurvitz
Journal: Clinical Cancer Research (2018)

Abstract The incidence of advanced breast cancer in premenopausal women is increasing, and breast cancer in younger women is often more aggressive and has a worse prognosis compared with breast cancer in older women. Premenopausal women with hormone receptor–positive (HR+) breast cancer are frequently under-represented in clinical trials, and treatment strategies in the premenopausal setting are usually extrapolated from data from postmenopausal patients, with the addition of ovarian function suppression to endocrine therapy in HR+ disease. However, the underlying biology of breast cancer in premenopausal women can be different from postmenopausal women, and treatment strategies should ideally be specifically tested in premenopausal patients. Recent phase III trials have now investigated cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in premenopausal patients with HR+, HER2− advanced breast cancer: Palbociclib and abemaciclib have been tested in a subset of premenopausal patients in the PALOMA-3 and MONARCH-2 studies, and ribociclib has been tested in the phase III MONALEESA-7 trial, which was entirely dedicated to premenopausal women. This comprehensive review summarizes the differences in the biology of HR+, HER2− breast cancer in the premenopausal population compared with the postmenopausal population; discusses special considerations for treatment of premenopausal women; and reviews the evidence from clinical trials investigating endocrine therapy, other targeted treatments, and ovarian function suppression in the HR+, HER2− advanced breast cancer setting. Clin Cancer Res; 24(21); 5206–18. ©2018 AACR.
RIBECCA: A phase IIIb, multi-center, open label study for women with estrogen receptor positive locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole—Results of the first interim analysis.
Authors: Peter A. Fasching, Arnd Nusch, Bernhard Heinrich, Sara Brucker, Thomas Decker, Christian M. Kurbacher, Hans Tesch, Petra Krabisch, Christoph Mundhenke, Tanja N. Fehm, Wolfgang Janni, Diana Lueftner, Andreas Schneeweiss, Martin H. Schuler, Gernot Guderian, Claudia Voges, Joerg Schubert, Sherko Kummel
Journal: Journal of Clinical Oncology (2018)

1051 Background: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7. Here we present the results of the first preplanned interim analysis. Methods: Main inclusion criteria allow enrollment of men or women with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, and histological or cytological confirmation of ER+, HER2- breast cancer, irrespective of their menopausal status. The primary objective is to assess the clinical benefit rate (CBR) after 6 months, secondary objectives include progression free survival (PFS), overall survival (OS), safety and changes in quality of life. Results: The cut-off date for this first interim analysis was 12 months after the enrollment of the first patient (24-Oct-2017). Here we describe the baseline characteristics and safety data of patients (pts) with at least 12 weeks follow up (n = 338). Baseline characteristics: of 338 pts, 336 were female and 2 male. Median age: 64 yrs; 46 pts pre-or perimenopausal, 290 postmenopausal; ECOC 0-1: 97.3%; median time since first recurrence: 2 months; 74.3% pts had bone metastases, 31.4% liver, 26.9% lung and 28.4% other metastases. 79.6% of pts had received at least one prior endocrine therapy or chemotherapy: 39.5% in the (neo-) adjuvant setting, 39.9% in the palliative setting. Median relative dose intensity was 0.944 for ribociclib and 1 for letrozole. The most common treatment emergent AEs (all grades) were neutropenia (42.3%), nausea (36.7%), fatigue (33.4%), alopecia (29%), diarrhea (20.7%), leukopenia (19.5%), constipation (17.8%), ALT increased (17.1%), AST increased (15.7%) headache (15.9%) and neutrophil count decreased (12.7%). Conclusions: The results of the first interim analysis in this additional patient population are in line with data published from the pivotal phase III studies MONALEESA-2 and MONALEESA-7. No new safety signals were detected. Clinical trial information: NCT03096847.
<i>Kras</i> and <i>Tp53</i> Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma
Authors: Margaret A. Hill, William B. Alexander, Bing Guo, Yasutaka Kato, Krushna Patra, Michael R. O'Dell, Matthew N. McCall, Christa L. Whitney-Miller, Nabeel Bardeesy, Aram F. Hezel
Journal: Cancer Research (2018)

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury, which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA, with intermediates along this spectrum. Here, we generated mouse models to examine the consequence of targeting mutant Kras and Tp53, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9+ population, predominantly consisting of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BilIN). In contrast, adult hepatocytes were relatively refractory to these mutations and formed rare HCC. In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing toward distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. Tp53 loss enhanced the reprogramming of hepatocytes to cholangiocytes, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by Kras and Tp53 may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype.Significance: The histopathogenesis of biliary tract cancer, driven by Tp53 and Kras mutations, can be differentially impacted by the cell of origin within the mature liver as well by major epidemiologic risk factors. Cancer Res; 78(16); 4445-51. ©2018 AACR.
Gastric neuroendocrine tumors display deep invasive features, with amorphous pit and irregular vascular pattern, using narrow-band imaging and magnification
Authors: Adrien Choné, Thomas Walter, Jérôme Rivory, Pierre-Marie Lavrut, Julien Forestier, Jean-Christophe Saurin, Mathieu Pioche
Journal: Endoscopy (2018)

To the best of our knowledge, gastric neuroendocrine tumors are rare, usually diagnosed with endoscopic ultrasound [1], and their endoscopic aspect has rarely been described in the literature [2].