tbuckley/cabot-search huggingface dataset:
Association of Rare Copy Number Variants With Risk of Depression
Authors: Kimberley Marie Kendall, Elliott Rees, Matthew Bracher-Smith, Sophie Legge, Lucy Riglin, Stanley Zammit, Michael Conlon O’Donovan, Michael John Owen, Ian Jones, George Kirov, James Tynan Rhys Walters
Journal: JAMA Psychiatry (2019)

The role of large, rare copy number variants (CNVs) in neuropsychiatric disorders is well established, but their association with common psychiatric disorders, such as depression, remains unclear.To examine the association of a group of 53 CNVs associated with neurodevelopmental disorders and burden of rare CNVs with risk of depression.This case-control study used data from the UK Biobank study sample, which comprised 502 534 individuals living in the United Kingdom. Individuals with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia, or bipolar affective disorder diagnoses were excluded. Analyses were further restricted to individuals of European genetic ancestry (n = 407 074). The study was conducted from January 2017 to September 2018.CNV carrier status.For the primary outcome, individuals who reported that a physician had told them they had a depression diagnosis were defined as cases. Analyses were repeated using 2 alternative depression definitions: self-reported lifetime depression with current antidepressant prescription at the time of visit 1, and hospital discharge diagnosis of depression.Copy number variants were identified in 488 366 individuals aged 37 to 73 years. In total, 407 074 individuals with European genetic ancestry (220 201 female [54.1%]; mean [SD] age of 56.9 [8.0] years) were included in the study. Of these individuals, 23 979 (5.9%) had self-reported lifetime depression and 383 095 (94.1%) reported no lifetime depression. The group of 53 neurodevelopmental CNVs was associated with self-reported depression (odds ratio [OR], 1.34; 95% CI, 1.19-1.49, uncorrected P = 1.38 × 10-7), and these results were consistent when using 2 alternative definitions of depression. This association was partially explained by physical health, educational attainment, social deprivation, smoking status, and alcohol consumption. A strong independent association remained between the neurodevelopmental CNVs and depression in analyses that incorporated these other measures (OR, 1.26; 95% CI, 1.11-1.43; P = 2.87 × 10-4). Eight individual CNVs were nominally associated with risk of depression, and 3 of these 8 CNVs (1q21.1 duplication, Prader-Willi syndrome duplication, and 16p11.2 duplication) survived Bonferroni correction for the 53 CNVs tested. After the exclusion of carriers of neurodevelopmental CNVs, no association was found between measures of CNV burden and depression.Neurodevelopmental CNVs appear to be associated with depression, extending the spectrum of clinical phenotypes that are associated with CNV carrier status.
TCTAP C-217 Danger in Plain Sight: Ostial Left Anterior Descending Artery Injury During Ablation of Left Ventricular Summit Premature Ventricular Complex
Authors: Suraya Hani Kamsani, Keng Tat Koh, Giky Karwiky, Al Fazir Omar, Azlan Hussin
Journal: Journal of the American College of Cardiology (2019)
LBP-29-BIO89-100, a novel PEG-FGF21 analogue, is efficacious following weekly and every 2-week subcutaneous dosing in spontaneous diabetic cynomolgus monkeys
Authors: Moti Rosenstock, Michal Ayalon, Hank Mansbach, Yongqiang Liu, Maya Margalit
Journal: Journal of Hepatology (2019)
Abstract 10426: One Year Impact of the 2013 Cholesterol Guidelines on Patterns of Lipid Lowering Treatment
Authors: Josephine N Tran, Tzu Chun Kao, Toros Caglar, Karen M Stockl, Heidi C Lew, Brian K Solow, Paul S Chan
Journal: Circulation (2015)

Background: In 2013, national organizations issued new cholesterol guidelines to emphasize evidence-based treatment with moderate- to high-dose statins for patients at high risk for atherosclerotic cardiovascular disease (ASCVD), which includes coronary heart disease, stroke, and peripheral arterial disease. Whether these new guidelines have influenced patterns of treatment one year after their dissemination is unknown. Methods: Using pharmacy and medical claims from a large U.S. health insurance organization, we identified 610,535 adult patients with ASCVD (n=301,440) or diabetes mellitus (n=309,095) and examined statin treatment rates before and one year after the new cholesterol guidelines. Among patients receiving statins post-guidelines, we also evaluated whether patients were treated with guideline-recommended intensity of statin therapy. A standardized difference (SD) of at least 10% was required to declare the effect size meaningful. Results: Overall, there was no change in statin treatment rates for patients with ASCVD (48.0% before guidelines vs. 47.3% after, SD [1.4]) or diabetes (50% vs. 51.5% after, SD [2.4]). Statin initiation rates among patients not on statins pre-guidelines were 10.1% in patients with ASCVD and 14.3% in patients with diabetes, and these gains were offset by 13.0% and 12.2% statin discontinuation rates among ASCVD and diabetes patients, respectively. Among patients taking statins one year post-guidelines, 80% of patients with ASCVD and &lt; 75 years of age were not on guideline-recommended high-intensity statin therapy, whereas &gt;75% of patients with ASCVD and &gt;75 years of age or patients with diabetes were on moderate- or high-intensity statin treatment. Conclusion: One year after dissemination of the new 2013 cholesterol guidelines, overall treatment rates with statins among patients with ASCVD and diabetes have not changed appreciably, and many patients remain either untreated or under-treated. Character Count: 1683
Efficacy of secukinumab without the initial weekly loading dose in patients with chronic plaque psoriasis
Authors: P. Gisondi, M. Rovaris, S. Piaserico, G. Girolomoni
Journal: British Journal of Dermatology (2019)

Secukinumab is administered at the labelled dose of 300 mg at weeks 0, 1, 2, 3, 4 (loading dose) and every 4 weeks thereafter.To investigate the efficacy of secukinumab administered without the initial loading dose in patients with psoriasis.This was a retrospective observational study including adult patients with psoriasis (n = 156) treated with secukinumab 300 mg administered either according to the labelled dose (n = 75) or without the initial loading dose (n = 81). Efficacy was evaluated by comparing the Psoriasis Area and Severity Index (PASI) 75 and PASI 90 response rates at week 8, 12, 16, 32 and 48.For patients who received the labelled dose vs. those who did not, PASI 75 response rates were achieved at week 8, 12, 16, 32 and 48 by 60% vs. 40% (P < 0·01), 72% vs. 61% (P < 0·01), 77% vs. 75%, 85% vs. 77% and 79% vs. 78%, respectively. PASI 90 responses were achieved at the same time points by 45% vs. 31% (P < 0·01), 49% vs. 40% (P < 0·01), 54% vs. 47%, 55% vs. 47% and 57% vs. 54% for those who received the labelled dose vs. those who did not, respectively. A greater proportion of patients receiving secukinumab without the loading dose discontinued treatment because of inefficacy (25% vs. 13%, P < 0·05), particularly those with body weight greater than 80 kg.Secukinumab administered without the loading dose is associated with a higher proportion of primary inefficacy, and achieved inferior results compared with the labelled dose at week 8 and week 12, but showed similar efficacy thereafter. What's already known about this topic? Secukinumab is an interleukin (IL)-17A inhibitor for chronic plaque psoriasis administered by subcutaneous injections at the labelled dose of 300 mg at weeks 0, 1, 2, 3, 4 (loading dose) and every 4 weeks thereafter (maintenance dose). Dose adjustment is common in clinical practice, and can consist of dose reduction when a prolonged remission is obtained or a dose increase in order to improve efficacy. What does this study add? The efficacy of secukinumab administered without the initial weekly loading dose was significantly inferior compared with the labelled dose in the short term, but was similar after week 16 and up to week 48. A greater proportion of patients receiving secukinumab without the loading dose showed primary inefficacy, particularly those with body weight greater than 80 kg.
SAT-462-Current non-invasive liver reserve models do not predict histological fibrosis severity in hepatocellular carcinoma
Authors: Teh-Ia Huo, Shu Yein Ho, Po-Hong Liu, Chia-Yang Hsu, Chien-Wei Su, Yi-Hsaing Huang, Ming-Chih Hou
Journal: Journal of Hepatology (2019)
FRI-366-Portal vein thrombosis in patients on the waiting list for liver transplantation: A single center cohort study
Authors: Josephine Bert, Anja Geerts, Aude Vanlander, Luis Abreu De Carvalho, Frederik Berrevoet, Roberto Ivan Troisi, Xavier Rogiers, Hans Van Vlierberghe, Verhelst Xavier
Journal: Journal of Hepatology (2019)
GC-biased gene conversion conceals the prediction of the nearly neutral theory in avian genomes
Authors: Paulina Bolívar, Laurent Guéguen, Laurent Duret, Hans Ellegren, Carina F. Mugal
Journal: Genome biology (2019)

The nearly neutral theory of molecular evolution predicts that the efficacy of natural selection increases with the effective population size. This prediction has been verified by independent observations in diverse taxa, which show that life-history traits are strongly correlated with measures of the efficacy of selection, such as the dN/dS ratio. Surprisingly, avian taxa are an exception to this theory because correlations between life-history traits and dN/dS are apparently absent. Here we explore the role of GC-biased gene conversion on estimates of substitution rates as a potential driver of these unexpected observations. We analyze the relationship between dN/dS estimated from alignments of 47 avian genomes and several proxies for effective population size. To distinguish the impact of GC-biased gene conversion from selection, we use an approach that accounts for non-stationary base composition and estimate dN/dS separately for changes affected or unaffected by GC-biased gene conversion. This analysis shows that the impact of GC-biased gene conversion on substitution rates can explain the lack of correlations between life-history traits and dN/dS. Strong correlations between life-history traits and dN/dS are recovered after accounting for GC-biased gene conversion. The correlations are robust to variation in base composition and genomic location. Our study shows that gene sequence evolution across a wide range of avian lineages meets the prediction of the nearly neutral theory, the efficacy of selection increases with effective population size. Moreover, our study illustrates that accounting for GC-biased gene conversion is important to correctly estimate the strength of selection.
FRI-136-Hepatitis B core antibody (anti-HBc) mirrors activation of hepatitis B virus-specific immune responses and exhibits direct effect on hepatitis B virus control
Authors: Chengcong Chen, Yongyin Li, Ling Guo, Yang Zhou, Xuan Yi, Xiaoyi Li, Weibin Wang, Xieer Liang, Rong Fan, Libo Tang, Jian Sun, Jinlin Hou
Journal: Journal of Hepatology (2019)
Therapeutic miRNAs delivered systemically using normal stem cell derived microparticles.
Authors: Agamemnon A. Epenetos
Journal: Journal of Clinical Oncology (2015)

e22174 Background: The objective is to develop a micro RNA based cancer targeted to tumors d via microparticles (MPs) derived from normal umbilical cord mesenchymal stem cells (MSCs). These MPs are loaded with specific miRNA molecules impacting the activity of genes associated with oncogenesis, metastasis and drug resistance. The proposed Hypothesis is that the engineered MPs home selectively to tumor sites via specific chemokine receptors, fuse with tumor cell membranes and incorporate miRNA directly into the target cancer cells exerting their therapeutic effect. Methods: Genomics technologies in combination with innovative imaging techniques in vivoflow cytometry, fluorescence and bioluminescence based reflectance imaging and computational modelling are used to conduct pharmacokinetics and pharmacodynamics and define the mode of action, safety and efficacy of the therapeutic technology. Results: We are currently optimizing the MP-miRNA technology through components and techniques such as: a) the standardization of the isolation and production of MSC-derived MPs, b) the optimization of MP size to achieve maximum delivery efficiency through experimental investigation of the size-dependent microparticle kinetics and biodistribution, c) validation of the miRNA-loaded MPs as targeted cancer therapy in appropriate preclinical animal cancer model and d) the advancement of in vivo imaging modalities needed to monitor the therapeutic potential of the therapeutic technology in animal models of disease. Data thus far, demonstrate the ability of MP-mi RNA to enter cancer cells in vivo and exert a biological effect. Conclusions: The MP-MiRNA technology is a new and potentially breakthrough development in the area of targeted cancer therapies. The proposed project may lead to the development of specific MP-miRNA complexes that are capable of selectively targeting malignant cells in cancer patients.
Raise and decline of KRAS mutant clones in colorectal cancers (CRCs) treated with multiple rounds of anti-EGFR antibodies.
Authors: Giulia Siravegna, Benedetta Mussolin, Michela Buscarino, Giorgio Corti, Giovanni Crisafulli, Agostino Ponzetti, Chiara Cremolini, Simona Lamba, Antonio Avallone, Giuseppe Rospo, Silvio Veronese, Alfredo Budillon, Clara Montagut, Patrizia Racca, Ryan Bruce Corcoran, Federica Di Nicolantonio, Fotios Loupakis, Salvatore Siena, Andrea Sartore-Bianchi, Alberto Bardelli
Journal: Journal of Clinical Oncology (2015)

11073 Background: We previously reported that acquired resistance to anti-EGFR antibodies (moAbs) is associated with the emergence of KRAS mutations that can be detected in the blood before disease progression (PD) is clinically manifest (Misale S et al. Nature 2012). It is unknown whether and how subsequent therapies affect KRAS clones, which were selected during treatment with anti-EGFR moAbs. Methods: We studied blood samples of 16 patients (pts) who responded and then progressed upon anti-EGFR therapy. For all pts, samples were available at baseline, at the time of first PD and at different time-points across subsequent lines of treatment. At least 4 longitudinal blood draws were available for each case. We analyzed the effect of drug withdrawal in populations of CRC cells (DiFi), which had acquired resistance to cetuximab (cmab). Results: In 11/16 pts, mutated KRAS alleles were detected in blood samples obtained at PD (2 exon 2 and 8 exon 3 mutations; 1 amplification). Mutant fractional abundance (MFA) varied from 0.09 to 23.46%. KRAS mutant clones (1 G12D, 1 G13D, 2 Q61H and 3 Q61L) were tracked in the blood of 7 pts who initially achieved benefit and then experienced PD after treatment with an anti-EGFR moAb (partial response maintained for 3-12 months). Mutant KRAS alleles, which rise in blood during EGFR blockade, decline upon withdrawal of anti-EGFR moAbs (from 7.3% MFA to undetectable levels) indicating that clonal evolution continues beyond clinical progression. In the blood of pts who benefit from multiple challenging with anti-EGFR moAbs the levels of KRAS mutations are dynamic. They raised during the first anti-EGFR treatment, declined and became undetectable when the anti-EGFR moAb was suspended and raised again during re-challenge with EGFR blockade (from 0.31 to 1.27% MFA). Pharmacogenomic analysis of CRC cells (DiFi), which acquired resistance to cmab, revealed that upon antibody withdrawal, KRAS clones decay while the population regains sensitivity to cmab. Conclusions: These results reveal that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of re-challenge therapies based on EGFR blockade.
Evolution of buffering in a genetic circuit controlling plant stem cell proliferation
Authors: Daniel Rodriguez-Leal, Cao Xu, Choon-Tak Kwon, Cara Soyars, Edgar Demesa-Arevalo, Jarrett Man, Lei Liu, Zachary H. Lemmon, Daniel S. Jones, Joyce Van Eck, David P. Jackson, Madelaine E. Bartlett, Zachary L. Nimchuk, Zachary B. Lippman
Journal: Nature Genetics (2019)
Seven Easy Steps
Authors: Jack Coulehan
Journal: Annals of Internal Medicine (2019)

On Being a Doctor16 April 2019Seven Easy StepsJack Coulehan, MD, MPHJack Coulehan, MD, MPHCenter for Medical Humanities, Compassionate Care, and Bioethics, Stony Brook University, Stony Brook, New York (J.C.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-2714 Audio Reading - “Seven Easy Steps” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Seven Easy Steps” by Jack Coulehan, MD, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I arrive in the waiting room nearly a half hour early and validate myself with two insurance cards and a questionnaire that asks me yet another time to list my illnesses, allergies, and medications. I notice that most of the seats are occupied by elderly people. They must be older and sicker than I am, because … well, they look old. One man is sitting with a walker poised in front of his chair. Another hasn't removed his plaid woolen coat, the kind of coat I imagine homeless men wore during the Depression as they warmed themselves around a bonfire. ... Author, Article, and Disclosure InformationAffiliations: Center for Medical Humanities, Compassionate Care, and Bioethics, Stony Brook University, Stony Brook, New York (J.C.)Corresponding Author: Jack Coulehan, MD, MPH, 51 Pineview Lane, Coram, NY 11727; e-mail, john.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “Seven Easy Steps” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Seven Easy Steps” by Jack Coulehan, MD, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 16 April 2019Volume 170, Issue 8Page: 575KeywordsAnxietyCranial nervesElderlyEmotionsFearHappinessMemoryProstate cancerQuestionnairesTouch ePublished: 16 April 2019 Issue Published: 16 April 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
SAT-377-Significant reductions in intrahepatic Mucosal Associated Invariant T cells with increased terminal activation marker expression amongst NAFLD patients following a 12 week aerobic exercise program: a paired liver biopsy study
Authors: Sara Naimimohasses, Philip O’Gorman, Ann Monaghan, Megan Kennedy, Dean Holden, Peter Beddy, Niall Conlon, Stephen Finn, Margaret Dunne, John Gormley, Jacintha O’Sullivan, Suzanne Norris
Journal: Journal of Hepatology (2019)
Efficacy and safety of nintedanib + docetaxel in lung adenocarcinoma patients (pts) following treatment with immune checkpoint inhibitors (ICIs): Updated results of the ongoing non-interventional study (NIS) VARGADO
Authors: C. Grohe, W. Gleiber, S. Haas, S. Krüger, M. Schulze, J. Atz, R. Kaiser
Journal: Annals of Oncology (2019)
Incidence, clinical features and prognostic relevance of BCR-ABL fusion oncogene in pediatric acute lymphoblastic leukemia patients
Authors: Mariam Faiz, Javed Iqbal Qazi, Waqar Hyder
Journal: Cancer Research (2008)

2995  BACKGROUND: Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) is a common cytogenetic abnormality in ALL and found in 25% to 50% in adult patients and 3% to 5% in paediatric patients. It is associated with poor outcome in children as well as in adults. This preliminary study is reported to define the frequency of prevalence of the BCR-ABL fusion subtypes in our paediatric ALL patients by reverse transcription-PCR (RT-PCR) and to ascertain the prognostic significance of t9:22 translocation, rate of complete remission and probability of event-free, overall survival according to standard prognostic factors and type of treatment. PATIENTS AND METHODS: Sixty paediatric ALL patients (2-15 years age) treated at our center between 2004 and 2007 comprised the study group. The diagnosis of patients was based on typical morphological criteria of marrow aspirate and biopsy specimens. ALL patients were treated with BFM induction regimen prednisone, vincristine, daunorubicine, asparaginase, methotrexate followed by courses of consolidation, CNS prophylaxis, reinduction and maintenance therapy. RESULTS: Among the patients included in this study, BCR-ABL fusion oncogene was present in 15 of 60 patients (25%). High incidence of BCR-ABL fusion oncogene was observed in paediatric patients as against reported from west where the frequency was 3-5%. The age of patients range from 2-15 years (median, 7 years).Comparison of clinical features between BCR/ABL positive and negative children showed no significant differences regarding WBC, percentage of blasts, splenomegaly, hepatomegaly and age. The type of breakpoint (m-BCR/p190: n= 10; M-BCR/p210: n=6) showed no correlation with clinical parameters. BCR-ABL+ patients were also characterized by higher median white bloodcell (WBC) counts (6.7x103/µLversus 74x103//µL P = .0001). A statistically significant difference in the initial responserate to induction therapy was observed. A complete remission(CR) was achieved in 36 of 45 (80%) BCR-ABL- patients and 10 of 15 (66%) BCR-ABL+ patients (P = .001). With the available therapeutic protocol, the presence of a BCR-ABL fusion predicted (P = .001)a lower survival. The Kaplan Meier estimate of event free survival (EFS) of BCR/ABL negative ALL patients was 75% at 2 years, whereas EFS of positive patients was 25%. Multivariate analysis confirmed WBC count and BCR-ABL resultand failure to achieve complete remission within four week as independent prognostic factors CONCLUSION: This study emphasizes that BCR-ABL gene fusion is an independent prognostic factor in ALL patients. High prevalence of this genetic identity was observed in our patients as compared to other reports. Identification and characterization of this genetic entity in ALL at diagnosis is crucial for understanding the nature of adult acute lymphoblastic leukaemia and for deciding optimal treatment