tbuckley/cabot-search huggingface dataset:
Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing
Authors: Alba Sanchis-Juan, Jonathan Stephens, Courtney E. French, Nicholas Gleadall, Karyn Mégy, Christopher Penkett, Olga Shamardina, Kathleen Stirrups, Isabelle Delon, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Detelina Grozeva, Luca Stefanucci, Gavin Arno, Andrew R. Webster, Trevor Cole, Topun Austin, Ricardo Garcia Branco, Willem H. Ouwehand, F. Lucy Raymond, Keren J. Carss
Journal: Genome Medicine (2018)

Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation.We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case.We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements.Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.
OA14 Phase 2 Study: Tepotinib + Gefitinib in MET+/Epidermal Growth Factor Receptor (EGFR)-Mutant Non-Small Cell Lung Cancer
Authors: Y. Cheng, J. Zhou, S. Lu, Y. Zhang, J. Zhao, H. Pan, Y. Chen, C. Chian, R. Bruns, A. Johne, J. Scheele, Y. Wu
Journal: Journal of Thoracic Oncology (2018)
Author Correction: A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite
Authors: Neville K Kisalu, Azza H Idris, Connor Weidle, Yevel Flores-Garcia, Barbara J Flynn, Brandon K Sack, Sean Murphy, Arne Schön, Ernesto Freire, Joseph R Francica, Alex B Miller, Jason Gregory, Sandra March, Hua-Xin Liao, Barton F Haynes, Kevin Wiehe, Ashley M Trama, Kevin O Saunders, Morgan A Gladden, Anthony Monroe, Mattia Bonsignori, Masaru Kanekiyo, Adam K Wheatley, Adrian B McDermott, S Katie Farney, Gwo-Yu Chuang, Baoshan Zhang, Natasha Kc, Sumana Chakravarty, Peter D Kwong, Photini Sinnis, Sangeeta N Bhatia, Stefan H I Kappe, B Kim Lee Sim, Stephen L Hoffman, Fidel Zavala, Marie Pancera, Robert A Seder
Journal: Nature Medicine (2018)
Telephone Call After Pediatric Discharge—Reply
Authors: Angela Statile, Jeffrey M. Simmons, Katherine A. Auger
Journal: JAMA Pediatrics (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
New Cancer Drug Approvals From the Perspective of a Universal Healthcare System: Analyses of the Pan-Canadian Oncology Drug Review Recommendations
Authors: Saroj Niraula, Zoann Nugent
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: FDA approvals do not consider cost, but they set the tone for regulatory approvals worldwide, including in countries with universal healthcare where cost-effectiveness, utility, and adoption feasibility are considered rigorously. Methods: Data from the pan-Canadian Oncology Drug Review (pCODR), a national drug review system that makes evidence-based funding recommendations to Canada's provinces and territories, were collected. Our objectives were to assess (1) temporal trends in cost and efficacy of drugs reviewed, (2) correlations among magnitude of benefits, cost, and pCODR decisions, and (3) predictors of approvals. Results: A total of 60 drugs for 91 indications were reviewed by pCODR from January 2012 to January 2018. Of the 91 reviews (approved previously by FDA), 18 received negative recommendations on the grounds of inadequate clinical benefits; 87% (64/73) of those approved were conditional on improvement in cost. Surrogate outcomes were used to support approvals in 83% of the reviews, which were not correlated with overall survival (rSpearman = +0.16; P=.24). Median cost/quality-adjusted life years (QALY) increased by 36% per annum (quantile regression, P=.0029), although benefits in overall and progression-free survival were stable (P=.21 and .65, respectively). Median-based incremental cost-effectiveness ratio (ICER) of new drugs was $186,403 CAD (range, $7,200 to $2.1 million). Higher ICER was a strong predictor of a negative pCODR recommendation (P<.01). Conclusions: A substantial number of cancer drugs that are FDA approved for public use do not meet Canadian standards for efficacy. Cost of cancer drugs increases by a third annually in Canada, but the benefits—measured mostly with surrogates that did not correlate with survival—are stable. With finite resources to share among multiple societal priorities, such as education and preventive health, cancer drug cost may be unsustainable despite price regulation.
The Role of Common Factors in Psychotherapy Outcomes
Authors: Pim Cuijpers, Mirjam Reijnders, Marcus J.H. Huibers
Journal: Annual Review of Clinical Psychology (2018)

Psychotherapies may work through techniques that are specific to each therapy or through factors that all therapies have in common. Proponents of the common factors model often point to meta-analyses of comparative outcome studies that show all therapies have comparable effects. However, not all meta-analyses support the common factors model; the included studies often have several methodological problems; and there are alternative explanations for finding comparable outcomes. To date, research on the working mechanisms and mediators of therapies has always been correlational, and in order to establish that a mediator is indeed a causal factor in the recovery process of a patient, studies must show a temporal relationship between the mediator and an outcome, a dose-response association, evidence that no third variable causes changes in the mediator and the outcome, supportive experimental research, and have a strong theoretical framework. Currently, no common or specific factor meets these criteria and can be considered an empirically validated working mechanism. Therefore, it is still unknown whether therapies work through common or specific factors, or both.
Engineered DNA Vaccination against Follicle-Stimulating Hormone Receptor Delays Ovarian Cancer Progression in Animal Models
Authors: Alfredo Perales-Puchalt, Krzysztof Wojtak, Elizabeth K. Duperret, Xue Yang, Anna M. Slager, Jian Yan, Kar Muthumani, Luis J. Montaner, David B. Weiner
Journal: Molecular Therapy (2018)

Ovarian cancer presents in 80% of patients as a metastatic disease, which confers it with dismal prognosis despite surgery and chemotherapy. However, it is an immunogenic disease, and the presence of intratumoral T cells is a major prognostic factor for survival. We used a synthetic consensus (SynCon) approach to generate a novel DNA vaccine that breaks immune tolerance to follicle-stimulating hormone receptor (FSHR), present in 50% of ovarian cancers but confined to the ovary in healthy tissues. SynCon FSHR DNA vaccine generated robust CD8+ and CD4+ cellular immune responses and FSHR-redirected antibodies. The SynCon FSHR DNA vaccine delayed the progression of a highly aggressive ovarian cancer model with peritoneal carcinomatosis in immunocompetent mice, and it increased the infiltration of anti-tumor CD8+ T cells in the tumor microenvironment. Anti-tumor activity of this FSHR vaccine was confirmed in a syngeneic murine FSHR-expressing prostate cancer model. Furthermore, adoptive transfer of vaccine-primed CD8+ T cells after ex vivo expansion delayed ovarian cancer progression. In conclusion, the SynCon FSHR vaccine was able to break immune tolerance and elicit an effective anti-tumor response associated with an increase in tumor-infiltrating T cells. FSHR DNA vaccination could help current ovarian cancer therapy after first-line treatment of FSHR+ tumors to prevent tumor recurrence.
Identification of serum microRNAs predicting the response to nivolumab in patients with advanced gastric cancer
Authors: T. Miyamoto, K. Kato, J. Matsuzaki, S. Takizawa, K. Sudo, H. Shoji, S. Iwasa, Y. Honma, A. Takashima, N. Okita, H. Sakamoto, N. Boku, O. Takahiro
Journal: Annals of Oncology (2018)

Background: Recent studies have reported that serum microRNAs (miRNAs) are potentially useful cancer biomarkers. In patients with gastric cancer (GC), the efficacy of nivolumab (Nivo), a PD-1 inhibitor, was shown in a phase III study, but predictive biomarkers of Nivo for gastric cancer have not been found. We investigated whether serum miRNAs could be predictive markers of the efficacy of Nivo in GC. Methods: The subjects of this study were 20 patients who were enrolled in the phase III study (ONO-4538-12) and received Nivo 3 mg/kg IV Q2W at our institution. Expressions of 2565 miRNAs in the serum samples before and during treatment were analyzed using "3D-Gene" Human miRNA Oligo Chip (Toray Industries, Inc.). We explored miRNAs that were significantly associated with the treatment response using receiver operating characteristic analysis and Cox regression analysis. Results: Median progression-free survival (PFS) was 2.3 month, and partial response was achieved in four of the 20 patients who received Nivo. Serum samples before (n = 20) and 4 weeks after (n = 17) the treatment of Nivo were available. Two different miRNAs, one before and the other after treatment, were identifiedwhich were related to response to Nivo. AUC of miR-A identified before treatment was 0.88, whereas that of miR-B after the first treatment was 0.85. The overall response rate (ORR) was 44% (4/9) in miR-A-high patients and 0% (0/11) in miR-A-low patients. The ORR was 50% (4/8) in miR-B-high patients and 0% (0/9) in miR-B-low patients. Median PFS was 14.3 m (95%CI: N/A-35.1) in miR-A-high patients and 1.6 m (95%CI: 0.9-2.3) in miR-A–low patients (HR = 0.19, log rank: p = 0.01), and those were 5.6 m (95%CI: N/A-35.1) and 1.6 m (95%CI: 0.9-2.3) in miR-B-high patients (HR = 0.21, log rank: p = 0.01), respectively. Conclusions: The two miRNAs in GC pts may be a predictive marker for identifying pts who derived greater benefit from Nivo therapy. Legal entity responsible for the study: Ken Kato. Funding: Has not received any funding. Disclosure: S. Takizawa: Personal fees: Toray Industries, Inc., outside the submitted work. O. Takahiro: Grants: Kewpie Corporation, Takeda, BioMimetics Sympathies, Rohto Pharmaceutical Co., Ltd., Inter Stem, Japan Atherosclerosis Research Foundation, Ono Pharmaceutical Co., Ltd., Daiichi-Sankyo Company. All other authors have declared no conflicts of interest.
Recalcitrant Vulvar Lichen Sclerosus Treated With Erbium YAG Laser
Authors: Julia G. Hobson, Sherrif F. Ibrahim, Mary Gail Mercurio
Journal: JAMA Dermatology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Improving vaccination coverage in India: lessons from Intensified Mission Indradhanush, a cross-sectoral systems strengthening strategy
Authors: Vandana Gurnani, Pradeep Haldar, Mahesh Kumar Aggarwal, Manoja Kumar Das, Ashish Chauhan, John Murray, Narendra Kumar Arora, Manoj Jhalani, Preeti Sudan
Journal: BMJ (2018)

<b>Vandana Gurnani and colleagues</b> report an analysis from the Intensified Mission Indradhanush strategy in India, showing that cross-sectoral participation can contribute to improved vaccination coverage of children at high risk
The International Collaboration to Improve Respiratory Health in Children (INCIRCLE) ERS Clinical Research Collaboration
Authors: Peter D. Sly, Zoltán Hantos
Journal: European Respiratory Journal (2018)

<b>The INCIRCLE ERS Clinical Research Collaboration has made great advances in developing new modalities of oscillometry for use in infants and young children, and this has evoked interest from the lung function device industry</b>http://ow.ly/FPYz30mC3La
John Lloyd Burton
Authors: Cameron Kennedy
Journal: BMJ (2018)

Although he spent his consultant career as a dermatologist, John Lloyd Burton had a very thorough training as a physician. He became increasingly widely known from the 1970s onwards through his writing—firstly for those studying for the membership examination of the Royal College of Physicians with Aids to Postgraduate Medicine , soon followed by Aids to Undergraduate Medicine , Aids to Medicine for Nurses , Aids to Medicine for Dental Students , and Essentials of Dermatology . In these slim texts John combined the essentials for understanding the subjects with an iconoclastic humour, such that the readers found that they could after all remember those lists that were needed to pass exams.

John was born in Buxton, Derbyshire, and was the first in his family to go to a grammar school and then on to a university. He had a highly successful undergraduate career, obtaining many prizes and a BSc in physiology before moving through a series of prestigious junior posts in medicine—the professorial unit in Manchester, the Hammersmith, the Brompton, then Edinburgh—where he undertook cardiovascular research …
Interim Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with Untreated Acute Myeloid Leukemia (AML)
Authors: Maro N. Ohanian, Tara L Lin, Ellen K. Ritchie, Michael Craig, Apurv Agrawal, Kathleen G. Halka, Vinit Karur, Naveen Pemmaraju, Gautam Borthakur, Sarah Aminov, Miranda Lim, Sherry A. Pierce, Natalie Sacarakis, Stacy Minor, Ana Tari Ashizawa, William Hahne, Hagop M. Kantarjian, Jorge E. Cortes, Gail J. Roboz
Journal: Blood (2018)
Abstract 12503: Liver Injury is Associated With Total Cardiovascular Disease, Heart Failure, Stroke, Coronary Heart Disease and Acute Myocardial Infarction Including Among Those Without Viral Hepatitis (B Or C), Hiv, Alcohol Abuse and Obesity
Authors: Kaku So-Armah, Janet Tate, Joseph Lim, Vincent Lo Re, Vincent Marconi, Jeffrey Samet, Cynthia Gibert, David Leaf, Adeel Butt, Matthew Goetz, David Rimland, Maria Rodriguez-Barradas, Matthew Budoff, Chung-Chou Chang, Amy Justice, Matthew Freiberg
Journal: Circulation (2015)

Introduction: Hepatitis C and human immunodeficiency virus (HCV, HIV) are associated with cardiovascular disease (CVD). Liver injury is common in HIV and HCV and is associated with pro-atherosclerotic conditions e.g. altered coagulation. We assessed whether liver injury independently predicts CVD risk including among participants without major liver-related co-morbidities. Methods: Participants from the Veterans Aging Cohort Study Virtual Cohort (VACS VC), without CVD at baseline (first clinical visit after 4/1/2003) were included. Liver injury was defined by liver fibrosis index 4 at baseline (FIB4 calculated using age, liver transaminases and platelets) and ICD-9 codes for cirrhosis and hepatic decompensation. Total fatal and non-fatal CVD were assessed using 1) National Death Index cause of death data; 2) VA; 3) VA Fee For Service; and 4) Medicare ICD-9 and procedure codes for acute myocardial infarction, heart failure (HF), coronary heart disease (CHD) and stroke. Follow-up ended after a CVD event, or death, or on 9/30/2012. Cox regression analyses were used to estimate the risk of total CVD, HF, stroke, CHD and AMI by liver injury. Results: Mean (SD) age was 49.6 (9.5) years in this cohort (N=104731, 90% male) followed for a median (IQR) of 7 (3, 9) years. LDL cholesterol and BMI decreased with increasing FIB4 while age increased. African American race, HIV, HCV, HBV, current smoking, type 2 diabetes, alcohol abuse, cocaine use and anemia were more common among participants with FIB4 &gt;1.45 compared to those with FIB4 &lt;1.45. Incident CVD rates increased with increasing FIB4. FIB4 &gt;3.25 or a clinical diagnosis of cirrhosis or hepatic decompensation was independently associated with significantly elevated CVD risk. This association persisted in Veterans without HCV, HBV, HIV, alcohol use disorder and BMI &gt;30 kg/m2. Conclusions: Liver injury is associated with increased risk of CVD. Future studies should assess whether FIB4 improves CVD risk prediction algorithms.
<i>EGFR</i>-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes
Authors: Nicolas Marcoux, Scott N. Gettinger, Grainne O’Kane, Kathryn C. Arbour, Joel W. Neal, Hatim Husain, Tracey L. Evans, Julie R. Brahmer, Alona Muzikansky, Philip D. Bonomi, Salvatore del Prete, Anna Wurtz, Anna F. Farago, Dora Dias-Santagata, Mari Mino-Kenudson, Karen L. Reckamp, Helena A. Yu, Heather A. Wakelee, Frances A. Shepherd, Zofia Piotrowska, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2018)

Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized.We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed.We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation.There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.
Abstract 15909: Race Differences in Sodium Accumulation in Muscle and Skin in Pre-hypertensive Individuals
Authors: Aseel Alsouqi, Serpil M Deger, Jason D Foss, Aihua Bian, Jasmine M Greer, Meena S Madhur, Baxter P Rogers, Thomas G Stewart, David G Harrison, Thomas J Wang, Talat A Ikizler
Journal: Circulation (2017)

Introduction: It has recently been shown that Na+ is stored in the skin and in muscle without commensurate water retention. The resulting increase in tissue Na+ concentration leads to activation of the immune system and hypertension. Because African American individuals have higher prevalence of hypertension and salt sensitivity we sought to investigate the differences in sodium accumulation in skin and muscle between pre-hypertensive African Americans and Caucasian subjects. Methods: Sixty-three (63) participants were enrolled in the study. Tissue sodium content was measured by 23NaMRI in the left calf. Results: Among the participants, 27 were African Americans (19 females, median age 42 years [Interquartile range (IQR): 36, 52]) and 36 were Caucasians (25 females, median age 54 years [IQR: 42, 61]). Mean and median blood pressures for the cohort were 132/77 mmHg and 129/77 mmHg, respectively. African American participants had significantly higher muscle sodium concentrations compared to Caucasians (17.3...