tbuckley/cabot-search huggingface dataset:
Somatic Mutations in Cerebral Cortical Malformations
Authors: Hiroyuki Morita, Issei Komuro
Journal: New England Journal of Medicine (2014)

BACKGROUND-Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.METHODS-Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocytederived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47).We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.RESULTS-Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype).Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B).Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA.We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.CONCLUSIONS-Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations.High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease.
Decreased Mitochondrial Mutagenesis during Transformation of Human Breast Stem Cells into Tumorigenic Cells
Authors: Eun Hyun Ahn, Seung Hyuk Lee, Joon Yup Kim, Chia-Cheng Chang, Lawrence A. Loeb
Journal: Cancer Research (2016)

Rare stochastic mutations may accumulate during dormancy of stem-like cells, but technical limitations in DNA sequencing have limited exploring this possibility. In this study, we employed a recently established deep-sequencing method termed Duplex Sequencing to conduct a genome-wide analysis of mitochondrial (mt) DNA mutations in a human breast stem cell model that recapitulates the sequential stages of breast carcinogenesis. Using this method, we found significant differences in mtDNA among normal stem cells, immortal/preneoplastic cells, and tumorigenic cells. Putative cancer stem-like cell (CSC) populations and mtDNA copy numbers increased as normal stem cells become tumorigenic cells. Transformed cells exhibited lower rare mutation frequencies of whole mtDNA than did normal stem cells. The predicted mtDNA rare mutation pathogenicity was significantly lower in tumorigenic cells than normal stem cells. Major rare mutation types in normal stem cells are C>T/G>A and T>C/A>G transitions, while only C>T/G>A are major types in transformed cells. We detected a total of 1,220 rare point mutations, 678 of which were unreported previously. With only one possible exception (m10342T>C), we did not find specific mutations characterizing mtDNA in human breast CSCs; rather, the mitochondrial genome of CSCs displayed an overall decrease in rare mutations. On the basis of our work, we suggest that this decrease (in particular T>C/A>G transitions), rather than the presence of specific mitochondrial mutations, may constitute an early biomarker for breast cancer detection. Our findings support the hypothesis that the mitochondrial genome is altered greatly as a result of the transformation of normal stem cells to CSCs, and that mtDNA mutation signatures may aid in delineating normal stem cells from CSCs. Cancer Res; 76(15); 4569-78. ©2016 AACR.
Shared decision making and patient decision aids in dermatology
Authors: J. Tan, E. Linos, M.A. Sendelweck, E.J. van Zuuren, S. Ersser, R.P. Dellavalle, H. Williams
Journal: British Journal of Dermatology (2016)

Shared decision making combines individual patient interests and values with clinical best evidence under the guiding principle of patient autonomy. Patient decision aids can support shared decision making and facilitate decisions that have multiple options with varying outcomes for which patients may attribute different values. Given the variable psychosocial impact of skin disease on individuals and relative uncertainty regarding best treatments and their adherence in many dermatological conditions, informed shared decision making, supported by patient decision aids, should constitute a central component of dermatological care.
Update: Shortened Interval for Postvaccination Serologic Testing of Infants Born to Hepatitis B-Infected Mothers
Authors: Sarah Schillie, Trudy V. Murphy, Nancy Fenlon, Stephen Ko, John W. Ward
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

Infants born to hepatitis B-infected mothers receive postexposure prophylaxis to reduce their risk for perinatal hepatitis B virus (HBV) infection. Postexposure prophylaxis consists of hepatitis B (HepB) vaccine and hepatitis B immune globulin administered within 12 hours of birth, followed by completion of the 3-dose or 4-dose HepB vaccine series. Postvaccination serologic testing (PVST) assesses an infant's response to HepB vaccination and has typically occurred at age 9-18 months. This report provides a CDC update recommending shortening the interval for PVST from age 9-18 months to age 9-12 months. Providers should order PVST (consisting of hepatitis B surface antigen [HBsAg] and antibody to HBsAg [anti-HBs]) for infants born to HBsAg-positive mothers at age 9-12 months (or 1-2 months after the final dose of the vaccine series, if the series is delayed). This recommendation was prompted by the discontinuation of production of Hib/HepB vaccine (Comvax) and new data from the Enhanced Perinatal Hepatitis B Prevention Program supporting PVST 1・2 months after receipt of the last HepB vaccine dose, and at age ≥9 months.
Myasthenia Gravis
Authors: Daniel B. Drachman
Journal: New England Journal of Medicine (1978)

(Second of Two Parts)Clinical CorrelationsMany of the features of myasthenia gravis that were previously poorly understood can now be explained satisfactorily in terms of the pathogenetic mechanisms outlined in the first part of this review. In this section, certain aspects of the clinical manifestations, diagnostic tests and therapy are re-examined in the light of the present concept of myasthenia as a systemic autoimmune disorder of acetylcholine receptors.WeaknessMuscular weakness, one of the cardinal features of myasthenia gravis, results from failure of neuromuscular transmission at many junctions, owing to the reduction of available acetylcholine receptors.27 The decreased number . . .
Abstract A04: LINC00467 regulates the autophagy signaling pathway STK11/AMPK
Authors: Sujuan Guo, Kevin Pridham, Zhi Sheng
Journal: Cancer Research (2016)

Abstract Mounting evidence has established a fundamental role of autophagy (a self-digestion process) in tumor initiation and progression. Hence, targeting autophagy is a promising strategy for developing effective therapies to treat cancer. In our previous genome-wide RNA interference screen, we identified a set of genes that regulate autophagy in human chronic myeloid leukemia K562 cells. One of the candidates is LINC00467 (long intergenic noncoding RNA 00467), a long non-coding RNA (LncRNA) known for apoptosis regulation in neuroblastoma. LncRNA is a new RNA species with important role in gene expression regulation. Although the role of LncRNAs in apoptosis has been extensively studied. Whether or how LncRNA regulate autophagy has not yet been explored. Our previous work has established that LINC00467 regulates autophagy in different types of cancers. However, how LINC00467 regulates autophagy is largely unknown. To address this question, we first determined the stage of autophagy LINC00467 targets using a combination treatment of LINC00467 depletion and chloroquine and measuring the protein level of p62. We then monitored the activity of STK11/AMPK and MTOR, two autophagy signaling pathways, in K562 cells upon inhibition of LINC00467. We found that shRNA knockdown of LINC00467 in conjunction with chloroquine treatment significantly induced the formation of autophagic compartments manifested by the increase of Cyto-ID fluorescence. Moreover, LINC00467 knockdown substantially decreased the protein level of P62. These results indicate that Linc00467 suppresses the initiation of autophagy. To further probe the mechanism, we measured the activity of autophagy-promoting kinases STK11/AMPK, and autophagy-inhibiting kinase MTOR. Our results showed that Linc00467 knockdown substantially enhanced the activity/expression of STK11/AMPK while inhibiting that of MTOR, consistent with the inhibition of BCR-ABL using imatinib. Furthermore, We showed that LINC00467 inhibition led to a delayed degradation of STK11 mRNA. Taken together, our data demonstrates that LINC00467 suppresses autophagy through blocking STK11/AMPK. These results not only reveal a new LINC00467/STK11/AMPK pathway in autophagy regulation but also provide a basis for future therapeutic development. Citation Format: Sujuan Guo, Kevin Pridham, Zhi Sheng. LINC00467 regulates the autophagy signaling pathway STK11/AMPK. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A04.
Abstract 321: Obesity Causes Enhanced Sensitivity Of The Mitochondrial Permeability Transition Pore
Authors: Judith Bernal-Ramírez, Adriana Riojas-Hernández, Flor E Morales-Marroquín, Elvía M Domínguez-Barragán, David Rodríguez-Mier, Gerardo García-Rivas, Julio Altamirano, Noemí García
Journal: Circulation Research (2014)

Several mechanisms have been implicated in heart failure (HF) development due to obesity, including altered Ca2+ homeostasis and mitochondrial increased reactive oxygen species (ROS). Besides their metabolic role, mitochondria are important cell death regulators, since their disruption induces apoptosis. The mitochondrial permeability transition pore (MPTP) formation is key in this process. Ca2+ and ROS are known inducers of MPTP, and mitochondria are the main ROS generators. However, it has not been demonstrated that MPTP formation is involved in cardiac cell death due to obesity. Therefore, the aim of this work was to determine whether Ca2+ alterations and/or MPTP opening underlie cardiac dysfunction. We used obese Zucker fa/fa rats (32 weeks old), displaying concentric hypertrophy and cardiac dysfunction. We measured: i) Systolic and diastolic Ca2+ signaling in isolated myocytes, in basal conditions and upon β-adrenergic stimulation (β-AS), and ii) in vitro mitochondrial function: respiration, ROS production and MPTP opening. We found that the main alteration in Ca2+ signaling in fa/fa myocytes was a decrease in SERCA Ca2+ removal capacity, since Ca2+ transient amplitude and spark frequency were unchanged. Furthermore, in fa/fa myocytes, β-AS response was preserved. On the other hand, fa/fa mitochondria respiration, in state 3 decreased, but was unchanged in state 4, when glutamate/malate were used as substrate, resulting in an small decrease in respiratory control. In addition, fa/fa mitochondria were more sensitive to MPTP opening, induced by Ca2+ and carboxyatractiloside (CAT). Moreover, fa/fa mitochondria showed increased H2O2 production, and in exposed thiol groups in the adenine nucleotide translocase, a regulatory MPTP component. Since Ca2+ signaling is relatively normal in fa/fa cells, it does not seem to be the main contributor to the cardiac contractile dysfunction. However, given that fa/fa mitochondria showed decrease respiratory performance, were more susceptible to MPTP opening, and showed enhanced H2O2 production. We conclude that fa/fa mitochondria were more vulnerable to enhanced oxidative stress, causing MPTP opening, which could be exacerbated by SERCA slower Ca2+ removal capacity, leading to myocyte apoptosis.
Stressful life events and the onset of a generalized anxiety syndrome
Authors: D Blazer, D Hughes, L K George
Journal: American Journal of Psychiatry (1987)

In a study of 2,902 subjects from the National Institute of Mental Health Epidemiologic Catchment Area Project in North Carolina, the association between life events and the onset of new cases of generalized anxiety syndrome varied across demographic subgroups and type of life event measure. Men reporting four or more life events had a risk of generalized anxiety syndrome 8.5 times that of men reporting zero to three life events; no association was found for women. Both men and women reporting one or more unexpected, negative, very important life events had a threefold increase in the risk of developing generalized anxiety syndrome.
Hair Dye Use and Breast Cancer
Authors: C M Burnett, J Menkart
Journal: JNCI Journal of the National Cancer Institute (1979)

Hair Dye Use and Breast Cancer Get access JNCI: Journal of the National Cancer Institute, Volume 62, Issue 6, June 1979, Page 1327, https://doi.org/10.1093/jnci/62.6.1327 Published: 01 June 1979
Deterioration in premorbid functioning in schizophrenia: a developmental model of negative symptoms in drug-free patients
Authors: M E Kelley, M Gilbertson, A Mouton, D P van Kammen
Journal: American Journal of Psychiatry (1992)

The authors examined the relationship between negative symptoms and premorbid variables in drug-free schizophrenic patients.The authors studied 63 clinically stable male schizophrenic inpatients who were not receiving any psychoactive medication. The patients were classified as having negative, positive, or mixed symptoms, and their premorbid functioning during childhood, early adolescence, and late adolescence was assessed by using the Premorbid Adjustment Scale. Correlational analyses were applied to the classification and developmental models.Patients with negative symptoms had significantly lower levels of premorbid functioning during late adolescence and significantly greater premorbid deterioration between childhood and early adolescence. Correlational analysis revealed significant positive relationships between premorbid variables and negative symptoms.The data suggest that a deterioration in social and intellectual functioning between childhood and adolescence is associated with the development of a negative symptom syndrome in schizophrenia. The premorbid deterioration appears to be an early prodrome of the disorder. Whether this residual negative symptom syndrome is in some way related to the deficit syndrome of schizophrenia awaits a prospective study.
Then and Now
Authors: Samuel Vaisrub
Journal: JAMA (1975)

Writers are known to go through periods of mental aridity when no ideas germinate. Medical editorialists are no exception. Facing the challenge of a blank page with a blank mind, how do they put pen to paper? How do they meet a deadline during such agraphic crises? "Crises"? Only a short time ago crisis to a physician meant a sudden resolution of lobar pneumonia, a new lease on life. Now, not to be outdone by the front-page oil crisis, environmental crisis, sex crisis, and the like, medicine features its own crises of medical school admissions, drug abuse, malpractice, and above all, the crisis in health care delivery. "Delivery"? Is it not something we used to associate with a physician assisting in the birth of a new life? Now the term evokes visions of messenger boys depositing newspapers at the door. Is it because medical care has become less significant? "Significant"?
Dilemmas in the evaluation and management of religious cultists
Authors: F G Maleson
Journal: American Journal of Psychiatry (1981)

Religious cultism defies easy generalizations. Motivating forces behind cult membership range from brainwashing-like processes to fulfillment of severe predisposing psychopathological needs; they operate to varying degrees in different individuals. Thus, the formulation of a rational and consistent therapeutic strategy may be difficult, particularly for the clinician inexperienced in this area. Treatment may be further complicated by parental pressures to adopt a deprogramming therapy model, which risks the clinician's independence, objectivity, and effectiveness. Two contrasting case histories highlight these and other evaluation and treatment dilemmas.
Prospective Assessment of the Diagnostic and Therapeutic Impact of Small-Bowel Push Enteroscopy
Authors: A C Taylor, R J Buttigieg, I G McDonald, P V Desmond
Journal: Endoscopy (2003)

Background and Study Aims: Although the reported diagnostic yield of push enteroscopy has been substantial in previous studies, its clinical impact has never been prospectively evaluated. The primary aim of this study was to prospectively determine the diagnostic and therapeutic impact of enteroscopy. In addition, the yield of new and clinically important findings was prospectively assessed. Patients and Methods: Consecutive patients referred for enteroscopy were studied. The referring clinician completed a form indicating the working diagnosis, degree of diagnostic certainty, and the management plan had enteroscopy been unavailable. Diagnostic certainty was indicated on a scale of 1 = very unlikely (1 - 9 %) to 6 = certain (100 %). Following enteroscopy, the referring doctor completed another form indicating these features in the light of the enteroscopic findings. Results: The study group comprised 77 patients referred for 79 push enteroscopies. There was a change in working diagnosis or management plan as a result of enteroscopy in 39/77 (51 %) patients. The working diagnosis and the management plan changed in 29/77 (38 %) and 34/77 (44 %), respectively, and the diagnostic certainty changed in a further 29 patients (38 %). There were clinically significant small-bowel findings in 16 (20 %) and new upper gastrointestinal findings in 16 (20 %), giving an overall diagnostic yield of 40 %. Conclusions: Enteroscopy has a significant impact on clinicians’ working diagnoses and management plans.
Atypical Presentation of a Complex Eyelid Choristoma Mimicking a Chalazion with Pyogenic Granuloma
Authors: Johnny Li, Jianying Zeng, Roman Shinder
Journal: Ophthalmology (2016)

Atypical Presentation of a Complex Eyelid Choristoma Mimicking a Chalazion with Pyogenic GranulomaA 55-year-old man presented with a 4-year history of a painless, enlarging, right upper eyelid mass (Fig 1A).Excisional biopsy revealed a complex choristoma containing cartilage and ectopic lacrimal gland (Fig 1B).Atypical features of this case include involvement of the palpebral conjunctiva and appearance late in middle age.
Aspirin and Myocardial Infarction:
Authors: B Cohen
Journal: JAMA (1975)

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Community support programs: program evaluation and public policy
Authors: H C Schulberg
Journal: American Journal of Psychiatry (1979)

The plight of chronic psychiatric patients in the community has led to a major federal effort to resolve fragmented and disorganized care. The Community Support Programs (CSPs) recently funded by NIMH offer the promise of reducing these difficulties by creating comprehensive human service systems at the local and state levels. However, the author points out that these demonstration projects should be evaluated lest they continue to operate on the basis of rhetoric rather than fact. He presents an evaluation framework whereby indexes pertinent to each program goal of the CSPs can be measured and the resulting data used for public policy purposes.
Inhibition of a Specific DNA Repair System and Nitrosourea Cytotoxicity in Resistant Human Cancer Cells
Authors: Bernard W. Futscher, Kenneth C. Micetich, Diane M. Barnes, Richard I. Fisher, Leonard C. Erickson
Journal: Cancer Communications (1989)

In this report we present evidence which suggests that pretreatment of a highly nitrosourea-resistant human colon tumor cell line with non-cytotoxic doses of streptozotocin (STZ) prior to, or simultaneously with, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) exposure produces synergistic increases in cytotoxicity of several logs over the cytotoxicity produced by exposure to BCNU alone. STZ pretreatment or simultaneous treatment with BCNU allowed BCNU-induced DNA interstrand crosslinks to form in this cell line, in which BCNU alone did not induce DNA interstrand-crosslinks. Reversal of the schedule (i.e., STZ following BCNU) was less effective in producing synergistic cell kill or increased DNA interstrand crosslinking. Replacement of BCNU with fresh BCNU was not effective in producing increased cell kill and produced no observable interstrand crosslinking. Direct assays for guanine O6-DNA alkyltransferase activity confirmed that more than 75% inhibition of this important DNA repair system occurred following exposure to 2.5 mM STZ and that the inhibition was virtually complete when STZ pretreatment was combined with BCNU exposure.
Metoprolol
Authors: Jan Koch-Weser
Journal: New England Journal of Medicine (1979)

METOPROLOL TARTRATE (Lopressor) is a β-adrenoceptor antagonist released for clinical use in the United States last year (Fig. 1). It is the first systemic β-blocker to be allowed on the United States market since propranolol was approved for the treatment of arrhythmias in 1967. Metoprolol was marketed in Sweden in 1974, and by 1978 more than a quarter of a million patients in 21 countries had used the drug. Treatment of hypertension is the only indication for metoprolol presently sanctioned by the Food and Drug Administration; this indication was approved for propranolol only in 1976 as the latest of many. . . .
Clinical Trial Registration
Authors: Christine Laine, Richard Horton, Catherine D. DeAngelis, Jeffrey M. Drazen, Frank A. Frizelle, Fiona Godlee, Charlotte Haug, Paul C. Hébert, Sheldon Kotzin, Ana Marusic, Peush Sahni, Torben V. Schroeder, Harold C. Sox, Martin B. Van Der Weyden, Freek W.A. Verheugt
Journal: JAMA (2007)

In 2005, the International Committee of Medical Journal Editors (ICMJE) initiated a policy requiring investigators to deposit information about trial design into an accepted clinical trials registry before the onset of patient enrollment.1 This policy aimed to ensure that information about the existence and design of clinically directive trials was publicly available, an ideal that leaders in evidence-based medicine have advocated for decades.2 The policy precipitated much angst among research investigators and sponsors, who feared that registration would be burdensome and would stifle competition. Yet, the response to this policy has been overwhelming. The ICMJE promised to reevaluate the policy . . .