tbuckley/cabot-search huggingface dataset:
Molecular prediction of time to metastasis from ocular melanoma fine needle aspirates
Authors: J. W. Harbour
Journal: Clinical Cancer Research (2006)

A77   Ocular (uveal) melanoma is the most common primary cancer of the eye and the second most common form of melanoma. Despite local therapy, about 50% of these cancers metastasize hematogenously to the liver, after which death occurs within a few months. The delay from ocular diagnosis and treatment to clinical detection of liver metastasis varies from a few months to many years, indicating that micrometastases can remain dormant for long periods of time. By the time metastatic disease becomes clinically detectable, it has grown to a large tumor burden that is highly resistant to therapy. If patients with micrometastatic disease could be identified prior to clinical presentation, prophylactic therapy may delay or prevent metastatic death. Various methods have been proposed for identifying patients with micrometastatic disease, including clinicopathologic algorithms and detection of circulating melanoma cells, but none of these methods has demonstrated adequate sensitivity and specificity for clinical decision-making in individual patients. However, we recently described a gene expression-based classification of ocular melanomas that predicts metastatic death with extremely high predictive accuracy. Primary tumors exhibiting a class 1 signature have a low risk and those with a class 2 signature a high risk of metastasis (P
PharmGKB Submission Update: IV. PMT Submissions of Genetic Variations in ATP-Binding Cassette Transporters to the PharmGKB Network
Authors: Tan D. Nguyen, Jason M. Gow, Leslie W. Chinn, Libusha Kelly, Hotcherl Jeong, Conrad C. Huang, Doug Stryke, Michiko Kawamoto, Susan J. Johns, Elaine Carlson, Travis Taylor, Thomas E. Ferrin, Andrej Sali, Kathleen M. Giacomini, Deanna L. Kroetz
Journal: Pharmacological Reviews (2006)

Category: genotype Project: Pharmacogenetics of Membrane Transporters [Table 1][1] provides HUGO Gene Nomenclature Committee (HGNC) symbols, PharmGKB submission URLs, submission dates, and release dates. [Table 2][2] provides HGNC symbols, HGNC names, synonyms, GenBank accession numbers, and locus
The Glycogen-Binding Domain on the AMPK β Subunit Allows the Kinase to Act as a Glycogen Sensor
Authors: Andrew McBride, Stephanos Ghilagaber, Andrei Nikolaev, D. Grahame Hardie
Journal: Cell Metabolism (2009)

AMPK beta subunits contain a conserved domain that causes association with glycogen. Although glycogen availability is known to affect AMPK regulation in vivo, the molecular mechanism for this has not been clear. We now show that AMPK is inhibited by glycogen, particularly preparations with high branching content. We synthesized a series of branched oligosaccharides and show that those with a single alpha1-->6 branch are allosteric inhibitors that also inhibit phosphorylation by upstream kinases. Removal of the outer chains of glycogen using phosphorylase, thus exposing the outer branches, renders inhibition of AMPK more potent. Inhibition by all carbohydrates tested was dependent on the glycogen-binding domain being abolished by mutation of residues required for carbohydrate binding. Our results suggest the hypothesis that AMPK, as well as monitoring immediate energy availability by sensing AMP/ATP, may also be able to sense the status of cellular energy reserves in the form of glycogen.
Fcγ Receptor Iib–Deficient Mice Develop Goodpasture's Syndrome upon Immunization with Type IV Collagen
Authors: Akira Nakamura, Takae Yuasa, Azusa Ujike, Masao Ono, Toshihiro Nukiwa, Jeffrey V. Ravetch, Toshiyuki Takai
Journal: The Journal of Experimental Medicine (2000)

The combination of hemorrhagic pneumonitis and rapidly progressive glomerulonephritis is a characteristic feature of Goodpasture's syndrome (GPS), an autoimmune disease resulting from the interaction of pathogenic anti–collagen type IV (C-IV) antibodies with alveolar and glomerular basement membranes. Lack of a suitable animal model for this fatal disease has hampered both a basic understanding of its etiology and the development of therapeutic strategies. We now report a novel model for GPS using mice deficient in a central regulatory receptor for immunoglobulin (Ig)G antibody expression and function, the type IIB Fc receptor for IgG (FcγRIIB). Mutant mice immunized with bovine C-IV reproducibly develop massive pulmonary hemorrhage with neutrophil and macrophage infiltration and crescentic glomerulonephritis. The distinctive linear, ribbon-like deposition of IgG immune complex seen in GPS was observed along the glomerular and tubulointerstitial membranes of diseased animals. These results highlight the role of FcγRIIB in maintaining tolerance and suggest that it may play a role in the pathogenesis of human GPS.
Psychiatric Resident Conceptualizations of Mood and Affect Within the Mental Status Examination
Authors: Michael Serby
Journal: American Journal of Psychiatry (2003)

To explore the ways in which psychiatry residents conceptualize the terms "mood" and "affect," a 14-item questionnaire was sent to residency programs in New York.The questions consisted of possible definitions of mood and affect; all questions required a "true" or "false" response. Residents (N=99) were asked how they viewed mood and affect from a temporal perspective (i.e., sustained versus momentary) and in terms of an objective-subjective (or external-internal) dichotomy.There were inconsistencies in the temporal view of mood (said to be sustained by 60.6% and momentary by 50.5%) and affect ("pervasive" by 26.3% and "momentary" by 66.3%). Residents overwhelmingly defined mood as being subjective and internal and affect as being objective and external.If mood and affect are to be viewed from both perspectives, psychiatrists must infer the enduring internal emotional tone (mood) of a patient over an entire interview.
Effect of Race/Ethnicity and Persistent Recognition of Depression on Mortality in Elderly Men With Type 2 Diabetes and Depression
Authors: Lisa K. Richardson, Leonard E. Egede, Martina Mueller
Journal: Diabetes Care (2008)

To determine whether mortality risk from depression among elderly men with type 2 diabetes differs by ethnicity and persistent recognition of depression.Data on a cohort of 14,500 male veterans with type 2 diabetes were analyzed. Diagnoses of depression and diabetes were based on ICD-9 codes. Persistent recognition was defined as an ICD-9 code for depression documented in at least the second or third visit after the initial diagnosis of depression. Hazards of death were compared using Cox proportional hazards regression models adjusting for relevant covariates.Over 10 years, 2,305 deaths were documented. Mortality risk was higher for depressed than nondepressed veterans with diabetes (hazard ratio [HR] 1.6 [95% CI 1.3-1.8]). Among those with depression, mortality risk was lower with persistent recognition (0-2 visits vs. >or=3 visits after initial diagnosis, HR 0.58 [0.40-0.89]) but higher for whites than blacks (1.60 [1.11-2.31]).Increased mortality from depression differs by ethnicity and persistent recognition.
5-AMINOSALICYLIC ACID ENEMAS
Authors: S. Muller-Lissner, K. Wah, M. Frey, G. Munst, F. Pace, A.L. Blum, A. Raitano, T. Mussi, S. Steccanella, S. Strazzari, M. Campieri, G.A. Lanfranchi, C. Brignola, G. Bazzocchi
Journal: The Lancet (1982)
Expression profiling in multistage hepatocarcinogenesis: Identification of HSP70 as a molecular marker of early hepatocellular carcinoma
Authors: M Chuma
Journal: Hepatology (2003)

Hepatocellular carcinoma (HCC) associated with chronic liver disease evolves from precancerous lesions and early HCC to a progressed form. Nodule-in-nodule–type HCC (progressed HCC within early HCC) represents the transition from early to progressed HCC and, therefore, is useful in molecular genetic analysis of HCC progression during multistage carcinogenesis. We compared expression profiles among 7 early components and 7 progressed components of nodule-in-nodule–type HCCs and their corresponding noncancerous liver tissues with oligonucleotide array. Of the approximately 12,600 genes that were analyzed, a set of 95 genes provided a molecular signature that distinguished between early HCC components and their noncancerous liver tissues, and a set of 92 genes distinguished between progressed and early HCC components. Of these genes, the most abundantly up-regulated gene in early HCC components (P < .001) was heat-shock protein 70 (HSP70). Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) confirmed this finding. Further immunohistochemical examination of HSP70 revealed its significant overexpression in early HCC compared with precancerous lesions (P < .001) and in progressed HCC compared with early HCC (P < .001). In conclusion, molecular signatures were clearly different in noncancerous liver tissue as compared with the early and progressed components of nodule-in-nodule–type HCC. Moreover, HSP70 could be a sensitive marker for the differential diagnosis of early HCC from precancerous lesion or noncancerous liver, a difficult distinction for pathologists due to very well differentiated histology with little atypia in early HCC.
Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease
Authors: Eva P. Szymanski, Janice M. Leung, Cedar J. Fowler, Carissa Haney, Amy P. Hsu, Fei Chen, Priya Duggal, Andrew J. Oler, Ryan McCormack, Eckhard Podack, Rebecca A. Drummond, Michail S. Lionakis, Sarah K. Browne, D. Rebecca Prevots, Michael Knowles, Gary Cutting, Xinyue Liu, Scott E. Devine, Claire M. Fraser, Hervé Tettelin, Kenneth N. Olivier, Steven M. Holland
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not.Objectives: To examine genetic variants in patients with PNTM, their unaffected family members, and a control group.Methods: Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person.Measurements and Main Results: A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 × 10−6 and P = 2.7 × 10−8, respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 × 10−17), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category.Conclusions: Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection.
Fetuin-A Regulation of Calcified Matrix Metabolism
Authors: Willi Jahnen-Dechent, Alexander Heiss, Cora Schäfer, Markus Ketteler
Journal: Circulation Research (2011)

The final step of biomineralization is a chemical precipitation reaction that occurs spontaneously in supersaturated or metastable salt solutions. Genetic programs direct precursor cells into a mineralization-competent state in physiological bone formation (osteogenesis) and in pathological mineralization (ectopic mineralization or calcification). Therefore, all tissues not meant to mineralize must be actively protected against chance precipitation of mineral. Fetuin-A is a liver-derived blood protein that acts as a potent inhibitor of ectopic mineralization. Monomeric fetuin-A protein binds small clusters of calcium and phosphate. This interaction results in the formation of prenucleation cluster-laden fetuin-A monomers, calciprotein monomers, and considerably larger aggregates of protein and mineral calciprotein particles. Both monomeric and aggregate forms of fetuin-A mineral accrue acidic plasma protein including albumin, thus stabilizing supersaturated and metastable mineral ion solutions as colloids. Hence, fetuin-A is a mineral carrier protein and a systemic inhibitor of pathological mineralization complementing local inhibitors that act in a cell-restricted or tissue-restricted fashion. Fetuin-A deficiency is associated with soft tissue calcification in mice and humans.
Diagnostic yield of specific inhalation challenge in hypersensitivity pneumonitis
Authors: Xavier Muñoz, Mónica Sánchez-Ortiz, Ferran Torres, Ana Villar, Ferran Morell, María-Jesús Cruz
Journal: European Respiratory Journal (2014)

Reliable methods are needed to diagnose hypersensitivity pneumonitis. The aim of the study was to establish the diagnostic yield of specific inhalation challenge (SIC) in patients with hypersensitivity pneumonitis. All patients with suspected hypersensitivity pneumonitis in whom SIC was performed (n=113) were included. SIC was considered positive when patients showed a decrease of &gt;15% in forced vital capacity (FVC) or &gt;20% in diffusing capacity of the lung for carbon dioxide, or a decrease of 10% to 15% in FVC accompanied by a temperature increase of 0.5°C within 24 h of inhalation of the antigen. SIC was positive to the agents tested in 68 patients: 64 received a diagnosis of hypersensitivity pneumonitis and SIC results were considered false-positive in the remaining four patients. In the SIC-negative group (n=45), 24 patients received a diagnosis of hypersensitivity pneumonitis and SIC results were considered false-negative, and 21 patients were diagnosed with other respiratory diseases. The sensitivity and specificity of the test were 72.7% and 84%, respectively. Having hypersensitivity pneumonitis caused by an antigen other than birds or fungi predicted a false-negative result (p=0.001). In hypersensitivity pneumonitis, positive SIC testing virtually confirms the diagnosis, whereas negative testing does not rule it out, especially when the antigenic sources are not birds or fungi.
Myosin Light Chain Mutation Causes Autosomal Recessive Cardiomyopathy With Mid-Cavitary Hypertrophy and Restrictive Physiology
Authors: Timothy M. Olson, Margaret L. Karst, Frank G. Whitby, David J. Driscoll
Journal: Circulation (2002)

Background — Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM. Methods and Results — We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the essential light chain of myosin locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism. Conclusions — Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.
Human Epidermal Growth Factor Receptor 2 Status Correlates With Lymph Node Involvement in Patients With Estrogen Receptor (ER) –Negative, but With Grade in Those With ER-Positive Early-Stage Breast Cancer Suitable for Cytotoxic Chemotherapy
Authors: John M.S. Bartlett, Ian O. Ellis, Mitch Dowsett, Elizabeth A. Mallon, David A. Cameron, Stephen Johnston, Emma Hall, Roger A'Hern, Clare Peckitt, Judith M. Bliss, Lindsay Johnson, Peter Barrett-Lee, Paul Ellis
Journal: Journal of Clinical Oncology (2007)

Purpose Human epidermal growth factor receptor 2 (HER-2) expression is associated with increased risk of high-grade disease, nodal metastasis, and absence of estrogen receptors (ERs) in early breast cancer. We tested interactions between ER and HER-2 to determine if they may modulate breast cancer nodal metastasis and proliferation. Patients and Methods Tumors from the Cancer Research UK Taxotere as Adjuvant Chemotherapy phase III trial were tested for HER-2 using current diagnostic procedures. ER status, progesterone status, clinicopathologic characteristics, and patient age were included in a logistic regression analysis to identify associations with HER-2 status (positive v negative). Results A total of 841 (23.6%) of 3,565 samples were HER-2 positive (3+ by immunohistochemistry or positive by fluorescent in situ hybridization). ER-negative tumors were more likely to be HER-2 positive than were ER-positive tumors (odds ratio [OR] = 1.87, ER negative v ER positive; P &lt; .001). For ER-positive tumors, risk of HER-2 positivity increased by grade (OR = 7.6, grade 3 v grade 1; P &lt; .001) but not nodal status (OR = 1.3, four or more positive nodes v node negative; P = .08). Conversely, ER negative node-positive tumors were markedly more frequently HER-2 positive than node-negative cases (OR = 3.05, four or more positive nodes v node negative; P &lt; .001) but independent of grade (OR = 0.82, grade 3 v grade 1; P = .76). Conclusion In early breast cancer patients selected for cytotoxic chemotherapy, we identified significant interactions between HER-2 and ER expression that correlate with tumor pathology. In ER-positive breast cancers, HER-2 expression correlates with grade, not nodal metastasis. In ER-negative breast cancers, HER-2 expression correlates with increased nodal positivity, not grade. ER and HER-2 expression may modify tumor pathology via ER/HER-2–mediated cross talk.
Phenotype Matters: The Case for Careful Characterization of Relevant Traits
Authors: Linda M. Brzustowicz, Anne S. Bassett
Journal: American Journal of Psychiatry (2008)

This issue of the Journal features an article by Almasy et al. ( 1) that presents the results of a genome-wide linkage study of schizophrenia, using both categorical diagnoses and quantitative scores on multiple neurocognitive tasks as phenotypes.Deficits in many neurocognitive functions have been observed in individuals with schizophrenia and their clinically unaffected relatives (2).The central hypothesis of the Almasy et al. study was that the use of such neurocognitive phenotypes would increase the power to localize genes related to illness.The study sample was comprised of a set of 43 extended families, with multiple members diagnosed with schizophrenia.On average, 16 persons per family participated in the study.Most families had two affected individuals, and one-third had between three and five affected family members.Although this would be considered a moderate-sized sample for a linkage study, the use of quantitative phenotypes provided additional strength to the study design.
Small Area Variations in Out-of-Hospital Cardiac Arrest: Does the Neighborhood Matter?
Authors: Comilla Sasson, Carla C. Keirns, Dylan Smith, Michael Sayre, Michelle Lea Macy, William Meurer, Bryan F. McNally, Arthur L. Kellermann, Theodore J. Iwashyna
Journal: Annals of Internal Medicine (2010)

The incidence and outcomes of out-of-hospital cardiac arrest vary widely across cities. It is unknown whether similar differences exist at the neighborhood level.To determine the extent to which neighborhoods have persistently high rates of cardiac arrest but low rates of bystander cardiopulmonary resuscitation (CPR).Multilevel Poisson regression of 1108 cardiac arrests from 161 census tracts as captured by the Cardiac Arrest Registry to Enhance Survival (CARES).Fulton County, Georgia, between 1 October 2005 to 30 November 2008.Incidence of cardiac arrest, by census tract and year and by rates of bystander CPR.Adjusted rates of cardiac arrest varied across neighborhoods (interquartile range [IQR], 0.57 to 0.73 per 1000 persons; mean, 0.64 per 1000 persons [SD, 0.11]) but were stable from year to year (intraclass correlation, 0.36 [95% CI, 0.26 to 0.50]; P < 0.001). Adjusted bystander CPR rates also varied by census tract (IQR, 19% to 29%; mean, 25% [SD, 10%]).Analysis was based on data from a single county.Surveillance data can identify neighborhoods with a persistently high incidence of cardiac arrest and low rates of bystander CPR. These neighborhoods are promising targets for community-based interventions.Robert Wood Johnson Foundation Clinical Scholars Program, National Institutes of Health, and Centers for Disease Control and Prevention.
RNA as a Source of Transposase for Sleeping Beauty-Mediated Gene Insertion and Expression in Somatic Cells and Tissues
Authors: Andrew Wilber, Joel L. Frandsen,, Jennifer L. Geurts, David A. Largaespada, Perry B. Hackett, R. Scott McIvor
Journal: Molecular Therapy (2005)

Sleeping Beauty (SB) is a DNA transposon capable of mediating gene insertion and long-term expression in vertebrate cells when co-delivered with a source of transposase. In all previous reports of SB-mediated gene insertion in somatic cells, the transposase component has been provided by expression of a co-delivered DNA molecule that has the potential for integration into the host cell genome. Integration and continued expression of a gene encoding SB transposase could be problematic if it led to transposon re-mobilization and reintegration. We addressed this potential problem by supplying the transposase-encoding molecule in the form of mRNA. We show that transposase-encoding mRNA can effectively mediate transposition in vitro in HT1080 cells and in vivo in mouse liver following co-delivery with a recoverable transposon or with a luciferase transposon. We conclude that in vitro-transcribed mRNA can be used as an effective source of transposase for SB-mediated transposition in mammalian cells and tissues.