tbuckley/cabot-search huggingface dataset:
IKr contributes to the altered ventricular repolarization that determines long-term cardiac memory
Authors: M OBREZTCHIKOVA, K PATBERG, A PLOTNIKOV, N OZGEN, I SHLAPAKOVA, A RYBIN, E SOSUNOV, P DANILOJR, E ANYUKHOVSKY, R ROBINSON
Journal: Cardiovascular Research (2006)

Cardiac memory (CM) is characterized by an altered T-wave morphology, which reflects altered repolarization gradients. We hypothesized that the delayed rectifier currents, I(Kr) and I(Ks), might contribute to these repolarization changes.We studied conscious, chronically instrumented dogs paced from the postero-lateral left ventricular (LV) wall at rates 5-10% faster than sinus rate for 3 weeks. ECGs during sinus rhythm were recorded on days 0, 7, 14 and 21 of pacing. Within 3 weeks, CM achieved steady state, hearts were excised, and epicardial and endocardial tissues and myocytes were studied.In unpaced controls, action potential duration to 50% and 90% repolarization (APD) in epicardium was shorter than in endocardium (P < 0.05); in CM epicardial APD increased at CL > or = 500 ms, while endocardial APD was either unchanged or decreased such that the transmural gradient seen in controls diminished (P < 0.05). A transmural I(Kr) gradient occurred in controls (epicardium>endocardium, P < 0.05) and was reversed in CM. No I(Ks) transmural gradient was found in controls, while in CM endocardial I(Ks) was greater than epicardial at greater than +50 mV. Canine ERG (cERG) mRNA and protein in epicardium > endocardium in controls (P < 0.05), and this difference was lost in CM. Expression levels of KCNQ1 and KCNE1 protein were similar in all groups.A transcriptionally induced change in epicardial I(Kr) contributes to the altered ventricular repolarization that characterizes CM.
Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA
Authors: I.E. Krop, N.U. Lin, K. Blackwell, E. Guardino, J. Huober, M. Lu, D. Miles, M. Samant, M. Welslau, V. Diéras
Journal: Annals of Oncology (2014)

We characterized the incidence of central nervous system (CNS) metastases after treatment with trastuzumab emtansine (T-DM1) versus capecitabine-lapatinib (XL), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study.
Analysis of Molecular Markers by Anatomic Tumor Site in Stage III Colon Carcinomas from Adjuvant Chemotherapy Trial NCCTG N0147 (Alliance)
Authors: Frank A. Sinicrope, Michelle R. Mahoney, Harry H. Yoon, Thomas C. Smyrk, Stephen N. Thibodeau, Richard M. Goldberg, Garth D. Nelson, Daniel J. Sargent, Steven R. Alberts
Journal: Clinical Cancer Research (2015)

To determine the frequency and prognostic association of molecular markers by anatomic tumor site in patients with stage III colon carcinomas.In a randomized trial of adjuvant FOLFOX ± cetuximab, BRAF(V600E) and KRAS (exon 2) mutations and DNA mismatch repair (MMR) proteins were analyzed in tumors (N = 3,018) in relationship to tumor location, including subsite. Cox models were used to assess clinical outcome, including overall survival (OS).KRAS codon 12 mutations were most frequent at the splenic flexure and cecum; codon 13 mutations were evenly distributed. BRAF mutation frequency sharply increased from transverse colon to cecum in parallel with deficient (d) MMR. Nonmutated BRAF and KRAS tumors progressively decreased from sigmoid to transverse (all P < 0.0001). Significantly, poorer OS was found for mutant KRAS in distal [HR, 1.98; 95% confidence interval (CI), 1.49-2.63; P < 0.0001] versus proximal (1.25; 95% CI, 0.97-1.60; P = 0.079) cancers. BRAF status and outcome were not significantly associated with tumor site. Proximal versus distal dMMR tumors had significantly better outcome. An interaction test was significant for tumor site by KRAS (P(adjusted) = 0.043) and MMR (P(adjusted) = 0.010) for OS. Significant prognostic differences for biomarkers by tumor site were maintained in the FOLFOX arm. Tumor site was independently prognostic with a stepwise improvement from cecum to sigmoid (OS: P(adjusted) = 0.001).Mutation in BRAF or KRAS codon 12 was enriched in proximal cancers whereas nonmutated BRAF/KRAS was increased in distal tumors. Significant differences in outcome for KRAS mutations and dMMR were found by tumor site, indicating that their interpretation should occur in the context of tumor location.
Pathogenesis and Management of Lactic Acidosis
Authors: R A Kreisberg
Journal: Annual Review of Medicine (1984)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Intracellular Signaling Pathways Activated by Neuropathic Factors
Authors: Rosalind A. Segal, Michael E. Greenberg
Journal: Annual Review of Neuroscience (1996)

Soluble and membrane embedded neurotrophic factors bind to specific receptors on responsive neurons and thereby initiate dramatic changes in the proliferation, differentiation, and survival of their target cells. Recent studies have elucidated many of the intracellular pathways by which neurotrophins and ciliary neurotrophic factor (CNTF) function to regulate gene expression and thereby achieve diverse biological responses. In this review we have focused particular attention on the importance of the Ras-MAP kinase pathway for neurotrophin signaling, and the role of the Jak-STAT pathway for CNTF signaling. Characterization of the enzymes, linker proteins, and transcription factors that are sequentially activated in response to neurotrophic factors has provided significant insight into the mechanisms by which these agents elicit specific biological responses during normal development and into the adaptive responses of mature neurons.
Vitamin D Levels in Subjects With and Without Type 1 Diabetes Residing in a Solar Rich Environment
Authors: Lindsey Bierschenk, John Alexander, Clive Wasserfall, Michael Haller, Desmond Schatz, Mark Atkinson
Journal: Diabetes Care (2009)

OBJECTIVE Previous studies, largely in northern Europe, have suggested an association between type 1 diabetes and reduced serum 25-hydroxy(OH) vitamin D levels, a concept we tested in individuals residing in a solar-rich region (Florida). RESEARCH DESIGN AND METHODS Serum samples from 415 individuals residing in Florida were cross-sectionally analyzed: 153 control subjects, 46 new-onset type 1 diabetic patients, 110 established type 1 diabetic patients (samples ≥5 months from diagnosis), and 106 first-degree relatives of the diabetic patients. RESULTS In this study, 25-OH vitamin D levels (median, range, interquartile range [IQR]) were similar among control subjects (20.1, below detection [bd]–163.5, 13.0–37.4 ng/ml), new-onset type 1 diabetic patients (21.2, bd–48.6, 12.2–30.2 ng/ml), established type 1 diabetic patients (23.2, bd–263.8, 13.8–33.9 ng/ml), and first-degree relatives (22.2, bd–59.9, 12.7–33.1 ng/ml) (P = 0.87). Mean 25-OH vitamin D levels were less than the optimal World Health Organization level of 30 ng/ml in all study groups. CONCLUSIONS Reduced serum 25-OH vitamin D levels were not specifically associated with type 1 diabetes. The uniform suboptimal 225-OH vitamin D levels, despite residence in a zone with abundant sunshine, support additional dietary vitamin D fortification practices.
Low Vitamin D and High Fibroblast Growth Factor 23 Serum Levels Associate with Infectious and Cardiac Deaths in the HEMO Study
Authors: Michel Chonchol, Tom Greene, Yingying Zhang, Andrew N. Hoofnagle, Alfred K. Cheung
Journal: Journal of the American Society of Nephrology (2015)

Longitudinal studies testing the relationship between repeated measures of vitamin D or fibroblast growth factor 23 (FGF23) and infectious and cardiac hospitalizations and death in hemodialysis patients have not been reported. We examined the association between yearly 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and FGF23 serum levels and various clinical outcomes using time-dependent Cox regression models with repeated yearly measures and fixed-covariate Cox models with only baseline values after controlling for important clinical covariates in the HEMO study. During a median follow-up of 3 years, 582 of the 1340 participants died, and 499 and 514 participants had a hospitalization or death attributed to infectious and cardiac causes, respectively. Patients in the highest 25(OH)D quartile had the lowest risk of infectious events (hazard ratio [HR] 0.66 versus the lowest quartile; 95% confidence interval [95% CI], 0.49-0.89), cardiac events (HR, 0.71; 95% CI, 0.53-0.96), and all-cause mortality (HR, 0.46; 95% CI, 0.34-0.62) in time-dependent analyses. No significant associations of 1,25(OH)2D with clinical outcomes were observed in time-dependent or fixed-covariate Cox models. In contrast, the highest FGF23 quartile was associated with a higher risk of infectious events (HR, 1.57 versus the lowest quartile; 95% CI, 1.13-2.18), cardiac events (HR, 1.49; 95% CI, 1.06-2.08), and all-cause mortality (HR, 1.50; 95% CI, 1.07-2.12) in fixed-covariate Cox models. The addition of inflammation markers into the statistical models did not attenuate these associations. Thus, disordered mineral metabolism may affect outcomes in chronic hemodialysis patients.
Adverse outcomes after total and unicompartmental knee replacement in 101 330 matched patients: a study of data from the National Joint Registry for England and Wales
Authors: Alexander D Liddle, Andrew Judge, Hemant Pandit, David W Murray
Journal: The Lancet (2014)

BackgroundTotal knee replacement (TKR) or unicompartmental knee replacement (UKR) are options for end-stage osteoarthritis. However, comparisons between the two procedures are confounded by differences in baseline characteristics of patients undergoing either procedure and by insufficient reporting of endpoints other than revision. We aimed to compare adverse outcomes for each procedure in matched patients.MethodsWith propensity score techniques, we compared matched patients undergoing TKR and UKR in the National Joint Registry for England and Wales. The National Joint Registry started collecting data in April 1, 2003, and is continuing. The last operation date in the extract of data used in our study was Aug 28, 2012. We linked data for multiple potential confounders from the National Health Service Hospital Episode Statistics database. We used regression models to compare outcomes including rates of revision, revision/reoperation, complications, readmission, mortality, and length of stay.Findings25 334 UKRs were matched to 75 996 TKRs on the basis of propensity score. UKRs had worse implant survival both for revision (subhazard ratio [SHR] 2·12, 95% CI 1·99–2·26) and for revision/reoperation (1·38, 1·31–1·44) than TKRs at 8 years. Mortality was significantly higher for TKR at all timepoints than for UKR (30 day: hazard ratio 0·23, 95% CI 0·11–0·50; 8 year: 0·85, 0·79–0·92). Length of stay, complications (including thromboembolism, myocardial infarction, and stroke), and rate of readmission were all higher for TKR than for UKR.InterpretationIn decisions about which procedure to offer, the higher revision/reoperation rate of UKR than of TKR should be balanced against a lower occurrence of complications, readmission, and mortality, together with known benefits for UKR in terms of postoperative function. If 100 patients receiving TKR received UKR instead, the result would be around one fewer death and three more reoperations in the first 4 years after surgery.FundingRoyal College of Surgeons of England and Arthritis Research UK.
Tracheobronchial mucociliary clearance in asthma: impairment during remission.
Authors: D Pavia, J R Bateman, N F Sheahan, J E Agnew, S W Clarke
Journal: Thorax (1985)

Tracheobronchial mucociliary clearance was measured in eight non-smoking patients with asthma in complete remission. The patients were symptom free and required no medication whatsoever for one to six months before assessment. Mucociliary clearance was measured with an objective, radioaerosol technique. For comparison, mucociliary clearance of eight non-smoking, healthy subjects with physical characteristics and pulmonary function similar to those of the asthmatics was also measured on two occasions. In their first assessment the healthy subjects inhaled the tracer radioaerosol under experimental conditions similar to those used for the asthmatics; in the second assessment they inhaled the radioaerosol rapidly to simulate the asthmatic pattern of deposition. Under similar experimental conditions the radioaerosol was deposited more proximally in the asthmatic subjects than in the normal subjects and the difference was statistically significant (p less than 0.01). When, however, the depth of radioaerosol lung penetration was similar in the two groups, there was evidence of a significantly (p less than 0.01) poorer mucociliary clearance six hours after radioaerosol inhalation in the asthmatic than in the healthy group. These findings raise the question whether asthma ever remits completely.
DMT1 expression: avoiding too much of a good thing
Authors: A P WALKER
Journal: Gut (2000)

See article on page 270 

Haemochromatosis is a common, inherited disorder of iron metabolism. The gene ( HFE ), which is mutated in the majority of patients, has been cloned. The HFE protein, however, is not an iron transporter, but rather is thought to function as a regulator of iron absorption. The cloning of the HFE gene was followed rapidly by the identification of further proteins involved in the iron absorption pathway in the duodenum and transfer to the main iron storage site in the liver. The identification of a new metal ion transporter in the rat provided the first molecular information on the active absorption of metal ions by mammalian cells.1 This divalent metal transporter 1 (DMT1) has a broad substrate specificity that includes Fe2+ and a range of other divalent metal cations.1 (DMT1 is also referred to as divalent cation transporter 1, DCT1, and natural resistance-associated macrophage protein 2, Nramp2.) DMT1 mRNA is widely expressed, with high levels in the proximal duodenum, the site of absorption of iron and most other divalent metal ions.1 The biological importance of this transporter is shown by its involvement in two naturally occurring animal mutants of iron metabolism. Homozygous mutation of DMT1 …
Novel ligands for zipping and unzipping the intercalated disk: today's experimental tools, tomorrow's therapies?
Authors: R. Veeraraghavan, S. Poelzing, R. G. Gourdie
Journal: Cardiovascular Research (2014)

This editorial refers to ‘Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function’ by A. Schlipp et al. , doi:10.1093/cvr/cvu206. 

Cardiac myocytes are mechanically coupled at intercalated disks by adherens junctions, desmosomes, and mixed composites of these two junction types.1,2 In addition to affording vital mechanical stability to a strongly contractile tissue, these junctions have also been demonstrated to stabilize closely apposed membranes of adjacent cells so as to facilitate electrical coupling via gap junctions.3 Therefore, it is scarcely surprising that mutations in various mechanical junction proteins have been associated with electrical abnormalities in pathologies such as arrhythmogenic cardiomyopathy.4 Given the array of mechanical junction proteins expressed by cardiac myocytes, there is a critical need to understand the specific role of each. In this context, Schlipp et al. 5 offer some intriguing results delineating the function of desmoglein-2 in mediating cell–cell interactions in HL-1 cells and demonstrate …
A new differentiation antigen (FT-1) shared with fetal thymocytes and leukemic cells in the mouse.
Authors: M Kasai, T Takashi, T Takahashi, T Tokunaga
Journal: The Journal of Experimental Medicine (1984)

A mouse monoclonal antibody (IgM) was obtained by cell hybridization between X63-Ag8.653 myeloma cells and spleen cells from a BALB mouse that was immunized with GRSL leukemia cells of the GR strain. This antibody identified a unique fetal antigen, which is expressed exclusively on embryonic thymocytes of all strains tested. Therefore, the antigen defined was named fetal thymus antigen-1, FT-1. The proportion of FT-1+ fetal thymocytes detected by immunofluorescence assay sharply decreases as gestation time increases, and finally they disappear from the thymus. On the other hand, Thy-1+ cells increase in inverse proportion. The immunofluorescence studies and absorption tests showed that FT-1 antigen is not detectable on brain, liver, kidney, or lymphoid tissue cells of adult mice. However, it is expressed on some leukemia cells of various mouse strains, which demonstrated that this is the first example of an oncofetal antigen of a mouse leukemia. The molecular weight of FT-1 antigen on leukemia cells was estimated to be 130,000 by means of biosynthetic labeling with [3H]galactose and [35S]methionine. The two-dimensional gel electrophoresis pattern of FT-1 antigen shows a family of glycoproteins with extensive charge heterogeneity. It was also shown that the FT-1 antigen molecule carries the receptor for DBA lectin.
Activated Coagulation Factor X: A Novel Mitogenic Stimulus for Human Mesangial Cells
Authors: RAFFAELLA MONNO, GIUSEPPE GRANDALIANO, ROBERTA FACCIO, ELENA RANIERI, CARMELA MARTINO, LORETO GESUALDO, FRANCESCO P. SCHENA
Journal: Journal of the American Society of Nephrology (2001)

Intraglomerular activation of the coagulation cascade is a common feature of mesangioproliferative glomerulonephritis. Besides thrombin, very little is known about the cellular effects of other components of the coagulation system. This study investigated the effect of activated factor X (FXa) on cultured human mesangial cells. This serine protease induced a significant and dose-dependent increase in DNA synthesis. In addition to its mitogenic effect, FXa caused a striking upregulation of platelet-derived growth factor (PDGF) A and B chain gene expression. Next, the intracellular mitogenic signaling pathways activated by FXa were investigated. FXa induced a rapid spike in cytosolic calcium concentration followed by a sustained plateau. This response was not influenced by the downregulation of thrombin receptors. In addition, FXa stimulated a significant upregulation of different tyrosine-phosphorylated proteins. One of these phosphorylated cellular proteins was represented by the c-jun N-terminal kinase, a member of the mitogen-activated protein kinase family. To evaluate the role of FXa enzymatic activity and of PDGF autocrine secretion, FXa-induced DNA synthesis was studied in the presence of leupeptin, a specific serine protease inhibitor, and neutralizing anti-PDGF antibody. To investigate the role of tyrosine kinase (TK) activation on FXa mitogenic effect, FXa-stimulated thymidine uptake was evaluated in the presence of genistein and herbimycin A, two powerful and specific TK inhibitors. FXa-elicited DNA synthesis was also examined after protein kinase C (PKC) downregulation by prolonged incubation with phorbol-12-myristate-13-acetate to study the influence of the phospholipase C-PKC axis. The proliferative effect of FXa required its proteolytic activity, and the activation of TK was only partially dependent on PKC activation while it was PDGF independent. Finally, it was shown by reverse transcription-PCR that mesangial cells do not express the signaling splicing variant of the putative FXa receptor, effector protease receptor-1. In conclusion, the present study demonstrated that FXa is a powerful mitogenic factor for human mesangial cells, and it induces its cellular effect not through effector protease receptor-1, but most likely by binding a protease-activated receptor and activating phospholipase C-PKC and TK signaling pathways.
Phase II trial of gemcitabine in patients with previously untreated metastatic cancer of the esophagus or gastroesophageal junction
Authors: A.B. Sandler, H.L. Kindler, L.H. Einhorn, E. Mitchell, G. Masters, M. Kraut, S. Nicol, D. Raghavan
Journal: Annals of Oncology (2000)
Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome
Authors: Jeanne Drouin, Nancy L. Carson, Odette Laneuville
Journal: American Journal of Hematology (2004)

Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient. Am. J. Hematol. 78:41–48, 2005. © 2004 Wiley-Liss, Inc.
NOCTURNAL INCONTINENCE IN CHILDREN
Authors: F. McG. Loughnane
Journal: BMJ (1930)

The Practitioner's Mirror and Retrospect.d0JfTie Ediior wiU ht Olad to receive offers of co-operation and This^latgdyw inthTcaL "of much valuable material full of interest and instruction ^ , rnffane hosvitals and (3) the great body ) he younger and less-known members of the hospital staff' (-) those 001 .
Cultured satellite cells as a model for the study of muscle dysfunction in COPD
Authors: Pascal Pomiès, Julie Rodriguez, Sami Sedraoui, Fares Gouzi, Gilles Carnac, Jacques Mercier, Christian Préfaut, Maurice Hayot
Journal: European Respiratory Journal (2013)

The mechanisms leading to muscle dysfunction in COPD have not been elucidated. One hypothesis is the exhausted muscle regenerative capacity of satellite cells, which would compromise muscle mass maintenance, but the capacity of satellite cells to proliferate and differentiate properly in COPD is unknown.  The objective was to compare the characteristics of satellite cells derived from COPD patients and healthy subjects, in terms of proliferative and differentiation capacities, morphological phenotype, and oxidative stress status. Therefore, we purified and cultivated satellite cells from frozen quadriceps biopsies of 8 COPD patients and 8 healthy controls. We examined proliferation parameters, the myogenic fusion index, myotube diameter, cell susceptibility to oxidative stress, antioxidant enzyme expression, protein carbonylation, and lipid peroxidation in cultured myoblasts and/or myotubes. The myogenic fusion index was similar in myotubes from controls and COPD patients. Myotube diameter was significantly smaller in COPD patients. Significant correlations were observed between the cultured myotube diameter and fiber cross sectional area as well as muscle voluntary contraction. Furthermore, myoblasts from COPD patients were significantly more susceptible to H2O2-induced oxidative stress than those from control subjects, and oxidative stress damage, like protein carbonylation and lipid peroxidation, was higher in COPD myoblasts and/or myotubes.  In conclusion, cultured satellite cells from COPD patients display characteristics of atrophy and oxidative stress similar to those in in vivo COPD limb muscles, suggesting that we have developed a cellular model for the study of muscle dysfunction in COPD.