tbuckley/cabot-search huggingface dataset:
Echocardiographic Assessment of Left Ventricular Mass and Systolic Function in Mice
Authors: Julius M. Gardin, Francis M. Siri, Richard N. Kitsis, John G. Edwards, Leslie A. Leinwand
Journal: Circulation Research (1995)

Abstract The increasing use of transgenic mouse models for investigating the mechanisms of cardiac growth and function has made it important to develop noninvasive methods for assessing murine cardiac anatomy, size, and function. At present, murine cardiac mass can be determined only at necropsy. Left ventricular (LV) function can be assessed by use of various catheterization techniques, but these approaches are usually terminal procedures and provide no information about chamber anatomy and dimensions. Although transthoracic echocardiography has been used to study the LVs of rats and larger animals, the considerably smaller LV masses and somewhat faster heart rates of mice pose significant challenges to obtaining good-quality echocardiograms. In this study we tested the hypothesis that transthoracic echocardiography can image the murine LV as well as provide assessments of LV mass and function. Our results in a series of 33 mice, including normal, transgenic, and aortic-banded subgroups, demonstrate the capability of transthoracic two-dimensionally directed M-mode echocardiography in mice to (1) obtain good-quality images, (2) produce estimates of LV mass having good correlations with directly determined LV mass in normal mice, (3) detect LV hypertrophy noninvasively in different experimental models, and (4) identify impaired LV systolic function. Thus, echocardiography appears to be a promising approach for noninvasively assessing LV mass and function in mice.
Chronological reading of radiographs in rheumatoid arthritis increases efficiency and does not lead to bias
Authors: Lilian H D van Tuyl, Désirée van der Heijde, Dirk L Knol, Maarten Boers
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To evaluate the difference between chronological and random sequence reading in a series of radiographs with 11 years' follow-up. In addition, the influence of the starting point and length of series was evaluated. <h3>Methods</h3> Two experienced readers independently and repeatedly scored digitised radiographs of 62 patients at time points 0, 2, 5, 8 and 11 years of follow-up from the COBRA follow-up database according to the Sharp/van der Heijde method. A linear mixed model was fitted to the data. <h3>Results</h3> Over 11 years the mean scores increased by 3.8 points per year. Compared to random reading, chronological reading resulted in a slightly increased progression rate of 0.4 points per year (p=0.008) and a lower standard error of the mean total progression rate of 0.30 (compared to 0.35 for random reading). Over 11 years, this results in a small difference in progression estimates of about five points, but a highly relevant difference of over 25% of patients needed in a study to find a difference in radiological outcome between two groups. Reading of short series, or series including a baseline radiograph, results in a significantly higher yearly progression rate compared to reading of long series, or series not including a baseline measurement. <h3>Conclusions</h3> Chronological reading of radiographs is preferred above random reading, due to decreased variability around the estimation of the progression rate; this increased efficiency translates into smaller sample sizes, or increased power to detect small differences. For studies with long-term follow-up, the same two readers should read all radiographs, including baseline.
Relationship of Glycemic Control, Exogenous Insulin, and C-Peptide Levels to Ischemic Heart Disease Mortality Over a 16-Year Period in People With Older-Onset Diabetes
Authors: Flavio E. Hirai, Scot E. Moss, Barbara E.K. Klein, Ronald Klein
Journal: Diabetes Care (2008)

The purpose of this study was to examine the relationship of glycemic control and exogenous and endogenous insulin levels with all-cause and cause-specific mortality (ischemic heart disease and stroke) in an older-onset diabetic population.The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) is an ongoing, prospective, population-based cohort study of individuals with diabetes first examined in 1980-1982. A stratified sample of all individuals with diabetes diagnosed at 30 years of age or older was labeled "older-onset" (n = 1,370). Those participating in the 1984-1986 examination phase (n = 1,007) were included in the analysis. Endogenous insulin was determined by measurements of plasma C-peptide (in nanomoles per liter), and exogenous insulin was calculated in units per kilogram per day. Glycemic control was determined by levels of glycosylated hemoglobin (HbA(1)).After 16 years of follow-up, 824 individuals died (all-cause mortality); 358 deaths involved ischemic heart disease and 137 involved stroke. C-peptide and HbA(1) were significantly associated with all-cause and ischemic heart disease mortality in our study. The hazard ratio (95% CI) values for all-cause mortality were 1.12 (1.07-1.17) per 1% increase in HbA(1), 1.20 (0.85-1.69) per 1 unit x kg(-1) x day(-1) increase in exogenous insulin, and 1.15 (1.04-1.29) per 1 nmol/l increase in C-peptide and for ischemic heart disease mortality were 1.14 (1.06-1.22), 1.50 (0.92-2.46), and 1.19 (1.02-1.39) for HbA(1), exogenous insulin, and C-peptide, respectively, after adjusting for relevant confounders. C-peptide was associated with stroke mortality only among men (1.65 [1.07-2.53]).Our results show that individuals with higher endogenous insulin levels are at higher risk of all-cause, ischemic heart disease, and stroke mortality.
Mutation Profiling and Microsatellite Instability in Stage II and III Colon Cancer: An Assessment of Their Prognostic and Oxaliplatin Predictive Value
Authors: Patrick G. Gavin, Linda H. Colangelo, Debora Fumagalli, Noriko Tanaka, Matthew Y. Remillard, Greg Yothers, Chungyeul Kim, Yusuke Taniyama, Seung Il Kim, Hyun Joo Choi, Nicole L. Blackmon, Corey Lipchik, Nicholas J. Petrelli, Michael J. O'Connell, Norman Wolmark, Soonmyung Paik, Kay L. Pogue-Geile
Journal: Clinical Cancer Research (2012)

The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer.Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR).BRAF mutations were associated with MMR-deficient tumors (P < 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20-1.79; P ≤ 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83-2.95; P < 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33-0.70; P < 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit.This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP.
Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia
Authors: Dietmar Seiffert, Andrew M. Stern, William Ebling, Richard J. Rossi, Yu Chen Barrett, Richard Wynn, Gregory F. Hollis, Bokang He, Cathy J. Kieras, Donna L. Pedicord, Debra A. Cromley, Tsushung A. Hua, Robert B. Stein, Robert N. Daly, Anthony Sferruzza, Henry J. Pieniaszek, Jeffrey T. Billheimer
Journal: Blood (2002)
Functional, Genetic, and Epigenetic Aspects of Base and Nucleotide Excision Repair in Colorectal Carcinomas
Authors: Jana Slyskova, Vlasta Korenkova, Andrew R. Collins, Pavel Prochazka, Ludmila Vodickova, Jiri Svec, Ludmila Lipska, Miroslav Levy, Michaela Schneiderova, Vaclav Liska, Lubos Holubec, Rajiv Kumar, Pavel Soucek, Alessio Naccarati, Pavel Vodicka
Journal: Clinical Cancer Research (2012)

Abstract Purpose: DNA repair capacity (DRC) is a determinant not only of cancer development but also of individual response to therapy. Previously, altered base and nucleotide excision repair (BER and NER) have been described in lymphocytes of patients with sporadic colorectal cancer. We, for the first time, evaluate both excision repair capacities in human colon biopsies to study their participation in colorectal tumorigenesis. Experimental design: Seventy pairs of tumor and adjacent healthy tissues were analyzed for BER- and NER-specific DRC by a comet repair assay. Tissue pairs were further compared for expression levels of a panel of 25 BER and NER genes complemented by their promoter methylation status. Results: We observed a moderate increase of NER-DRC (P = 0.019), but not of BER-DRC in tumors. There was a strong correlation between both tissues for all investigated parameters (P &amp;lt; 0.001). However, 4 NER (CSB, CCNH, XPA, XPD) and 4 BER (NEIL1, APEX1, OGG1, PARP1) genes showed a 1.08- to 1.28-fold change difference in expression in tumors (P &amp;lt; 0.05). Individual gene expression levels did not correlate with overall DRC, and we did not detect any aberrant methylation of the investigated genes. Conclusions: Our complex analysis showed that tumor cells are not deficient in BER and NER, but rather follow patterns characteristic for each individual and are comparable with adjacent tissue. Alteration of excision repair pathways is not a pronounced event in colorectal carcinogenesis. This study shows the feasibility of DRC evaluation in human solid tissues, representing a complex marker of multigene DNA repair processes. Clin Cancer Res; 18(21); 5878–87. ©2012 AACR.
Phase II Study of the Proteasome Inhibitor Bortezomib (PS-341) in Patients with Metastatic Neuroendocrine Tumors
Authors: Manisha H. Shah, Donn Young, Hedy L. Kindler, Iain Webb, Barbara Kleiber, John Wright, Michael Grever
Journal: Clinical Cancer Research (2004)

This phase II study was undertaken to assess objective response, toxicity, tumor marker response, and pharmacodynamics of bortezomib in patients with metastatic neuroendocrine (carcinoid and islet cell) tumors.A total of 16 patients with measurable metastatic carcinoid (n=12) or islet cell (n=4) tumors received i.v. bolus of single agent bortezomib at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11 every 21 days. Tumor response was assessed at 12-week intervals using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. All patients were chemotherapy naïve and had Eastern Cooperative Oncology Group performance status of 0 to 1.No patient achieved a partial or a complete remission. The patients received total of 264 doses of therapy with a median of 15 doses per patient. Grade 4 toxicities were not observed. The most common grade 3 adverse events included peripheral sensory neuropathy (37%), diarrhea (25%), vomiting (18%), and ileus (18%). Six of 10 patients who experienced grade 2 to 3 peripheral sensory neuropathy also had grade 2 to 3 dizziness (n=2), orthostatic hypotension (n=2), syncope (n=1), ileus (n=2), or abdominal cramps (n=1). Changes in tumor marker levels did not correlate with tumor response. The mean percentage of 20S proteasome inhibition achieved in whole blood at 1 and 24 hours after bortezomib administration was 68 and 30%, respectively.Despite achieving the surrogate biologic end point, single-agent bortezomib did not induce any objective responses in patients with metastatic carcinoid or islet cell tumors. Additional investigation is warranted to clarify the possible association of autonomic neuropathy with bortezomib.
A Pkd1-Fbn1 Genetic Interaction Implicates TGF-β Signaling in the Pathogenesis of Vascular Complications in Autosomal Dominant Polycystic Kidney Disease
Authors: Dongyan Liu, Connie J. Wang, Daniel P. Judge, Marc K. Halushka, Jie Ni, Jennifer P. Habashi, Javid Moslehi, Djahida Bedja, Kathleen L. Gabrielson, Hangxue Xu, Feng Qian, David Huso, Harry C. Dietz, Gregory G. Germino, Terry Watnick
Journal: Journal of the American Society of Nephrology (2013)

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-β binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-β signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-β signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-β. Our data link the interaction of two important diseases to a fundamental signaling pathway.
Increased HLA-DR and decreased CD3 on human intestinal intraepithelial lymphocytes: evidence of activation?
Authors: M Abuzakouk, D Kelleher, C Feighery, C O'Farrelly
Journal: Gut (1996)

BACKGROUND: Activation of circulating T lymphocytes results in expression of HLA-DR, interleukin-2 receptor (IL-2R), transferrin receptor (TrR), and decreased amounts of surface CD3. AIM: To examine the activation status of human intestinal intraepithelial lymphocytes (IELs) by flow cytometry. PATIENTS AND METHODS: Duodenal biopsy specimens from 12 patients provided a source of intestinal lymphocytes. Dual colour analysis was used to compare activation marker expression by IELs with peripheral blood (PB) T lymphocytes from the same patients. RESULTS: All human IEL populations express HLA-DR and their density of expression is lower than on the small population of HLA-DR+ resting PB T lymphocytes (mean fluorescence intensity (MFI) 52.9, range 19.8-94.8 v 152.6 range, 49.1-320.3; p &lt; 0.01). The density of CD3 was significantly reduced on IELs (MFI 465.8, range 228.7-660), compared with PB T lymphocytes (756.3, range 444.5-1573.7; p &lt; 0.009). IL-2R was not detected on IELs; nor were the activation markers, TrR, M21 C5, or M2 B3. CONCLUSION: HLA-DR expression on IELs together with decreased CD3 expression suggest previous stimulation. However, the absence of additional markers of T cell activation may reflect a unique pathway of activation.
Insulin Detemir in Pregnancy: A Small but Significant Step Forward?
Authors: Aidan McElduff
Journal: Diabetes Care (2012)

Pregnancies complicated by diabetes are at increased risk of adverse fetal and maternal outcomes and longer-term health problems in the offspring. Treatments directed at improving glycemic control reduce these risks. However, observational studies show that pregnancies complicated by either type 1 or type 2 diabetes, compared with nondiabetic pregnancies, still have more adverse outcomes, including increased perinatal mortality (1,2).

The recent Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study (3) has established a continuum of risk between glycemic levels obtained during a glucose tolerance test and a variety of adverse fetal and maternal outcomes. Two large randomized controlled trials (4,5) of women with gestational diabetes mellitus, variously diagnosed, have demonstrated that treating and reducing glucose levels during pregnancy reduces many of these complications.

The poor fetal outcomes in preexisting diabetes are largely related to the degree of maternal glycemic control. This is very well documented for the risk of miscarriage, congenital malformations, and excessive fetal weight (3,6–8). Unfortunately, the currently available insulin preparations and the treatment paradigms used in an attempt to achieve normoglycemia are generally inadequate for the task. This is especially true for type 1 diabetes. Specifically, the current insulin therapies cannot mimic the complex physiology required to maintain normal blood glucose concentrations. …
Pseudomonas aeruginosa in the home environment of newly infected cystic fibrosis patients
Authors: P. Schelstraete, S. Van daele, K. De Boeck, M. Proesmans, P. Lebecque, J. Leclercq-Foucart, A. Malfroot, M. Vaneechoutte, F. De Baets
Journal: European Respiratory Journal (2007)

The source of acquisition of Pseudomonas aeruginosa in cystic fibrosis (CF) patients remains unknown. Patient-to-patient transmission has been well documented but the role of the environment as a source of initial infection is as yet unclear. In the present study, the origin of the first P. aeruginosa isolate in CF patients was investigated by comparing the P. aeruginosa genotype(s) from newly infected patients with genotypes of P. aeruginosa isolates from the home environment and from other patients from the same CF centre. A total of 50 newly infected patients were studied. P. aeruginosa could be cultured from 5.9% of the environmental samples, corresponding to 18 patients. For nine of these, the genotype of the environmental P. aeruginosa isolate was identical to the patient's isolate. In total, 72% of the environmental P. aeruginosa isolates were encountered in the bathroom. Patient-to-patient transmission within the CF centre could not be ruled out for three patients. In summary, a low prevalence of Pseudomonas aeruginosa was found in the home environment of the newly infected cystic fibrosis patients. The bathroom should be targeted in any preventive cleaning procedures. An environmental source of the new infection could not be ruled out in nine patients.
Build it up-Tear it down: protein quality control in the cardiac sarcomere
Authors: M. S. Willis, J. C. Schisler, A. L. Portbury, C. Patterson
Journal: Cardiovascular Research (2008)

The assembly and maintenance of the cardiac sarcomere, which contains the basic contractile components of actin and myosin, are essential for cardiac function. While often described as a static structure, the sarcomere is actually dynamic and undergoes constant turnover, allowing it to adapt to physiological changes while still maintaining function. A host of new factors have been identified that play a role in the regulation of protein quality control in the sarcomere, including chaperones that mediate the assembly of sarcomere components and ubiquitin ligases that control their specific degradation. There is clear evidence of sarcomere disorganization in animal models lacking muscle-specific chaperone proteins, illustrating the importance of these molecules in sarcomere structure and function. Although ubiquitin ligases have been found within the sarcomere structure itself, the role of the ubiquitin proteasome system in cardiac sarcomere regulation, and the factors that control its activity, are only just now being elucidated. The number of ubiquitin ligases identified with specificity for sarcomere proteins, each with distinct target substrates, is growing, allowing for tight regulation of this system. In this review, we highlight the dynamic interplay between sarcomere-specific chaperones and ubiquitin-dependent degradation of sarcomere proteins that is necessary in order to maintain structure and function of the cardiac sarcomere.
Incidence and survival of children with central nervous system primitive tumors in the French National Registry of Childhood Solid Tumors
Authors: E. Desandes, S. Guissou, P. Chastagner, B. Lacour
Journal: Neuro-Oncology (2014)

Central nervous system (CNS) tumors are the second most common childhood malignancy. The French National Registry of Childhood Solid Tumors (NRCST) makes it possible to describe this variety of distinct tumor types and to provide incidence and survival data in France on a nationwide basis. All children aged 0–14 years, who were registered with a primary CNS tumor in the NRCST of France between 2000 and 2008, were identified. Tumors were classified according to the International Classification of Childhood Cancer, third edition. Approximately 57% of pediatric CNS tumors were gliomas, with astrocytomas of the pilocytic type predominating. Distributions of subtypes by age showed that primitive neuroectodermal tumors and ependymomas mainly occurred in children aged <5 years. The mean annual incidence rate of CNS tumors was 39 per million. No statistically significant change in time trends of incidence rate was observed during 2000–2008. For all tumors combined, overall survival was 84.8% (95% CI, 83.7%–85.9%) at 1 year and 72.9% (95% CI, 71.5%–74.3%) at 5 years. Survival time trends were studied in a multivariate analysis observing a reduction in the risk of death in periods of diagnosis 2003–2005 (HR = 0.8; 95% CI, 0.7–0.9) and 2006–2008 (HR = 0.7; 95% CI, 0.6–0.9) compared with 2000–2002. The stable incidence rates during the last 10 years could indicate that major changes in environmental risk factors are unlikely, but the ongoing need for population-based surveillance remains relevant. Results indicate a positive trend in the survival probability still persistent in the 2000s.
Chromosomal location of the genes encoding the leukocyte adhesion receptors LFA-1, Mac-1 and p150,95. Identification of a gene cluster involved in cell adhesion.
Authors: A L Corbi, R S Larson, T K Kishimoto, T A Springer, C C Morton
Journal: The Journal of Experimental Medicine (1988)

The adhesion receptors Mac-1, LFA-1, and p150,95 are cell surface alpha/beta heterodimers that play a key role in leukocyte adhesion processes. The genes for Mac-1, LFA-1, and p150,95 alpha subunits have been located to chromosome 16 by means of Southern blot analysis using a series of somatic cell hybrids. Chromosomal in situ hybridization has demonstrated that the genes for the three alpha subunits map to the short arm of chromosome 16, between bands p11 and p13.1, defining a cluster of genes involved in leukocyte adhesion. The gene encoding the LFA-1/Mac-1/p150,95 beta subunit, and defective in leukocyte adhesion deficiency, has been located on chromosome 21, band q22. The leukocyte adhesion receptor alpha and beta subunits are mapped to chromosomal regions that have been shown to be involved in cytogenetic rearrangements in certain patients with acute myelomonocytic leukemia and the blast phase of chronic myelogenous leukemia, respectively.