tbuckley/cabot-search huggingface dataset:
Risk factors for the development of left ventricular hypertrophy in a prospectively followed cohort of dialysis patients.
Authors: J D Harnett, G M Kent, P E Barre, R Taylor, P S Parfrey
Journal: Journal of the American Society of Nephrology (1994)

The objective of this study was to determine the role of hypertension, age, anemia, and hyperparathyroidism in the pathogenesis of left ventricular hypertrophy (LVH) developing after the initiation of dialysis for ESRD. A cohort of dialysis patients who were being treated for ESRD and whose initial echocardiograms after the start of dialysis therapy do not show LVH were studied. Three hundred and thirty-nine patients have been monitored at three centers since 1985. Serial echocardiograms have been performed with M-mode and two-dimensional echocardiography. Data on blood pressure, height, weight, hemoglobin, number and type of antihypertensive medications, and the presence of functioning vascular access have been collected prospectively. Prospective data on serum calcium, serum phosphorus, alkaline phosphatase, and parathyroid hormone levels and skeletal x-rays have also been collected. By the use of set criteria and blinding to echocardiographic outcome, the presence and severity of hyperparathyroidism were graded by consensus. Fifty-one patients met eligibility criteria for inclusion; of these, 14 developed LVH (cases) and 37 did not (controls). Cases had significantly higher systolic blood pressure (P = 0.009) and were older (P = 0.01) than controls. Systolic blood pressure correlated significantly with final posterior left ventricular wall thickness (r = 0.39; P < 0.01). By the use of multivariate analysis, age and systolic blood pressure were significantly and independently associated with increased left ventricular mass index. The frequency of hyperparathyroidism was low and equal in both groups. There was a trend toward more severe anemia in cases that did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
CRISPR/Cas9: a powerful genetic engineering tool for establishing large animal models of neurodegenerative diseases
Authors: Zhuchi Tu, Weili Yang, Sen Yan, Xiangyu Guo, Xiao-Jiang Li
Journal: Molecular Neurodegeneration (2015)

Animal models are extremely valuable to help us understand the pathogenesis of neurodegenerative disorders and to find treatments for them. Since large animals are more like humans than rodents, they make good models to identify the important pathological events that may be seen in humans but not in small animals; large animals are also very important for validating effective treatments or confirming therapeutic targets. Due to the lack of embryonic stem cell lines from large animals, it has been difficult to use traditional gene targeting technology to establish large animal models of neurodegenerative diseases. Recently, CRISPR/Cas9 was used successfully to genetically modify genomes in various species. Here we discuss the use of CRISPR/Cas9 technology to establish large animal models that can more faithfully mimic human neurodegenerative diseases.
DX-8951f, a Hexacyclic Camptothecin Analog, on a Daily-Times-Five Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies
Authors: Eric K. Rowinsky, Thomas R. Johnson, Charles E. Geyer, Lisa A. Hammond, S. Gail Eckhardt, Ronald Drengler, Leslie Smetzer, John Coyle, Jinee Rizzo, Garry Schwartz, Anthony Tolcher, Daniel D. Von Hoff, Robert L. De Jager
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m 2 /d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m 2 /d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model. CONCLUSION: The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m 2 /d for MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule.
Total Serum IgE and Specific IgE levels in 10-15 years old children with respiratory symptoms and healthy controls in Sicily and Malta
Authors: Martin Balzan, David Bilocca, Christopher Zammit, Fabio Cibella, Paolo Colombo, Valeria Longo, Charles Borg, Giuseppe Piva, Stephen Montefort, Giovanni Viegi
Journal: European Respiratory Journal (2014)

Introduction:  The RESPIRA study (EU Funded-Italia-Malta) was performed in the district of Gela (Southern Sicily) and Malta in 2012/3 in 10-15 years old schoolchildren (n=2,047) by means of standard respiratory questionnaires (ISAAC),and clinical exam of case and control subjects.   Aims and Objectives : To measure total serum IgE levels in cases (n=127, males=45) and controls (n=142, Males=64), specific IgEs in cases (n=90, Males=53), and controls (n=82, Males=38).   Materials and Methods:  Cases reported wheeze and/or use of asthma medications in the last 12 months, while controls answered negatively to both and rhinitis.   Results:  Total Serum IgE (n=269) was raised (>144 IU/l) in 70/127 cases vs 25/142 controls (p=.0001). In males 30/76 of cases vs 11/64 controls (p=.005), while in females cases 15/51 vs 14/78, (p=.14). Positive specific IgE (>0.34 U/ml) was noted for at least one allergen in 54/90 cases vs 30/82 controls (p=.002). House dust mite (HDM) was positive in 27/90 cases vs 12/82 controls (p=.0001), Parietaria positive 12/90 cases vs 2/82 controls (p=.011), cat 22/90 vs 13/82 controls (p=.19), while in male subgroup 14/53 of cases were positive vs 4/38 controls (p=.06). Dog 9/90 cases vs 8/82 controls (NS). Olive positive in 13/90 cases vs 8/82 controls (NS). Alternaria positive in 6/90 cases vs 2/82 controls (NS). Goldenrod Solidago Virgaurea positive in 2/90 cases vs 1/82 controls, and Cladosporium 0/90 cases, 1/82 controls.   Conclusion:  Positive Total serum IgE and specific IgE to HDM and Parietaria in all patients and cat in males only were higher in cases than in controls.
Antigens of a Human Breast Carcinoma Cell Line (BT 20). I. Synthesis of Serum Proteins, Membrane-Associated Antigens, and Oncofetal-Associated Antigens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J Hurlimann, R Dayal
Journal: JNCI Journal of the National Cancer Institute (1978)

The synthesis of various products by a human mammary cell line (BT 20) was studied by incorporation of 14Clabeled amino acids, choline, glucosamine, or galactosamine into nondialyzable materials. These products had molecular weights ranging from less than 12,300 daltons to more than 200,000 daltons. They were analyzed by immunoelectrophoresis and double diffusion in agar. Among the synthesized products, the following proteins were identified: β2-glycoprotein I, α2HS-glycoprotein, α2-lipoprotein, actin, β2-microglobulin, carcinoembryonic antigen, three oncofetal-associated antigens, and various erythrocyte membrane-associated antigens (namely, glycophorin). Synthesis of milk proteins was not detectable. Only the protein moiety of the glycophorin molecule seemed to be synthesized. The β2-microglobulin was synthesized in an unbound state as well as bound to a glycoprotein whose relationship with the transplantation or tumor antigens must be determined. The three oncofetal-associated antigens were also synthesized in vitro by human fetal tissues and neoplastic and dysplastic human mammary tissues.
Drug-drug interactions in hospitalized patients with chronic obstructive pulmonary disease
Authors: Tina Roblek, Katja Trobec, AleÅ¡ Mrhar, Mitja LainÅ¡c
Journal: European Respiratory Journal (2012)

Aim:   Chronic obstructive pulmonary disease (COPD) patients are treated with several drugs for their primary disease and comorbidity, which carries the risk of clinically relevant drug-drug interactions (DDIs). We aimed to evaluate DDI in hospitalized COPD patients.   Methods:   This retrospective study included COPD patients hospitalized from January 2011 to July 2011 in a tertiary care clinic. Pharmacological therapy at admission and discharge was evaluated for DDI with electronic Lexi-Comp database: C- monitor therapy; D- consider therapy modification; X- avoid combination.   Results:   We included 196 patients (68% male, age 71 ±9 years). The average number of prescribed drugs was significantly lower at hospital admission than at discharge (6 ±3 vs. 7 ±2, p 2 -agonists (10% of cases) and the most prevalent type D interaction between β-blocker and α-blocker (9%). There were 15 type X interactions recorded at discharge, among which the most common was between non selective β-blocker and β2-adrenoreceptor agonist (8 cases)   Conclusion:   DDI are common in hospitalized patients with COPD but few carry clinically relevant risk. Most type X interactions were between non-selective β-blocker and β2-adrenoreceptor agonist which likely was indicated and should be safe in COPD patients.
The mammalian Na+/H+ exchanger gene family--initial structure/function studies.
Authors: M Tse, S Levine, C Yun, S Brant, J Pouyssegur, M Donowitz
Journal: Journal of the American Society of Nephrology (1993)

A gene family of mammalian Na+/H+ exchangers has been identified. Three isoforms have been cloned, sequenced, and stably expressed, and structure/function studies have been begun. Several of the isoforms are found in the epithelia, and one of them is epithelial specific.
Association of<i>KIF3A</i>, but not<i>OVOL1</i>and<i>ACTL9</i>, with atopic eczema in Italian patients
Authors: T. Lepre, R. Cascella, M. Ragazzo, E. Galli, G. Novelli, E. Giardina
Journal: British Journal of Dermatology (2012)

Atopic eczema (AE) (OMIM %603165) is the most common chronic inflammatory skin disease characterized by xerosis, pruritus, and erythematous lesions with increased transepidermal water loss. It's a complex disease due to the interaction between environmental and genetics factors. To date, different loci have been related to the disease.To verify the association, between AE and rs479844, rs2164983, and rs2897442, target for OVOLI (11q13), ACTL9 (19p13.2), and in KIF3A (5q31) genes in the Italian population. Recently, these SNPs have been validated as associated to the disease.A case-control study testing a cohort of 359 AE cases and 778 controls.We confirmed the association between rs2897442 in KIF3A gene and the disease at both allele and genotype level (P-value: 4.8 × 10(-4) and P-value: 6.3 × 10(-4), respectively). The C allele of the SNP showed an Odds Ratio (OR) of 1.46 (95% CI 1.18-1.82), moreover the CC genotype achieved an OR of 2.77 (95% CI 1.66-4.61). We failed to reveal association between AE and the other two SNPs tested.Our study indicated KIF3A as a novel gene implicated in the development of AE in the Italian population.
Palmitate Has Proapoptotic and Proinflammatory Effects on Articular Cartilage and Synergizes With Interleukin‐1
Authors: Oscar Alvarez‐Garcia, Nicole H. Rogers, Roy G. Smith, Martin K. Lotz
Journal: Arthritis & Rheumatology (2014)

Obesity is a major risk factor for the development of osteoarthritis (OA) that is associated with a state of low-grade inflammation and increased circulating levels of adipokines and free fatty acids (FFAs). The aim of this study was to analyze the effects of saturated (palmitate) and monounsaturated (oleate) FFAs on articular chondrocytes, synoviocytes, and cartilage.Human articular chondrocytes and fibroblast-like synoviocytes obtained from young healthy donors and OA chondrocytes from patients undergoing total knee replacement surgery were treated with palmitate or oleate alone or in combination with interleukin-1β (IL-1β). Cell viability, caspase activation, and gene expression of proinflammatory factors, extracellular matrix (ECM) proteins, and proteases were studied. In addition, chondrocyte viability, IL-6 production, and matrix damage were assessed in bovine and human articular cartilage explants cultured with FFAs in the presence or absence of IL-1β.Palmitate, but not oleate, induced caspase activation and cell death in IL-1β-stimulated normal chondrocytes, and up-regulated the expression of IL-6 and cyclooxygenase 2 in chondrocytes and fibroblast-like synoviocytes through Toll-like receptor 4 (TLR-4) signaling. In cartilage explants, palmitate induced chondrocyte death, IL-6 release, and ECM degradation. Palmitate synergized with IL-1β in stimulating proapoptotic and proinflammatory cellular responses. Pharmacologic inhibition of caspases or TLR-4 signaling reduced palmitate and IL-1β induced cartilage damage.Palmitate acts as a proinflammatory and catabolic factor that, in synergy with IL-1β, induces chondrocyte apoptosis and articular cartilage breakdown. Collectively, our data suggest that elevated levels of saturated FFAs that are often found in patients who are obese may contribute to the pathogenesis of OA.
Identification of patients at high risk for Clostridium difficile infection: development and validation of a risk prediction model in hospitalized patients treated with antibiotics
Authors: C.H. van Werkhoven, J. van der Tempel, R. Jajou, S.F.T. Thijsen, R.J.A. Diepersloot, M.J.M. Bonten, D.F. Postma, J.J. Oosterheert
Journal: Clinical Microbiology and Infection (2015)
Increased risk of preschool wheeze both with higher BMI in infancy and at age 4 years
Authors: Emma Goksör, Bernt Alm, Rolf Pettersson, Per Möllborg, Laslo Erdes, Nils Åberg, Göran Wennergren
Journal: European Respiratory Journal (2012)

Background: Overweight has been associated with wheezing and asthma both in children and adults. It is debated whether overweight early in life predisposes for later wheeze or if the association is due to asthmatic children being less active. The aim of this study was to explore the relationship between body mass index, BMI, and recurrent wheeze (≥ 3 episodes during the last 12 months) at preschool age.

Methods: Data were obtained from a prospective, longitudinal study of a cohort of children born in Western Sweden in 2003. 8176 families (50% of the birth cohort) were randomly selected. The parents answered questionnaires at 6 and 12 months and at 4.5 years of age. The response rate at 4.5 years was 4496, i.e. 83% of the 5398 questionnaires distributed at 4.5 years. Odds ratios were calculated with BMI as a continuous variable.

Results: In multivariate analyses, the risk of recurrent wheeze at preschool age was increased both by a higher BMI at age 12 months (OR 1.2, 95% CI 1.03-1.4) and by a higher BMI at age 4 years (OR 1.2, 1.04-1.4).

Adjusting for recurrent wheeze during infancy or excluding children with recurrent wheeze during infancy had no major influence on the ORs.

In addition, recurrent wheeze in infancy did not increase the risk of overweight at 4 years.

The analyses controlled for preterm birth, smoking during pregnancy, family history of atopy, own allergic disease in infancy, parental education, short breast-feeding, small for gestational age, gender and maternal overweight before pregnancy.

Conclusion: A higher BMI at 12 months or at 4 years both increased the risk of recurrent wheeze at preschool age. Wheezing during infancy did not explain the associations seen.
Phase I Trial of Twice-Weekly Gemcitabine and Concurrent Radiation in Patients With Advanced Pancreatic Cancer
Authors: A. William Blackstock, Stephen A. Bernard, Frederick Richards, Kaye S. Eagle, L. Douglas Case, Michael E. Poole, Paul D. Savage, Joel E. Tepper
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer. PATIENTS AND METHODS: Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m 2 by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m 2 increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed. RESULTS: The dose-limiting toxicities at 60 mg/m 2 given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m 2 dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression. CONCLUSION: A dose of twice-weekly gemcitabine at 40 mg/m 2 produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.
The JAK3 inhibitor CP-690550 is a potent anti-fibrosis agent in a murine model of pulmonary fibrosis induced by bleomycin
Authors: Beixian Zhou, Zhiping Fu, Yansheng Wang, Jun Xu
Journal: European Respiratory Journal (2012)

Rationale: We previously suggested that JAK3, a cytoplasmic tyrosine kinase involved in receptor signaling for cytokines storm, is a molecular determinant in exacerbated innate immune inflammation. A selective JAK3 inhibitor can alleviate immunopathologic injury. Dose it has a potential for treating the lung fibrosis associated with autoimmunity? In the present study, CP-690550, a novel inhibitor of JAK3, was subjected to examination of its effects on lung fibrosis in a murine model of Bleomycin(BLM)-induced pulmonary inflammation. Methods&Results: Flow cytometry for typing bronchoalveolar lavage fluid (BAL) cells showed much higher level of T cells containing high frequencies of CD3+CD8+ and NKT+ cells in the BLM-challenged mice than control, but no significant changes were detected in the mice with CP-690550 treatment(15 mg/kg/d for two weeks) or JAK3-/- mice where pathology displayed attenuation of the lung fibrosis, corresponding to significantly increased survival rates(38.5% of BLM-challenged mice v.s.100% of the mice treated with CP-690550 or 84.6% of JAK3-/- mice following BLM challenge, P
Prediagnostic Anthropometry and Incident Urothelial Cancer in the Malmö Diet and Cancer Study: Link Between Obesity and Low-Risk but not High-Risk Disease
Authors: K. Boman, J. Manjer, G. Ahlgren, K. Jirström
Journal: Annals of Oncology (2014)

ABSTRACT   Aim: While epidemiological studies have shown that obesity is associated with an increased risk of several forms of cancer, the links with urothelial cancer (UC) are inconsistent. Here, we examined associations of prediagnostic anthropometry with risk of UC, overall and in relation to clinicopathological characteristics, in a prospective population-based cohort study.  Methods: Among 28098 participants the Malmo Diet and Cancer Study, 355 incident UC cases had been registered by Dec 31 2010; 335 (94.4%) of which were located in the bladder. Seven anthropometric factors; height, weight, bodyfat %, hip circumference, waist circumference, BMI and waist-hip ratio (WHR) were categorized into quartiles (Q). Hazard ratios (HR) of UC, overall as well as of low-risk (Ta, grade 1 and 2) and high-risk (Ta grade3, CIS and T1-4) tumours, were calculated using multivariable Cox regression models, adjusted for sex, age, smoking and alcohol intake.  Results: An elevated BMI, but no other anthropometric measurement, was associated with an increased overall UC risk in the entire cohort (HR for Q1(ref)-Q4: 1.0, 0.98, 1.09, 1.32, ptrend= 0.050), and in men (HR for Q1-4: 1.0, 0.87, 0.96 and 1.42, ptrend= 0.037). There were no associations between obesity and UC risk in women. Obesity was not associated with high-risk tumours in the entire cohort, but several anthropometric factors were significantly associated with low-risk tumours; i.e. weight (HR for Q1-4: 1.0, 1.45, 2.24, 2.07, ptrend 0.023), waist (HR for Q1-4: 1.0, 1.16, 2.18, 1.99, ptrend 0.043), hip (HR for Q1-4: 1.0, 1.76, 1.05, 2.13, ptrend 0.028), and BMI (HR for Q1-4: 1.0, 0.86, 1.30, 1.70, ptrend 0.009). Sex-stratified analyses revealed no significant associations between obesity and high-risk UC, but significant associations were found between BMI and low-risk tumours in men and between weight and low-risk tumours in women. Obesity had no impact on survival in UC cases.  Conclusions: These findings provide support for a link between obesity and low-risk but not high-risk urothelial cancer and, hence, underline the importance of taking tumour characteristics into consideration in epidemiological studies.  Disclosure: All authors have declared no conflicts of interest.
Function of Cd3ε-Mediated Signals in T Cell Development
Authors: Connie L. Sommers, Jan B. Dejarnette, Kun Huang, Jan Lee, Dalal El-Khoury, Elizabeth W. Shores, Paul E. Love
Journal: The Journal of Experimental Medicine (2000)

The T cell antigen receptor (TCR) and pre-TCR complexes are composed of multiple signal-transducing subunits (CD3 gamma, CD3 delta, CD3 epsilon, and zeta) that each contain one or more copies of a semiconserved functional motif, the immunoreceptor tyrosine-based activation motif (ITAM). Although biochemical studies indicate that individual TCR-ITAMs may bind selectively or with different affinity to various effector molecules, data from other experiments suggest that at least some ITAMs are functionally equivalent. In this study, we examined the role of CD3straightepsilon ITAM-mediated signals in T cell development by genetically reconstituting CD3 epsilon-deficient mice with transgenes encoding either wild-type or ITAM-mutant (signaling defective) forms of the protein. The results demonstrate that signals transduced by CD3 epsilon are not specifically required for T cell maturation but instead contribute quantitatively to TCR signaling in a manner similar to that previously observed for zeta chain. Unexpectedly, analysis of TCR-transgenic/CD3 epsilon-mutant mice reveals a potential role for CD3 epsilon signals in T cell survival.