tbuckley/cabot-search huggingface dataset:
Interleukin-4 and Interleukin- 13 Act on Glomerular Visceral Epithelial Cells
Authors: JOSÉ G. VAN DEN BERG, JAN ATEN, M. ANWAR CHAND, NIKE CLAESSEN, LISETTE DIJKINK, JOHN WIJDENES, FADI G. LAKKIS, JAN J. WEENING
Journal: Journal of the American Society of Nephrology (2000)

Abstract. In minimal change nephrosis (MCN), proteinuria is associated with structural changes of the glomerular visceral epithelial cells (GVEC). The occurrence of MCN has been associated with T-helper2 lymphocyte-dependent conditions. To examine a direct role for type 2 cytokines in GVEC injury, the expression of interleukin (IL)-4/IL-13 receptors by GVEC and direct effects of IL-4 and IL-13 on GVEC were studied. Reverse transcription-PCR showed that isolated human and rat glomeruli and cultured human and rat GVEC expressed mRNA for IL-4Rα, IL-13Rα1, and IL-13Rα2. Protein expression of IL-4Rα and IL-13Rα2 by GVEC in human kidney biopsies and by cultured human GVEC was detected by immunohistochemistry. Western blotting demonstrated phosphorylation of STAT6 in cultured GVEC upon incubation with IL-4 or IL-13. This indicated signal transduction via the heterodimeric receptor complex IL-4R2, which is composed of the IL-4Rα and the IL-13Rα1. Direct effects on GVEC function were examined in monolayer experiments. IL-4 and IL-13 dose-dependently decreased transepithelial electrical resistance of monolayers of rat GVEC to approximately 30 and 40% of baseline values, respectively. The transepithelial electrical resistance decrease was associated with a significant increase in short-circuit current, whereas no changes were observed in the transmonolayer flux of the macromolecules horseradish peroxidase (molecular weight, 44 kD) and 14 C-mannitol (molecular weight, 182 Da). No changes in cell structure were observed with electron microscopy. It is concluded that by binding to specific IL-4/IL-13 receptors, IL-4 and IL-13 can exert specific effects on GVEC function, which could be of pathogenetic relevance for glomerular injury in MCN.
Insulin pumps improve glucose control in children with type 1 diabetes, study finds
Authors: S. Mayor
Journal: BMJ (2015)

Treatment with an insulin pump provides significantly better glycaemic control than injecting insulin in children and adolescents with type 1 diabetes, a study analysing data from three large international registries has found—yet these pumps are used infrequently in the United Kingdom because guidelines limit their use.

The study, published in Diabetologia ,1 looked at the effect of treating type 1 diabetes with an insulin pump on glycated haemoglobin (HbA1c) in 54 410 children and adolescents aged under 18 over the period 2011-12. Researchers obtained the data from the German/Austrian …
Indices Predicting Long-term Survival after Valve Replacement in Patients with Aortic Regurgitation and Patients with Aortic Stenosis
Authors: JOHN W. HIRSHFELD, STEPHEN E. EPSTEIN, ARTHUR J. ROBERTS, D. LUKE GLANCY, ANDREW G. MORROW
Journal: Circulation (1974)

The long-term results of aortic valve replacement were reviewed in all 88 patients with isolated aortic regurgitation and all 103 patients with isolated aortic stenosis who were operated upon at the National Heart and Lung Institute from 1963 to 1971. Survival curves were compared to determine whether any of 30 preoperative clinical and hemodynamic findings correlated with long-term survival. The indices that were of predictive value in patients with aortic regurgitation were found to be different from those in aortic stenosis. Symptoms, cardiac index, and cardiothoracic ratio did not influence survival in patients with aortic regurgitation. In these patients, survival was inversely correlated with the level of left ventricular end-diastolic pressure (LVEDP): six-year survival was 74% in patients with LVEDP ≤ 10 mm Hg, 41% with LVEDP 11-20 ( P &lt; .05), and 30% with LVEDP &gt; 20 ( P &lt; .01). Survival also was lower in patients with aortic regurgitation who had elevated pulmonary arterial and left atrial pressures, and in patients with electrocardiographic evidence of severe left ventricular hypertrophy (LVH). Using an LVH point score method (Romhilt-Estes), 56% of patients with a score ≤ 6 survived six years; 29% with a score &gt; 6 survived ( P &lt; .02). Survival in aortic stenosis did not relate to any of the above, but did correlate with preoperative functional class. Five-year survival was 70% in class II, but only 40% in class III-IV ( P &lt; .02). Moreover, cardiothoracic ratio in patients with aortic stenosis correlated with survival in an unexpected way. Eleven of 31 patients with cardiothoracic ratio ≤ .45 had sudden unexplained death postoperatively, compared to only six of 72 patients with cardiothoracic ratio &gt; .45 ( P &lt; .01). This difference did not correlate with postoperative hemodynamic measurements, including magnitude of the transprosthetic gradient. We conclude that certain preoperative indices are of value in predicting long-term prognosis after valve replacement for aortic regurgitation and for aortic stenosis, but that the specific predictive indices for the two groups differ.
AGED GARLIC EXTRACT AND COENZYME Q10 HAS FAVORABLE EFFECT ON OXIDATIVE AND INFLAMMATORY MARKERS AND CORONARY ATHEROSCLEROSIS PROGRESSION
Authors: Irfan Zeb, Naser Ahmadi, Jigar Kadakia, Vahid N. Larijani, Lily Honoris, Ferdinand Flores, Matthew Budoff
Journal: Journal of the American College of Cardiology (2012)
Serum levels and genotype distribution of α<sub>1</sub>-antitrypsin in the general population
Authors: Ilaria Ferrarotti, Gian Andri Thun, Michele Zorzetto, Stefania Ottaviani, Medea Imboden, Christian Schindler, Arnold von Eckardstein, Lucia Rohrer, Thierry Rochat, Erich W Russi, Nicole M Probst-Hensch, Maurizio Luisetti
Journal: Thorax (2012)

<h3>Rationale</h3> α1-Antitrypsin (AAT) deficiency is one of the commonest rare respiratory disorders worldwide. Diagnosis, assessment of risk for developing chronic obstructive pulmonary disease (COPD), and management of replacement therapy require the availability of precise and updated ranges for protein serum levels. <h3>Objective</h3> This paper aims to provide ranges of serum AAT according to the main genotype classes in the general population. <h3>Methods</h3> The authors correlated mean AAT serum levels with the main <i>SERPINA1</i> variants (M1Ala/M1Val (rs6647), M3 (rs1303), M2/M4 (rs709932), S (rs17580) and Z (rs28929474)) in 6057 individuals enrolled in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) cohort. <h3>Results</h3> The following ranges (5th–95th percentile) of AAT were found in the serum (g/litre): 1.050–1.640 for PI*MM, 0.880–1.369 for PI*MS, 0.730–1.060 for PI*SS, 0.660–0.997 for PI*MZ and 0.490–0.660 for PI*SZ. There was very little overlap in AAT serum levels between genotype classes generally not believed to confer an enhanced health risk (MM and MS) and those associated with an intermediate AAT deficiency and a potentially mildly enhanced health risk (SS, MZ). <h3>Conclusion</h3> This work resulted in three important findings: technically updated and narrower serum ranges for AAT according to PI genotype; a suggestion for a population-based 'protective threshold' of AAT serum level, used in decision-making for replacement therapy; and more precise ranges framing the intermediate AAT deficiency area, a potential target for future primary prevention.
Strongly Enhanced Antitumor Activity of Trastuzumab and Pertuzumab Combination Treatment on HER2-Positive Human Xenograft Tumor Models
Authors: Werner Scheuer, Thomas Friess, Helmut Burtscher, Birgit Bossenmaier, Josef Endl, Max Hasmann
Journal: Cancer Research (2009)

The human epidermal growth factor receptor (HER) family plays an important role in cell survival and proliferation, and is implicated in oncogenesis. Overexpression of HER2 is associated with aggressive disease and poor prognosis. Trastuzumab is a humanized monoclonal antibody targeting HER2 and has proven survival benefit for women with HER2-positive early and metastatic breast cancer. Pertuzumab, another monoclonal antibody, is a HER2 dimerization inhibitor that binds to a different epitope on HER2 than trastuzumab and inhibits HER2 dimer formation with other HER family members such as HER3 and HER1. We investigated the antitumor activity of these agents alone and in combination in HER2-positive breast and non-small cell lung cancer xenografts. Our data show that the combination of trastuzumab and pertuzumab has a strongly enhanced antitumor effect and induces tumor regression in both xenograft models, something that cannot be achieved by either monotherapy. The enhanced efficacy of the combination was also observed after tumor progression during trastuzumab monotherapy. Near-IR fluorescence imaging experiments confirm that pertuzumab binding to tumors is not impaired by trastuzumab pretreatment. Furthermore, we show by in vitro assay that both trastuzumab and pertuzumab potently activate antibody-dependent cellular cytotoxicity. However, our data suggest that the strongly enhanced antitumor activity is mainly due to the differing but complementary mechanisms of action of trastuzumab and pertuzumab, namely inhibition of HER2 dimerization and prevention of p95HER2 formation.
Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder
Authors: Leonardo Salmena, Razqallah Hakem
Journal: The Journal of Experimental Medicine (2005)

Caspase-8 is best known for its cell death function via death receptors. Recent evidence indicates that caspase-8 also has nonapoptotic functions. Caspase-8 deficiency is associated with pathologies that are unexpected for a proapoptotic molecule, such as abrogation of activation-induced lymphocyte proliferation, perturbed immune homeostasis, and immunodeficiency. In this study, we report the long-term physiological consequences of T cell-specific deletion of caspase-8 (tcasp8-/-). We show that tcasp8-/- mice develop an age-dependent lethal lymphoproliferative and lymphoinfiltrative immune disorder characterized by lymphoadenopathy, splenomegaly, and accumulation of T cell infiltrates in the lungs, liver, and kidneys. Peripheral casp8-/- T cells manifest activation marker up-regulation and are proliferating in the absence of any infection or stimulation. We also provide evidence suggesting that this immune disorder is different from the autoimmune lymphoproliferative syndrome. Interestingly, the condition described in tcasp8-/- mice manifests features consistent with the disorder described in humans with Caspase-8 deficiency. These findings suggest that tcasp8-/- mice may serve as an animal model to evaluate Caspase-8-deficient patient prognosis and therapy. Overall, our study uncovers novel in vivo functions for caspase-8 in immune regulation.
Sequences Homologous to the hobo Transposable Element in E Strains of Drosophila melanogaster
Authors: M. I. Galindo, Y. Bigot, M. D. Sánchez, G. Periquet, L. Pascual
Journal: Molecular Biology and Evolution (2001)

Hobo is one of the three Drosophila melanogaster transposable elements, together with the P and I elements, that seem to have recently invaded the genome of this species. Surveys of the presence of hobo in strains from different geographical and temporal origins have shown that recently collected strains contain complete and deleted elements with high sequence similarity (H strains), but old strains lack hobo elements (E strains). Besides the canonical hobo sequences, both H and E strains show other poorly known hobo-related sequences. In the present work, we analyze the presence, cytogenetic location, and structure of some of these sequences in E strains of D. melanogaster. By in situ hybridization, we found that euchromatic hobo-related sequences were in fixed positions in all six E strains analyzed: 38C in the 2L arm; 42B and 55A in the 2R arm; 79E and 80B in the 3L arm; and 82C, 84C, and 84D in the 3R arm. Sequence comparison shows that some of the hobo-related sequences from Oregon-R and iso-1 strains are similar to the canonical hobo element, but their analysis reveals that they are substantially diverged and rearranged and cannot code for a functional transposase. Our results suggest that these ubiquitous hobo-homologous sequences are immobile and are distantly related to the modern hobo elements from D. melanogaster.
Evidence for a specific receptor site for lidocaine, quinidine, and bupivacaine associated with cardiac sodium channels in guinea pig ventricular myocardium.
Authors: C W Clarkson, L M Hondeghem
Journal: Circulation Research (1985)

According to the modulated receptor hypothesis, sodium channels have a specific receptor site for local anesthetic and antiarrhythmic drugs. Thus, in the presence of a high concentration of two drugs, competitive displacement of one drug by another may occur. Furthermore, if a drug that has relatively rapid post-stimulation recovery kinetics (e.g., lidocaine) displaces another drug with relatively slow recovery kinetics (i.e., quinidine or bupivacaine), then a net reduction in sodium channel blockade is expected at certain stimulation rates. We tested this prediction, using the maximum upstroke velocity of the ventricular action potential as an indicator of drug-free sodium channels. A single sucrose gap technique was used to stimulate guinea pig papillary muscles, and to control membrane voltage at all times except during the action potential upstroke. Drug-induced inhibition of maximum upstroke velocity increased as the stimulation rate was increased, and was significant (P less than 0.05) at stimulation rates between 2.5 and 4 Hz in the presence of 43 microM lidocaine (n = 5), and between 0.15 and 4 Hz in the presence of 3.5 microM bupivacaine (n = 4). The addition of 43 microM lidocaine to a perfusate containing 3.5 microM bupivacaine resulted in a net increase in maximum upstroke velocity that was significant at rates between 1 and 3.3 Hz, with a maximum increase of 25 +/- 6% at 1.6 Hz. In contrast, addition of 43 microM lidocaine to a perfusate containing 15 microM quinidine did not result in a significant change in maximum upstroke velocity at driving rates between 0.05 and 3.3 Hz (P greater than 0.2; n = 4). However, evidence for displacement of quinidine by lidocaine could be demonstrated by measuring post-stimulation recovery after a conditioning train of 19 10-msec pulses applied at 28 Hz. With this stimulation protocol, 41 +/- 4% of maximum upstroke velocity recovered slowly from block with a time constant of 3.7 +/- 1.2 seconds at - 100 mV in the presence of 15 microM quinidine (n = 5). In the presence of a mixture of 43 microM lidocaine and 15 microM quinidine, this slow component was significantly reduced to 16 +/- 7% (n = 5; P less than 0.01), while 71 +/- 13% of maximum upstroke velocity recovered with a time constant of 115 +/- 21 msec, typical of lidocaine-blocked channels. A two-drug version of the modulated receptor theory was formulated. The effects of drug mixtures could be accounted for by this model.(ABSTRACT TRUNCATED AT 400 WORDS)
Noninfectious Pneumonitis after Everolimus Therapy for Advanced Renal Cell Carcinoma
Authors: Dorothy A. White, Philippe Camus, Masahiro Endo, Bernard Escudier, Emiliano Calvo, Hideyuki Akaza, Hirotsugu Uemura, Euloge Kpamegan, Andrea Kay, Matthew Robson, Alain Ravaud, Robert J. Motzer
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors.To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus.Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis.Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%).Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124).
Cardiovascular Morbidity and Mortality After Treatment for Ductal Carcinoma In Situ of the Breast
Authors: Naomi B. Boekel, Michael Schaapveld, Jourik A. Gietema, Emiel J. T. Rutgers, Michel I. M. Versteegh, Otto Visser, Berthe M. P. Aleman, Flora E. van Leeuwen
Journal: JNCI Journal of the National Cancer Institute (2014)

Recent concerns about potential overdiagnosis and overtreatment of ductal carcinoma in situ of the breast (DCIS) render evaluation of late effects of treatment, such as cardiovascular disease (CVD), of great importance. We studied cardiovascular morbidity and mortality in a large population-based cohort of DCIS patients.Data on all incident DCIS case patients in the Netherlands between 1989 and 2004 who were diagnosed before the age of 75 years were obtained (n = 10468). CVD data was acquired through linkage with population-based registries. Standardized mortality ratios were calculated by comparing mortality in our cohort with that in the Dutch female population, taking into account person-years of observation. Within-cohort comparisons were based on multivariable competing-risk regression.Compared with the general population, 5-year survivors of DCIS had a similar risk of dying due to any cause (standardized mortality ratio [SMR] = 1.04; 95% confidence interval [CI] = 0.97 to 1.11) but a lower risk of dying of CVD (SMR = 0.77; 95% CI = 0.67 to 0.89). No difference in CVD risk was found when comparing 5-year survivors treated with radiotherapy with those treated with surgery only. Left-sided vs right-sided radiotherapy also did not increase this risk (hazard ratio [HR] = 0.94; 95% CI = 0.67 to 1.32). In a subgroup analysis of all DCIS patients diagnosed between 1997 and 2005, we were able to account for history of CVD and did not observe a risk difference between treatment groups (left-sided vs right-sided radiotherapy: HR = 0.94; 95% CI = 0.68 to 1.29).After a median follow-up of 10 years, we did not find an increased risk for cardiovascular morbidity or mortality after radiotherapy for DCIS when comparing surgery and radiotherapy vs surgery only, nor when comparing radiotherapy for left-sided vs right-sided DCIS. Compared with the general population, DCIS patients have a decreased risk of cardiovascular death, independent of treatment.
Messenger RNA Expression Ratios among Four Genes Predict Subtypes of Renal Cell Carcinoma and Distinguish Oncocytoma from Carcinoma
Authors: Yao-Tseng Chen, Jiangling J. Tu, Jean Kao, Xi K. Zhou, Madhu Mazumdar
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Morphologic distinction among clear cell, papillary, and chromophobe types of renal cell carcinoma (RCC) can be difficult, as is the differential diagnosis between oncocytoma and RCC. Whether these renal tumors can be distinguished by their mRNA expression profile of a few selected genes was examined. Experimental Design: The expression of four genes in renal tumor was evaluated by quantitative reverse transcription-PCR: carbonic anhydrase IX (CA9), methylacyl-CoA racemase (AMACR), parvalbumin (PVALB), and chloride channel kb (CLCNKB). Thirty-one fresh-frozen and 63 formalin-fixed, paraffin-embedded tumor specimens were analyzed. Results: CA9 expression was highest in clear cell carcinoma and lowest in chromophobe RCC and in oncocytoma. AMACR expression was highest in papillary RCC, and CLCNKB was highest in chromophobe RCC/oncocytoma. PVALB was highest in chromophobe RCC, variable in oncocytoma, and low in clear cell and papillary types. Similar findings were observed in fresh-frozen and formalin-fixed specimens. The mRNA expression ratios among these genes (i.e., CA9/AMACR and AMACR/CLCNKB ratios) further accentuate the gene expression differences among these tumors, and a molecular diagnostic algorithm was established. This algorithm accurately classified the 31 fresh-frozen tumors into 14 clear cell, 5 papillary, 6 chromophobe, and 6 oncocytomas. In the formalin-fixed group, the molecular criteria accurately classified the cases into 15 clear cell, 16 papillary, and 32 in the chromophobe/oncocytoma group but could only separate some, but not all, oncocytomas from chromophobe RCC. Conclusions: RNA expression ratios based on the four-gene panel can accurately classify subtypes of RCC as well as help distinguish some oncocytomas from chromophobe RCC.
1392 NOVEL CERULOPLASMIN MUTATION CAUSING ACERULOPLASMINEMIA WITH SEVERE HEPATIC IRON OVERLOAD AND EARLY ONSET OF DIABETES MELLITUS BUT WITHOUT NEUROLOGICAL SYMPTOMS
Authors: M. Rusticeanu, L. Schleithoff, V. Zimmer, U. Hübschen, F. Grünhage, F. Lammert
Journal: Journal of Hepatology (2012)
Toll-like receptor 9 agonist enhances anti-tumor immunity and inhibits tumor-associated immunosuppressive cells numbers in a mouse cervical cancer model following recombinant lipoprotein therapy
Authors: Li-Sheng Chang, Chih-Hsiang Leng, Yi-Chen Yeh, Chiao-Chieh Wu, Hsin-Wei Chen, Hai-Mei Huang, Shih-Jen Liu
Journal: Molecular Cancer (2014)

Although cytotoxic T lymphocytes (CTLs) play a major role in eradicating cancer cells during immunotherapy, the cancer-associated immunosuppressive microenvironment often limits the success of such therapies. Therefore, the simultaneous induction of cancer-specific CTLs and reversal of the immunosuppressive tumor microenvironment may be more effectively achieved through a single therapeutic vaccine. A recombinant lipoprotein with intrinsic Toll-like receptor 2 (TLR2) agonist activity containing a mutant form of E7 (E7m) and a bacterial lipid moiety (rlipo-E7m) has been demonstrated to induce robust CTL responses against small tumors. This treatment in combination with other TLR agonists is able to eliminate large tumors. Mouse bone marrow-derived dendritic cells (DCs) were employed to determine the synergistic production of pro-inflammatory cytokines upon combination of rlipo-E7m and other TLR agonists. Antigen-specific CTL responses were investigated using immunospots or in vivo cytolytic assays after immunization in mice. Mice bearing various tumor sizes were used to evaluate the anti-tumor effects of the formulation. Specific subpopulations of immunosuppressive cells in the tumor infiltrate were quantitatively determined by flow cytometry. We demonstrate that a TLR9 agonist (unmethylated CpG oligodeoxynucleotide, CpG ODN) enhances CTL responses and eradicates large tumors when combined with rlipo-E7m. Moreover, combined treatment with rlipo-E7m and CpG ODN effectively increases tumor infiltration by CTLs and reduces the numbers of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) in the tumor microenvironment. These findings suggest that the dramatic anti-tumor effects of the recombinant lipoprotein together with CpG ODN may reflect the amplification of CTL responses and the repression of the immunosuppressive environment. This promising approach could be applied for the development of additional therapeutic cancer vaccines.