tbuckley/cabot-search huggingface dataset:
Differential effect of IL10 and TNF genotypes on determining susceptibility to discoid and systemic lupus erythematosus
Authors: A Suarez
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To ascertain the possible involvement of functional interleukin 10 (IL10) and tumour necrosis α (TNFα) cytokine promoter polymorphisms on the susceptibility to discoid and systemic lupus erythematosus (DLE, SLE), and their associations with immunological features. <b>Methods:</b> Single nucleotide polymorphisms of the IL10 (−1082, −819, and −592) and TNFα (−308) genes were determined using allele specific probes in 248 lupus patients and 343 matched controls. To assess functional significance of genotypes, basal mRNA cytokine levels were quantified in 106 genotyped healthy controls by real time RT-PCR. Specific autoantibodies and cutaneous manifestations were analysed in SLE patients and associated with functional genotypes. <b>Results:</b> After analysing the distribution of IL10 and TNFα transcript levels according to promoter genotypes in healthy individuals, patients and controls were classified into functional single and combined genotypes according to the expected high or low constitutive cytokine production. High TNFα genotypes (−308AA or AG) were associated with SLE independently of IL10 alleles, whereas the risk of developing DLE and the prevalence of discoid lesion in SLE were higher in the high IL10/low TNFα producer group (−1082GG/−308GG). Cytokine interaction also influences the appearance of autoantibodies. Antibodies against Sm are prevalent among low producer patients for both cytokines, a genotype not associated with lupus incidence, whereas low IL10/high TNFα patients have the highest frequency of antibodies to SSa and SSb. <b>Conclusions:</b> IL10/TNFα interaction influences susceptibility to DLE and the appearance of specific autoantibodies in SLE patients, whereas high TNFα producer genotypes represent a significant risk factor for SLE.
Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice
Authors: Ding Ai, Chiyuan Chen, Seongah Han, Anjali Ganda, Andrew J. Murphy, Rebecca Haeusler, Edward Thorp, Domenico Accili, Jay D. Horton, Alan R. Tall
Journal: Journal of Clinical Investigation (2012)

Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9-/- mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy.
PMO-148 Evaluation of liver fibrosis in young adult patients with chronic hepatitis B virus
Authors: C Patel, U S Gill, W Alazawi, P Shaw, E Alstead, Y Kallis, P Kooner, R Marley, S Naik, J ChinAleong, R D Goldin, G R Foster, P T F Kennedy
Journal: Gut (2012)

<h3>Introduction</h3> Current guidelines do not recommend treatment of Chronic Hepatitis B (CHB) in young adults as they are believed to be immune tolerant with minimal liver damage. Recently we demonstrated that young CHB patients have evidence of immune activity comparable to older patients. Therefore, a proportion of young patients will develop fibrosis as a consequence of immune mediated liver injury. Despite this, the most appropriate modality to assess liver fibrosis remains controversial. We compare the utility of liver biopsy and digital image analysis with FibroScan for assessment of CHB in young adults. <h3>Methods</h3> Young adult CHB patients were followed in a dedicated clinic and seen 3-monthly. Liver biopsy was performed where indicated and compared with FibroScan scores. Digital image analysis was performed on a selected number of Sirius red stained sections to evaluate percentage fibrosis. 167 patients were assessed; 101/167 (male=63); median age 26 (range 16–30) underwent liver biopsy and were included for analysis. <h3>Results</h3> 47/101 patients were eAg+. Overall median ALT was 41IU/L (range 14–426) &amp; HBV DNA was 5.22 logIU/ml (range 1.4–9.3). Median Ishak fibrosis score was 1 (range 0–6); median FibroScan score was 5.95 kPa (range 2.6–35.2). There was no difference in the FibroScan score in patients with advanced (F5/6) and minimal fibrosis (F0/1); median FibroScan scores were 6 and 5.95 respectively, (p=ns). The correlation co-efficient between fibrosis and FibroScan was not statistically significant (p=0.46). FibroScan scores were confounded by ALT; using Prati criteria to define normal ALT (female &lt;19 IU/l, male &lt;30 IU/l), we noted an ALT twice ULN revealed a higher FibroScan score, regardless of fibrosis (p=0.05 and 0.04; males and females respectively). On the contrary, digital image analysis more accurately reflected fibrosis stage irrespective of ALT. <h3>Conclusion</h3> A proportion of young adult patients with CHB have significant liver disease on biopsy. This study highlights the limitations of FibroScan in assessing liver fibrosis in this cohort. Our data demonstrates the utility of digital image analysis in benchmarking fibrosis in young patients, potentially providing a more accurate methodology to assess progression of fibrosis over time. <h3>Competing interests</h3> None declared.
Two Novel ALK Mutations Mediate Acquired Resistance to the Next-Generation ALK Inhibitor Alectinib
Authors: Ryohei Katayama, Luc Friboulet, Sumie Koike, Elizabeth L. Lockerman, Tahsin M. Khan, Justin F. Gainor, A. John Iafrate, Kengo Takeuchi, Makoto Taiji, Yasushi Okuno, Naoya Fujita, Jeffrey A. Engelman, Alice T. Shaw
Journal: Clinical Cancer Research (2014)

The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance.We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE.We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib.We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs.
Diabetes Associated With Short Survival in Pancreatic Cancer
Authors: Yixiang Mao, Min Tao, Xiaoyan Jia, Donghui Li
Journal: Journal of Clinical Oncology (2015)

association between long-term diabetes and poor overall survival among patients with diabetes and pancreatic cancer in three longitudinal studies. The authors reported a 40% to 50% increased risk of death for patients with long-term diabetes (duration of 4 years) compared with those without diabetes (P .05) in two prospective cohort studies 2,3 and a clinic-based study. 1 In contrast, no statistically significant association between short-term diabetes (duration of 4 years) and survival was observed. Thus, the authors concluded that there is a link between chronic glucose intolerance and pancreatic cancersurvival,whereasshort-termdiabetesdoesnotportendaworse prognosis among patients with pancreatic adenocarcinoma. We have a concern about the authors’ conclusion regarding the association between short-term diabetes and survival. Because the information on diabetes was collected via a biennial questionnaire in the cohort studies, it is possible that the number of patients with short-term diabetes was greatly underestimated, which may have biased the risk estimate toward null. The prevalence of patients with short-term diabetes was 4.67% (47 of 1,006) and 18.65% (72 of 386), whereas the prevalence of patients with any type of diabetes was 17.99% (181 of 1,006) and 31.35% (121 of 386) in the cohort and the clinic-based studies, respectively. The prevalence of diabetes in the clinic-based study was quite similar to the numbers previously reported by other studies. Short-term diabetes was associated with a nonsignificant but increased risk of death in this clinic series (hazard ratio [HR], 1.22; 95% CI, 0.89 to 1.67). In our recently completed studyof1,328patientswithpathologicallyconfirmedpancreaticductal adenocarcinoma of all stages at MD Anderson Cancer Center, we foundthatshort-termdiabetes(durationof3years)wasassociated with a significantly increased risk of death (HR, 1.23; 95% CI, 1.09 to 1.40).Wehavealsoconductedameta-analysisof29studiesondiabetesandoverallsurvivalofpatientswithpancreaticcancerandfounda reduced survival of patients with diabetes in 25 clinic-based studies (pooled HR, 1.13; 95% CI, 1.02 to 1.25), but not in four cohort studies 4-7 (pooled HR, 1.12; 95% CI, 0.95 to 1.32). The prevalence of patients with diabetes was 28.61% (4,133 of 14,446) and 20.92% (1,124 of 5,372) in the clinic and cohort studies, respectively. These observations suggest that short-term diabetes is associated with a higher risk of death in patients with pancreatic cancer. The inconsistentobservationswithrespecttotheassociationbetweendiabetesand
Analysis of novel sph (spherocytosis) alleles in mice reveals allele-specific loss of band 3 and adducin in α-spectrin–deficient red cells
Authors: Raymond F. Robledo, Amy J. Lambert, Connie S. Birkenmeier, Marius V. Cirlan, Andreea Flavia M. Cirlan, Dean R. Campagna, Samuel E. Lux, Luanne L. Peters
Journal: Blood (2010)
Vitamin D and parathyroid hormone and bone mineralisation in adults with cystic fibrosis.
Authors: R J Stead, S Houlder, J Agnew, M Thomas, M E Hodson, J C Batten, P Dandona
Journal: Thorax (1988)

Vitamin D and parathyroid hormone concentrations were assessed in 31 adults with cystic fibrosis (mean age 24, range 17-52 years), in 28 of whom the bone mineral index in the forearm was also determined. Serum 25-hydroxyvitamin D was subnormal in eight patients, of whom five were receiving vitamin D supplements in standard doses. 1,25-dihydroxyvitamin D and parathyroid hormone concentrations showed no consistent abnormalities. The bone mineral index was lower in patients with cystic fibrosis (p less than 0.02) than in controls. Five patients with unequivocally reduced bone mineral index had a subnormal mean serum 25-hydroxyvitamin D and significantly worse lung function than the other patients. There was a positive correlation between age and bone mineral index (r = 0.68, p less than 0.001). Thus a significant proportion of patients with cystic fibrosis living in a temperate climate are at risk of vitamin D deficiency. Osteopenia is common and is probably related to a combination of hypovitaminosis D, delay in puberty, hypo-oestrogenism in women, and reduced physical activity, rather than to secondary hyperparathyroidism. Since most patients with deficiency of 25-hydroxyvitamin D were receiving oral supplements, parenteral vitamin D supplementation may be appropriate for selected patients who are unable to maintain adequate 25-hydroxyvitamin D concentrations despite oral vitamin D supplements.
Colocalization of Carbonic Anhydrase 9 Expression and Cell Proliferation in Human Head and Neck Squamous Cell Carcinoma
Authors: Ilse J. Hoogsteen, Henri A.M. Marres, Karien I.E.M. Wijffels, Paul F.J.W. Rijken, Johannes P.W. Peters, Franciscus J.A. van den Hoogen, Egbert Oosterwijk, Albert J. van der Kogel, Johannes H.A.M. Kaanders
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Tumor cells undergo a variety of biological changes under sustained hypoxic conditions, allowing cells to survive and retain their clonogenic potential. The purpose of this study is to relate the expression of the hypoxia marker carbonic anhydrase 9 (CA9) to the uptake of iododeoxyuridine (IdUrd), a marker of proliferation, in head and neck squamous cell carcinomas. Colocalization of IdUrd and CA9 may identify an important subpopulation of tumor cells that might be responsible for repopulation and disease progression. Experimental Design: Expression of CA9, IdUrd labeling, and colocalization between IdUrd and CA9 was examined by immunohistochemistry in biopsies of head and neck squamous cell carcinomas. Biopsies were taken from 51 patients recruited between 1998 and 2001 after administration of the proliferation marker IdUrd. Results: A large variation was observed between the tumors in CA9 expression (range 0-39%), IdUrd labeling (range 0-81%), and colocalization between IdUrd and CA9 [FId(CA9); range 0-53%]. FId(CA9), the fraction of IdUrd-labeled cells positive for CA9, was highest at an intermediate distance from the blood vessels (100-150 μm). IdUrd labeling was higher in T4 carcinomas relative to lower stage tumors (P = 0.04). High FId(CA9) correlated with the worst disease-free survival rates (P = 0.04). Conclusions: Colocalization between IdUrd labeling and CA9 expression was observed in head and neck squamous cell carcinomas, suggesting the presence of a population of tumor cells under intermediate hypoxic conditions which still has proliferative capacity. The size of this subpopulation may be indicative of tumor aggressiveness and is associated with the worst disease-free survival rates.
Diagnosis-related deterioration of lung function after extracorporeal membrane oxygenation
Authors: Marjolein Spoel, Roxanne Laas, Saskia J. Gischler, Wim J.C. Hop, Dick Tibboel, Johan C. de Jongste, Hanneke Ijsselstijn
Journal: European Respiratory Journal (2012)

The aim of the study was to assess lung function longitudinally after neonatal extracorporeal membrane oxygenation (ECMO), and to identify any effects of diagnosis and perinatal characteristics. 121 neonatal ECMO-treated children (70 with meconium aspiration syndrome, 20 congenital diaphragmatic hernia and 31 with other diagnoses) performed a total of 191 lung function measurements at 5, 8 and/or 12 yrs. We assessed dynamic and static lung volumes, reversibility of airway obstruction and diffusion capacity. Mean SDS forced expiratory volume in 1 s (FEV<sub>1</sub>) at 5 yrs before and after bronchodilation (-0.51 and 0.07) was significantly higher than at 8 (-0.79 and -0.4; p&lt;0.04) and 12 yrs (-1.10 and -0.52; p&lt;0.003). Mean SDS for all spirometric parameters before and after bronchodilation were significantly lower in the congenital diaphragmatic hernia group compared with the other diagnostic groups (all p≤0.025). A significant volume of trapped air was observed in 86% patients with congenital diaphragmatic hernia, 50% with meconium aspiration syndrome and 58% with other diagnoses. After bronchodilation, mean SDS FEV<sub>1</sub> and forced vital capacity were negatively influenced by duration of ventilation (both p&lt;0.001) and duration of ECMO (p=0.003 and p=0.02, respectively). Long-term pulmonary sequelae after neonatal ECMO-treatment mainly occur in congenital diaphragmatic hernia patients and tend to deteriorate over time.
<i>ORMDL3</i> Gene Is Associated with Asthma in Three Ethnically Diverse Populations
Authors: Joshua Galanter, Shweta Choudhry, Celeste Eng, Sylvette Nazario, José R. Rodríguez-Santana, Jesús Casal, Alfonso Torres-Palacios, Jorge Salas, Rocio Chapela, H. Geoffrey Watson, Kelley Meade, Michael LeNoir, William Rodríguez-Cintrón, Pedro C. Avila, Esteban González Burchard
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association.A whole-genome association study identified ORMDL3 as a promising candidate gene for asthma in white populations. Here, we attempted to confirm the role of ORMDL3 genetic variants in asthma in three ethnically diverse populations: Mexican, Puerto Rican, and African American.We used family-based analyses to test for association between seven candidate single-nucleotide polymorphisms (SNPs) in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parent-child trios. We also evaluated these seven SNPs and an additional ORMDL3 SNP in 264 African American subjects with asthma and 176 healthy control subjects.We found significant associations between two SNPs within ORMDL3 (rs4378650 and rs12603332) and asthma in Mexicans and African Americans (P = 0.028 and 0.001 for rs4378650 and P = 0.021 and 0.001 for rs12603332, respectively), and a trend toward association in Puerto Ricans (P = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger among Mexican and Puerto Rican subjects with asthma with IgE levels greater than 100 IU/ml. We did not find any association between ORMDL3 SNPs and baseline lung function or response to the bronchodilator albuterol.Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma.
Distinct Roles for Secreted Semaphorin Signaling in Spinal Motor Axon Guidance
Authors: Andrea B. Huber, Artur Kania, Tracy S. Tran, Chenghua Gu, Natalia De Marco Garcia, Ivo Lieberam, Dontais Johnson, Thomas M. Jessell, David D. Ginty, Alex L. Kolodkin
Journal: Neuron (2005)
The Patient's Anastrozole Compliance to Therapy (PACT) Program: a randomized, in-practice study on the impact of a standardized information program on persistence and compliance to adjuvant endocrine therapy in postmenopausal women with early breast cancer
Authors: P. Hadji, M. Blettner, N. Harbeck, C. Jackisch, H.-J. Lück, C. Windemuth-Kieselbach, S. Zaun, R. Kreienberg
Journal: Annals of Oncology (2013)
Persistence of Glucose Metabolism After Exercise in Trained and Untrained Soleus Muscle
Authors: Arend Bonen, Meng H Tan, Lynn A Megeney, J C McDermott
Journal: Diabetes Care (1992)

We tested the hypothesis that increments in glucose metabolism in muscles from trained animals are caused by training adaptations in skeletal muscle and not by the residual effects of the last training session. The effects of a single bout of exercise on glucose metabolism (glycolysis and glycogenesis) were compared, against appropriate controls, in untrained (experiment 1) and trained (experiment 2) rat soleus muscles immediately (t = 0) and 3, 6, 24, 48, and 96 h after a standardized bout of exercise. [3H]Glucose incorporation into glycogen and glycolysis was measured in vitro in the absence and presence of insulin (0.1 and 10 nM). Experiment 1: A single bout of exercise provoked an increase in glycogenesis in the exercised, untrained muscles compared with the nonexercised, untrained muscles (0–96 h; P = 0.006). Glycolysis was not altered (0–96 h; P &amp;gt; 0.05). Experiment 2: In the exercised trained soleus, rates of glycolysis were &amp;gt; in the exercised, untrained soleus, at insulin concentrations of 0.1 nM (0–96 h; P = 0.005) and 10 nM (0–96 h; P = 0.01), but not in the absence of insulin (0–96 h; P &amp;gt; 0.05). No differences were observed in the rates of glycogenesis (0–96 h; P &amp;gt; 0.05). Therefore, acute exercise provokes increments in glycogenesis, whereas training increases glycolysis, in the presence of insulin, for some time after exercise. We speculate that insulin-dependent increments in glycolysis in trained muscles are a consequence of increased glucose transport caused by a greater pool of insulin-translocatable, intracellular glucose transporters.
Survival analysis for apparent diffusion coefficient measures in children with embryonal brain tumours
Authors: M. Grech-Sollars, D. E. Saunders, K. P. Phipps, J. D. Clayden, C. A. Clark
Journal: Neuro-Oncology (2012)

Embryonal brain tumors constitute a large and important subgroup of pediatric brain tumors. Apparent diffusion coefficient (ADC) measures have been previously used in the analysis of these tumors. We investigated a newly described ADC-derived parameter, the apparent transient coefficient in tumor (ATCT), a measure of the gradient change of ADC from the peri-tumoral edema into the tumor core, to study whether ATCT correlates with survival outcome. Sixty-one patients with histologically proven embryonal brain tumors and who had diffusion-weighted imaging (DWI) as part of their clinical imaging were enrolled in a retrospective study correlating ADC measures with survival. Kaplan-Meier survival curves were constructed for extent of surgical resection, age <3 years at diagnosis, tumor type, and metastasis at presentation. A multivariate survival analysis was performed that took into consideration ATCT and variables found to be significant in the Kaplan-Meier analysis as covariates. Results from the multivariate analysis showed that ATCT was the only significant covariate (P < .001). Survival analysis using Kaplan-Meier curves, dividing the patients into 4 groups of increasing values of ATCT, showed that more negative values of ATCT were significantly associated with a poorer prognosis (P < .001). A statistically significant difference was observed for survival data with respect to the change in ADC from edema into the tumor volume. Results show that more negative ATCT values are significantly associated with a poorer survival among children with embryonal brain tumors, irrespective of tumor type, extent of resection, age <3 years at diagnosis, and metastasis at presentation.