tbuckley/cabot-search huggingface dataset:
Inhibition of Early Atherogenesis by Losartan in Monkeys With Diet-Induced Hypercholesterolemia
Authors: William B. Strawn, Mark C. Chappell, Richard H. Dean, Salah Kivlighn, Carlos M. Ferrario
Journal: Circulation (2000)

Background —Angiotensin II may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. This study determined, in a primate model of diet-induced atherosclerosis, the effect of AT 1 blockade on fatty-streak formation, plasma lipids, and surrogate markers of vascular injury. Methods and Results —Male cynomolgus monkeys fed a diet containing 0.067 mg cholesterol/kJ for 20 weeks were given losartan (180 mg/d, n=6) or vehicle (n=8) for 6 weeks starting at week 12 of the dietary regimen. Arterial pressure, heart rate, plasma total and lipoprotein cholesterol concentrations, and lipoprotein particle sizes and subclass distributions were unaffected by treatment. Losartan caused significant ( P &lt;0.05) increases in plasma angiotensin II and angiotensin-(1–7). Compared with vehicle-treated controls, losartan reduced the extent of fatty streak in the aorta, the coronary arteries, and the carotid arteries by ≈50% ( P &lt;0.05). A significant ( P &lt;0.05) reduction in the susceptibility of LDL to in vitro oxidation, serum levels of monocyte chemoattractant protein-1, and circulating monocyte CD11b expression were also associated with losartan treatment. In addition, serum levels of vascular cell adhesion molecule-1 and E-selectin did not change during treatment but increased after discontinuation of losartan. Serum C-reactive protein, platelet aggregability, and white cell counts were not modified by losartan. Conclusions —This study demonstrates for the first time an antiatherogenic effect of AT 1 receptor blockade in nonhuman primates. Losartan inhibited fatty-streak formation through mechanisms that may include protection of LDL from oxidation and suppression of vascular monocyte activation and recruitment factors.
Serum Levels of Adipokine Retinol-Binding Protein-4 in Relation to Renal Function
Authors: Michaela Ziegelmeier, Anette Bachmann, Jeannette Seeger, Ulrike Lossner, Jürgen Kratzsch, Matthias Blüher, Michael Stumvoll, Mathias Fasshauer
Journal: Diabetes Care (2007)

Retinol-binding protein (RBP)-4 was recently identified as an adipokine that induces insulin resistance. In the current study, we investigated RBP-4 serum levels in diabetic and nondiabetic patients on chronic hemodialysis (CD) compared with control subjects with a glomerular filtration rate >50 ml/min. The majority of the diabetic subjects used oral hypoglycemic agents or insulin.RBP-4 was determined by enzyme-linked immunosorbent assay in control subjects (n = 59) and CD patients (n = 58) and correlated with clinical and biochemical measures of renal function, glucose and lipid metabolism, and inflammation in both groups.Mean serum RBP-4 levels were almost fourfold higher in CD patients (102 +/- 30 mg/l) compared with control subjects (28 +/- 8 mg/l). Furthermore, serum creatinine independently predicted RBP-4 concentrations in multiple regression analyses in both control subjects and CD patients. In addition, C-reactive protein and systolic blood pressure independently and negatively correlated with RBP-4 serum concentrations in CD patients but not control subjects. In contrast, markers of glucose and lipid metabolism were not independently related to serum RBP-4 in control subjects or CD patients.We show that markers of renal function are independently related to serum RBP-4 levels.
Increased prevalence of poor sulphoxidation in patients with rheumatoid arthritis: effect of changes in the acute phase response and second line drug treatment.
Authors: P Emery, H Bradley, A Gough, V Arthur, R Jubb, R Waring
Journal: Annals of the Rheumatic Diseases (1992)

A minority of normal subjects have an impaired ability to oxidise sulphur, which is associated with an increased risk of side effects when they receive sulphur containing drugs. In 114 patients with rheumatoid arthritis a greatly increased prevalence of poor sulphoxidation was found in 82 (72%) patients compared with 70/200 (35%) healthy controls, 45/121 (37%) controls matched for age, and 4/35 (11%) of the normal aged general population. In a longitudinal study of 37 patients there was no significant alteration in sulphoxidation status after the introduction of a second line drug or with marked changes in the acute phase response. It seems, therefore, that the poor sulphoxidation status in patients with RA is not an epiphenomenon and may be an important factor in determining the clinical features of rheumatoid disease.
Infrequent normal B lymphocytes express features of B-chronic lymphocytic leukemia.
Authors: F Caligaris-Cappio, M Gobbi, M Bofill, G Janossy
Journal: The Journal of Experimental Medicine (1982)

An infrequent (2-3%) B lymphocyte subpopulation was found in the normal human tonsil and lymph nodes that shows the phenotypic characteristics of B-chronic lymphocytic leukemia (B-CLL) (rosette formation with mouse erythrocytes, weak expression of membrane Ig, staining for HLA-DR, and OKT1 or Leu-1 detecting a T cell-associated p65 antigen). Preliminary evidence suggests that at least a subpopulation of these cells is found, in small proportions, within the germinal centers. These cells were not observed in the human bone marrow. B-CLL may involve this peripheral B lymphocyte subset.
Intrauterine Hyperglycemia Is Associated With an Earlier Diagnosis of Diabetes in HNF-1α Gene Mutation Carriers
Authors: Amanda Stride, Maggie Shepherd, Timothy M. Frayling, Mike P. Bulman, Sian Ellard, Andrew T. Hattersley
Journal: Diabetes Care (2002)

OBJECTIVE—In animals, experimentally induced maternal hyperglycemia during pregnancy results in hyperglycemic offspring. Similarly, Pima Indian offspring with mothers who are diabetic at the time of pregnancy have increased risk of early-onset diabetes. We hypothesized that exposure to hyperglycemia in utero would decrease the age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY) due to a mutation in the hepatocyte nuclear factor 1α (HNF-1α) gene. RESEARCH DESIGN AND METHODS—We analyzed the affect of maternal diabetes on age at diagnosis of diabetes in 150 HNF-1α gene mutation carriers from 55 families. RESULTS—Age at diagnosis in HNF-1α mutation carriers was younger when the mother was diagnosed before pregnancy compared with when the mother was diagnosed after pregnancy (15.5 ± 5.4 vs. 27.5 ± 13.1 years, P &amp;lt; 0.0001). This is unlikely to represent a generalized familial decrease in age at diagnosis due to a more severe mutation, because no difference was seen in age of the offspring at diagnosis of diabetes when the father was diagnosed at a young age, and a similar trend was seen when only the single common mutation, P291fsinsC, was analyzed. CONCLUSIONS—We conclude that maternal hyperglycemia during pregnancy probably increases the penetrance of HNF-1α mutations. The potential role of exposure to hyperglycemia in utero in a monogenic diabetic subgroup warrants prospective study.
Hyperhomocysteinemia Alters Cardiac Substrate Metabolism by Impairing Nitric Oxide Bioavailability Through Oxidative Stress
Authors: Nobuhiro Suematsu, Caroline Ojaimi, Shintaro Kinugawa, Zipping Wang, Xiaobin Xu, Akos Koller MD, Fabio A. Recchia, Thomas H. Hintze
Journal: Circulation (2007)

Hyperhomocysteinemia (HHcy) has been considered a vascular disease associated with increased levels of oxidative stress that results in scavenging of NO. However, little is known of the impact of HHcy on cardiac function and especially myocardial metabolism.L-Homocysteine was intravenously infused into conscious dogs, and the dogs were fed methionine to increase plasma homocysteine to 10 micromol/L for acute and 24 micromol/L for chronic HHcy. There was no significant change in hemodynamics with HHcy. Veratrine-induced, NO-dependent, coronary vasodilation (Bezold-Jarisch reflex) was reduced by 32% but was restored by simultaneous intravenous infusion of ascorbic acid or apocynin. Acute and chronic HHcy significantly increased uptake of glucose and lactate and decreased uptake of free fatty acid by the heart. HHcy significantly decreased bradykinin- or carbachol-induced reduction of myocardial oxygen consumption in vitro, and this effect was completely restored by coincubation with ascorbic acid, Tempol, or apocynin. Western blot analysis indicated an increase in Nox2 (82%) and a reduction in endothelial nitric oxide synthase (39%), phospho-endothelial nitric oxide synthase (39%), and superoxide dismutase-1 (45%). Microarray analysis of gene expression in heart tissue from chronic HHcy indicated a switch in cardiac phenotype to enzymes that metabolize glucose.HHcy directly modulates substrate use by the heart independent of changes in hemodynamics or ventricular function by reducing NO bioavailability through the generation of superoxide. The progression of cardiac or coronary heart disease associated with HHcy should be evaluated in light of the impact of alterations in the regulation of cardiac metabolism and substrate use.
How Does Our Brain Constitute Defense Mechanisms? First-Person Neuroscience and Psychoanalysis
Authors: Georg Northoff, Felix Bermpohl, Frank Schoeneich, Heinz Boeker
Journal: Psychotherapy and Psychosomatics (2007)

Current progress in the cognitive and affective neurosciences is constantly influencing the development of psychoanalytic theory and practice. However, despite the emerging dialogue between neuroscience and psychoanalysis, the neuronal processes underlying psychoanalytic constructs such as defense mechanisms remain unclear. One of the main problems in investigating the psychodynamic-neuronal relationship consists in systematically linking the individual contents of first-person subjective experience to third-person observation of neuronal states. We therefore introduced an appropriate methodological strategy, ‘first-person neuroscience’, which aims at developing methods for systematically linking first- and third-person data. The utility of first-person neuroscience can be demonstrated by the example of the defense mechanism of sensorimotor regression as paradigmatically observed in catatonia. Combined psychodynamic and imaging studies suggest that sensorimotor regression might be associated with dysfunction in the neural network including the orbitofrontal, the medial prefrontal and the premotor cortices. In general sensorimotor regression and other defense mechanisms are psychoanalytic constructs that are hypothesized to be complex emotional-cognitive constellations. In this paper we suggest that specific functional mechanisms which integrate neuronal activity across several brain regions (i.e. neuronal integration) are the physiological substrates of defense mechanisms. We conclude that first-person neuroscience could be an appropriate methodological strategy for opening the door to a better understanding of the neuronal processes of defense mechanisms and their modulation in psychoanalytic psychotherapy.
EGFRvIII mCAR-Modified T-Cell Therapy Cures Mice with Established Intracerebral Glioma and Generates Host Immunity against Tumor-Antigen Loss
Authors: John H. Sampson, Bryan D. Choi, Luis Sanchez-Perez, Carter M. Suryadevara, David J. Snyder, Catherine T. Flores, Robert J. Schmittling, Smita K. Nair, Elizabeth A. Reap, Pamela K. Norberg, James E. Herndon, Chien-Tsun Kuan, Richard A. Morgan, Steven A. Rosenberg, Laura A. Johnson
Journal: Clinical Cancer Research (2013)

Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues.We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma.At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens.All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies.
52-kD SS-A/Ro: genomic structure and identification of an alternatively spliced transcript encoding a novel leucine zipper-minus autoantigen expressed in fetal and adult heart.
Authors: E K Chan, F Di Donato, J C Hamel, C E Tseng, J P Buyon
Journal: The Journal of Experimental Medicine (1995)

The 52-kD SS-A/Ro protein is one of the antigenic targets strongly associated with the autoimmune response in mothers whose children have manifestations of neonatal lupus. In addition to the cDNA clone we previously reported for the full-length 52-kD SS-A/Ro protein, an interesting MOLT-4 cDNA clone, p52-2, was found to have an internal deletion of 231 nucleotides including the domain encoding the leucine zipper motif. To further investigate the nature of this deletion, genomic DNA clones were isolated from a lambda FIXII library. The complete gene for the full-length 52-kD protein (alpha form, 52 alpha) spans 10 kb of DNA and is composed of seven exons. Exon 1 contains only the 5' untranslated sequence, while the translation initiation codon is located 3 kb downstream in exon 2, which also encodes the three zinc finger motifs. Exon 4 encodes amino acids 168-245, including the coiled coil/leucine zipper domain. Exon 7 is the longest and encodes the rfp-like domain and the 3' untranslated region. The cDNA p52-2 can now be accounted for as a product of alternative messenger RNA (mRNA) derived from the splicing of exon 3 to exon 5, skipping exon 4, which results in a smaller protein (52 beta) with a predicted molecular weight of 45,000. An initial approach to identifying this alternatively spliced form in the human heart used a ribonuclease protection assay. Using an RNA probe corresponding to bases 674-964 of the full-length cDNA, two protected mRNA fragments were identified, a 290-bp fragment corresponding to expression of 52 alpha and a smaller fragment of 144 bp, the predicted size of 52 beta. Using reverse transcription followed by polymerase chain reaction, cDNAs from a 16-wk fetal heart, 24-wk heart, and adult heart were amplified with primers flanking exon 4. Two polymerase chain reaction products were observed in each tissue, one 1.0 kb likely representing 52 alpha and a second 0.78 kb, consistent with 52 beta. The 0.78-kb fragment identified in the 16-wk heart was cloned, and DNA sequencing confirmed the 52 beta type. Immunoprecipitation of in vitro-translated 35S-labeled 52 beta form was performed to evaluate the antigenicity of this novel form of 52-kD SS-A/Ro. 26 (87%) of 30 sera tested from mothers whose children were known to have neonatal lupus immunoprecipitated the 52 beta form.(ABSTRACT TRUNCATED AT 400 WORDS)
Nebulised salbutamol without oxygen in severe acute asthma: how effective and how safe?
Authors: J G Douglas, P Rafferty, R J Fergusson, R J Prescott, G K Crompton, I W Grant
Journal: Thorax (1985)

Thirty two patients with severe acute asthma, all of whom were hypoxaemic, entered a double blind comparative assessment of three doses of salbutamol (1.25, 2.5, and 5 mg) nebulised by an electrically operated air compressor. The study lasted for two hours, during which oxygen and corticosteroid treatment were withheld. All patients were observed in an intensive care area during this period. Four patients had to be withdrawn from the study. Two became distressed immediately after receiving salbutamol and were excluded from further analysis. Two other patients were withdrawn, one with persistent respiratory distress and an unchanged one second forced expiratory volume (FEV1) and the other because of the development of profound hypoxaemia and a deteriorating FEV1 within 60 minutes of treatment. No significant differences were observed between the three dosage groups. In the 28 patients completing the study there were only small increases in mean FEV1 (0.8 to 1.1 l) and forced vital capacity (FVC) (1.3 to 1.8 l) over the two hours. There was a fall in the mean pulse rate at 120 minutes of 15 beats per minute (117-102). No significant change in oxygen tension (PaO2) was observed at 15 or 60 minutes after administration of nebulised salbutamol in any of the three groups. Salbutamol nebulised in air, in a single dose of 5 mg, produces only slight relief of airflow obstruction and no worsening of hypoxaemia in severe acute asthma.
Microsatellite Instability and 8p Allelic Imbalance in Stage B2 and C Colorectal Cancers
Authors: K. C. Halling, A. J. French, S. K. McDonnell, L. J. Burgart, D. J. Schaid, B. J. Peterson, L. Moon-Tasson, M. R. Mahoney, D. J. Sargent, M. J. O'Connell, T. E. Witzig, G. H. Farr, R. M. Goldberg, S. N. Thibodeau
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Microsatellite instability (MSI) and allelic imbalance involving chromosome arms 5q, 8p, 17p, and 18q are genetic alterations commonly found in colorectal cancer. We investigated whether the presence or absence of these genetic alterations would allow stratification of patients with Astler-Coller stage B2 or C colorectal cancer into favorable and unfavorable prognostic groups. METHODS: Tumors from 508 patients were evaluated for MSI and allelic imbalance by use of 11 microsatellite markers located on chromosome arms 5q, 8p, 15q, 17p, and 18q. Genetic alterations involving each of these markers were examined for associations with survival and disease recurrence. All P values are two-sided. RESULTS: In univariate analyses, high MSI (MSI-H), i.e., MSI at 30% or more of the loci examined, was associated with improved survival ( P = .02) and time to recurrence ( P = .01). The group of patients whose tumors exhibited allelic imbalance at chromosome 8p had decreased survival ( P = .02) and time to recurrence ( P = .004). No statistically significant associations with survival or time to recurrence were observed for markers on chromosome arms 5q, 15q, 17p, or 18q. In multivariate analyses, MSI-H was an independent predictor of improved survival (hazard ratio [ HR] = 0.51; 95% confidence interval [CI] = 0.31-0.82; P = .006) and time to recurrence (HR = 0.42; 95% CI = 0.24-0.74; P = .003), and 8p allelic imbalance was an independent predictor of decreased survival (HR = 1.89; 95% CI = 1.25-2.83; P = .002) and time to recurrence (HR = 2.07; 95% CI = 1.32-3.25; P = .002). CONCLUSIONS: Patients whose tumors exhibited MSI-H had a favorable prognosis, whereas those with 8p allelic imbalance had a poor prognosis; both alterations served as independent prognostic factors. To our knowledge, this is the first report of an association between 8p allelic imbalance and survival in patients with colorectal cancer.
Intrinsic Subtypes, <i>PIK3CA</i> Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in the NSABP B-31 Trial
Authors: Katherine L. Pogue-Geile, Nan Song, Jong-Hyeon Jeong, Patrick G. Gavin, Seong-Rim Kim, Nicole L. Blackmon, Melanie Finnigan, Priya Rastogi, Louis Fehrenbacher, Eleftherios P. Mamounas, Sandra M. Swain, D. Lawrence Wickerham, Charles E. Geyer, Joseph P. Costantino, Norman Wolmark, Soonmyung Paik
Journal: Journal of Clinical Oncology (2015)

Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) -positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31.Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (n = 671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease-free survival as the end point.Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64).Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting.
Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study
Authors: Béatrice Larroque, Pierre-Yves Ancel, Stéphane Marret, Laetitia Marchand, Monique André, Catherine Arnaud, Véronique Pierrat, Jean-Christophe Rozé, Jean Messer, Gérard Thiriez, Antoine Burguet, Jean-Charles Picaud, Gérard Bréart, Monique Kaminski
Journal: The Lancet (2008)
Low Glycated Hemoglobin and Liver Disease in the U.S. Population
Authors: Andrea L. Christman, Mariana Lazo, Jeanne M. Clark, Elizabeth Selvin
Journal: Diabetes Care (2011)

OBJECTIVE To characterize the association of low HbA1c values (&amp;lt;4.0%) with liver enzymes and steatosis. RESEARCH DESIGN AND METHODS Cross-sectional study of 12,533 participants without diabetes aged &amp;lt;20 years in the Third National Health and Nutrition Examination Survey (1988–1994). Logistic regression models were adjusted for demographic, lifestyle, and health status variables. RESULTS HbA1c values ranged from 3.2 to 15.7%, and 84 participants had HbA1c &amp;lt;4.0% in the population (mean age 44, 52% female, 15% black or Hispanic). We observed J-shaped associations between HbA1c and liver enzymes and hepatic steatosis. In adjusted models, HbA1c &amp;lt;4.0% was strongly associated with elevated alanine aminotransferase (OR 3.62 [95% CI 1.09–12.02]) and aspartate aminotransferase (6.80 [2.99–15.43]). CONCLUSIONS Low HbA1c values were associated with liver enzymes and steatosis in the U.S. population. Liver disease may partially explain the association of HbA1c with mortality and other long-term outcomes.