tbuckley/cabot-search huggingface dataset:
Efficacy of a Continuous GLP-1 Infusion Compared With a Structured Insulin Infusion Protocol to Reach Normoglycemia in Nonfasted Type 2 Diabetic Patients: A Clinical Pilot Trial
Authors: Harald Sourij, Isabella Schmölzer, Eva Kettler-Schmut, Michaela Eder, Helga Pressl, Antonella deCampo, Thomas C. Wascher
Journal: Diabetes Care (2009)

OBJECTIVE Continuously administered insulin is limited by the need for frequent blood glucose measurements, dose adjustments, and risk of hypoglycemia. Regimens based on glucagon-like peptide 1 (GLP-1) could represent a less complicated treatment alternative. This alternative might be advantageous in hyperglycemic patients hospitalized for acute critical illnesses, who benefit from near normoglycemic control. RESEARCH DESIGN AND METHODS In a prospective open randomized crossover trial, we investigated eight clinically stable type 2 diabetic patients during intravenous insulin or GLP-1 regimens to normalize blood glucose after a standardized breakfast. RESULTS The time to reach a plasma glucose below 115 mg/dl was significantly shorter during GLP-1 administration (252 ± 51 vs. 321 ± 43 min, P &amp;lt; 0.01). Maximum glycemia (312 ± 51 vs. 254 ± 48 mg/dl, P &amp;lt; 0.01) and glycemia after 2 h (271 ± 51 vs. 168 ± 48 mg/dl, P = 0.012) and after 4 h (155 ± 51 vs. 116 ± 27 mg/dl, P = 0.02) were significantly lower during GLP-1 administration. CONCLUSIONS GLP-1 infusion is superior to an established insulin infusion regimen with regard to effectiveness and practicability.
Increased Incidence of Type 1 Diabetes in the South of Spain
Authors: Juan P. López-Siguero, Almudena Del Pino-De La Fuente, María J. Martínez-Aedo, José A. Moreno-Molina
Journal: Diabetes Care (2002)

Recent studies, both within and outside Europe, of the incidence of type 1 diabetes in children have produced dissimilar results, although they generally agree on an important annual increase, especially in children <5 years of age (1). Data from Spain solely concerning the population of Catalonia (∼15% of the Spanish population) showed a stable incidence from 1990 to 1994, with 12.3 type 1 diabetic subjects per 100,000 children <15 years of age (2). We present data concerning the change in the incidence of type 1 diabetes in the population of the pronvince of Malaga (Andalusia) over a period of 19 years. These data are in contrast with those reported by EURODIAB for the Spanish population (3 …
Papilloma Development Is Delayed in Osteopontin-Null Mice: Implicating an Antiapoptosis Role for Osteopontin
Authors: Yu-Hua Hsieh, M. Margaret Juliana, Patricia H. Hicks, Gong Feng, Craig Elmets, Lucy Liaw, Pi-Ling Chang
Journal: Cancer Research (2006)

Abstract Osteopontin is a secreted, adhesive glycoprotein, whose expression is markedly elevated in several types of cancer and premalignant lesions, implicating its association with carcinogenesis. To test the hypothesis that induced osteopontin is involved in tumor promotion in vivo, osteopontin-null and wild-type (WT) mice were subjected to a two-stage skin chemical carcinogenesis protocol. Mice were initiated with 7,12-dimethylbenz(a)anthracene (DMBA) applied on to the dorsal skin followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 27 weeks. Osteopontin-null mice showed a marked decrease both in tumor/papilloma incidence and multiplicity compared with WT mice. Osteopontin is minimally expressed in normal epidermis, but on treatment with TPA its expression is highly induced. To determine the possible mechanism(s) by which osteopontin regulates tumor development, we examined cell proliferation and cell survival. Epidermis from osteopontin-null and WT mice treated with TPA thrice or with DMBA followed by TPA for 11 weeks showed a similar increase in epidermal hyperplasia, suggesting that osteopontin does not mediate TPA-induced cell proliferation. Bromodeoxyuridine staining of papillomas and adjacent epidermis showed no difference in cell proliferation between groups. However, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling analyses indicated a greater number of apoptotic cells in DMBA-treated skin and papillomas from osteopontin-null versus WT mice. These studies are the first to show that induction of the matricellular protein osteopontin facilitates DMBA/TPA-induced cutaneous carcinogenesis most likely through prevention of apoptosis. (Cancer Res 2006; 66(14): 7119-27)
FDG PET/CT and Diffusion-Weighted Imaging of Head and Neck Squamous Cell Carcinoma
Authors: Masatoyo Nakajo, Masayuki Nakajo, Yoriko Kajiya, Atsushi Tani, Takuro Kamiyama, Ryuji Yonekura, Yoshihiko Fukukura, Tsutomu Matsuzaki, Kengo Nishimoto, Mitsuharu Nomoto, Chihaya Koriyama
Journal: Clinical Nuclear Medicine (2012)

Purpose: To compare primary tumor 18F-fluorodeoxyglucose (FDG) maximum standardized uptake value (SUVmax) and diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) obtained in the same patients with head and neck squamous cell carcinoma (HNSCC) to clarify the prognostic significance of both indexes. Materials and Methods: The study population comprised 26 patients with HNSCC visible on both pretreatment FDG PET/CT and DWI. Correlation between SUVmax and ADC (b values; 0 and 800 seconds/mm2) was analyzed by the Spearman's rank test. Disease-free survival (DFS) was calculated by the Kaplan-Meier method. Prognostic significance was assessed by the long-rank test and Cox proportional hazards analysis. Results: SUVmax and ADC correlated significantly and negatively (ρ = −0.566, P = 0.005). High (>12.1) SUVmax (P < 0.001), low (≤0.88) ADC (P = 0.009), high (T3–4) T stage (P = 0.030), and high (N2–3) N stage (P = 0.007) were significant in predicting poor 2-year DFS. The accuracy for predicting disease events was 81% (21/26) for SUVmax (>12.1) and 73% (19/26) for ADC(≤0.88) without significant difference between them (P = 0.52). Disease event hazards ratios for significant unadjusted SUVmax (P = 0.015) and ADC (P = 0.039) remained significant when adjusted for other dichotomized clinical covariates (SUVmax; P = 0.009–0.039, ADC; P = 0.017–0.037) except SUVmax for ADC and ADC for SUVmax and T stage. Conclusion: These results suggest that pretreatment primary tumor SUVmax and ADC correlate significantly and negatively and both may have similar potential to predict DFS or disease events of HNSCC.
Medulloblastoma Comprises Four Distinct Molecular Variants
Authors: Paul A. Northcott, Andrey Korshunov, Hendrik Witt, Thomas Hielscher, Charles G. Eberhart, Stephen Mack, Eric Bouffet, Steven C. Clifford, Cynthia E. Hawkins, Pim French, James T. Rutka, Stefan Pfister, Michael D. Taylor
Journal: Journal of Clinical Oncology (2010)

Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups.We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays.Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status.Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.
THE IFNγ RECEPTOR:A Paradigm for Cytokine Receptor Signaling
Authors: Erika A. Bach, Michel Aguet, Robert D. Schreiber
Journal: Annual Review of Immunology (1997)

During the last several years, the mechanism of IFN gamma-dependent signal transduction has been the focus of intense investigation. This research has recently culminated in the elucidation of a comprehensive molecular understanding of the events that underlie IFN gamma-induced cellular responses. The structure and function of the IFN gamma receptor have been defined. The mechanism of IFN gamma signal transduction has been largely elucidated, and the physiologic relevance of this process validated. Most recently, the molecular events that link receptor ligation to signal transduction have been established. Together these insights have produced a model of IFN gamma signaling that is nearly complete and that serves as a paradigm for signaling by other members of the cytokine receptor superfamily.
Effects of cigarette smoke and hypoxia on pulmonary circulation in the guinea pig
Authors: E. Ferrer, V.I. Peinado, J. Castañeda, J. Prieto-Lloret, E. Olea, M.C. González-Martín, M.V. Vega-Agapito, M. Díez, D. Domínguez-Fandos, A. Obeso, C. González, J.A. Barberà
Journal: European Respiratory Journal (2011)

Cigarette smoke (CS) and chronic hypoxia (CH) can produce pulmonary hypertension. Similarities and differences between both exposures and their interaction have not been explored. The aim of the present study was to investigate the effects of CS and CH, as single factors or in combination, on the pulmonary circulation in the guinea pig. 51 guinea pigs were exposed to CS for 12 weeks and 32 were sham-exposed. 50% of the animals in each group were additionally exposed to CH for the final 2 weeks. We measured pulmonary artery pressure ( P pa ), and the weight ratio between the right ventricle (RV) and left ventricle plus the septum. Pulmonary artery contractility in response to noradrenaline (NA), endothelium-dependent vasodilatation and distensibility were evaluated in organ bath chambers. The number of small intrapulmonary vessels showing immunoreactivity to smooth muscle (SM) α-actin and double elastic laminas was assessed microscopically. CS and CH induced similar increases of P pa and RV hypertrophy (p&lt;0.05 for both), effects that were further enhanced when both factors were combined. CH increased the contractility to NA (p&lt;0.01) and reduced the distensibility (p&lt;0.05) of pulmonary arteries. Animals exposed to CS showed an increased number of small vessels with positive immunoreactivity to SM α-actin (p&lt;0.01) and those exposed to CH a greater proportion of vessels with double elastic laminas (p&lt;0.05). We conclude that CH amplifies the detrimental effects of CS on the pulmonary circulation by altering the mechanical properties of pulmonary arteries and enhancing the remodelling of pulmonary arterioles.
The Central Nervous System as a Site of Action for the Coronary Vasoconstrictor Effect of Digoxin
Authors: Hasan Garan, Thomas W. Smith, Wm. John Powell
Journal: Journal of Clinical Investigation (1974)

Digitalis is known to have a vasoconstrictor effect in the coronary circulation. Recent studies have demonstrated that the coronary vasoconstrictor effects of acetylstrophanthidin and digoxin are neurally mediated via alpha adrenergic fibers. In the present study, experiments were done in 20 dogs anesthetized with chloralose and urethane to study the central nervous system as a possible site of action for this vasoconstrictor effect of digoxin. After the intravenous administration of 1.0 mg digoxin, cerebrospinal fluid concentrations of digoxin rose to a peak of 2.3+/-0.4 (SEM) ng/ml at 15 min, temporally corresponding to the peak in coronary vascular resistance change of +20.0+/-2.5% of control in the paced canine heart. Submicrogram digoxin injections into the lateral cerebral ventricle produced a significant increase in coronary vascular resistance, the latter injection producing a peak increase in coronary vascular resistance of 12.4+/-1.2% of control. Cross-perfusion experiments, where the isolated head of the operative dog was perfused from a donor dog receiving digoxin, thus keeping digoxin levels in the remainder of the operative dog very low, showed a similar degree of coronary vasoconstriction. Thus, the central nervous system appears to be an important site of action for the early coronary vasoconstrictor effect of digoxin.
Rad51 inhibition is an effective means of targeting DNA repair in glioma models and CD133+ tumor-derived cells
Authors: S. C. Short, S. Giampieri, M. Worku, M. Alcaide-German, G. Sioftanos, S. Bourne, K. I. Lio, M. Shaked-Rabi, C. Martindale
Journal: Neuro-Oncology (2011)

High grade gliomas (HGGs) are characterized by resistance to radiotherapy and chemotherapy. Targeting Rad51-dependent homologous recombination repair may be an effective target for chemo- and radiosensitization. In this study we assessed the role of Rad51-dependent repair on sensitivity to radiation and temozolomide (TMZ) as single agents or in combination. Repair protein levels in established glioma cell lines, early passage glioblastoma multiforme (GBM) cell lines, and normal human astrocytes (NHAs) were measured using western blot. Viability and clonogenic survival assays were used to measure the effects of Rad51 knockdown with radiation (XR) and TMZ. Immunocytochemistry was used to evaluate kinetics of Rad51 and γ-H2AX repair foci. Immunohistochemistry was used to assess Rad51 protein levels in glioma specimens. Repair proteins including Rad51 are upregulated in HGG cells compared with NHA. Established glioma cell lines show a dose-dependent increase in Rad51 foci formation after XR and TMZ. Rad51 levels are inversely correlated with radiosensitivity, and downregulation markedly increases the cytotoxicity of TMZ. Rad51 knockdown also promotes more residual γ-H2AX foci 24 h after combined treatment. Newly established GBM cell lines also have high Rad51 levels and are extremely sensitive to Rad51 knockdown. Clinical samples from recently resected gliomas of varying grades demonstrate that Rad51 levels do not correlate with tumor grade. Rad51-dependent repair makes a significant contribution to DNA repair in glioma cells and contributes to resistance to both XR and TMZ. Agents targeting Rad51-dependent repair would be effective adjuvants in standard combination regimens.
Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction
Authors: M.J. Brisco, J. Condon, E. Hughes, S-H. Neoh, P.J. Sykes, R. Seshadri, A.A. Morley, I. Toogood, K. Waters, G. Tauro, H. Ekert
Journal: The Lancet (1994)
Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin
Authors: Anthony W. Tolcher, Christopher J. Sweeney, Kyri Papadopoulos, Amita Patnaik, Elena G. Chiorean, Alain C. Mita, Kamalesh Sankhala, Eric Furfine, Jochem Gokemeijer, Lisa Iacono, Cheryl Eaton, Bruce A. Silver, Monica Mita
Journal: Clinical Cancer Research (2011)

To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies.Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.
S-nitrosoglutathione reductase–dependent PPARγ denitrosylation participates in MSC-derived adipogenesis and osteogenesis
Authors: Yenong Cao, Samirah A. Gomes, Erika B. Rangel, Ellena C. Paulino, Tatiana L. Fonseca, Jinliang Li, Marilia B. Teixeira, Cecilia H. Gouveia, Antonio C. Bianco, Michael S. Kapiloff, Wayne Balkan, Joshua M. Hare
Journal: Journal of Clinical Investigation (2015)

Bone marrow-derived mesenchymal stem cells (MSCs) are a common precursor of both adipocytes and osteoblasts. While it is appreciated that PPARγ regulates the balance between adipogenesis and osteogenesis, the roles of additional regulators of this process remain controversial. Here, we show that MSCs isolated from mice lacking S-nitrosoglutathione reductase, a denitrosylase that regulates protein S-nitrosylation, exhibited decreased adipogenesis and increased osteoblastogenesis compared with WT MSCs. Consistent with this cellular phenotype, S-nitrosoglutathione reductase-deficient mice were smaller, with reduced fat mass and increased bone formation that was accompanied by elevated bone resorption. WT and S-nitrosoglutathione reductase-deficient MSCs exhibited equivalent PPARγ expression; however, S-nitrosylation of PPARγ was elevated in S-nitrosoglutathione reductase-deficient MSCs, diminishing binding to its downstream target fatty acid-binding protein 4 (FABP4). We further identified Cys 139 of PPARγ as an S-nitrosylation site and demonstrated that S-nitrosylation of PPARγ inhibits its transcriptional activity, suggesting a feedback regulation of PPARγ transcriptional activity by NO-mediated S-nitrosylation. Together, these results reveal that S-nitrosoglutathione reductase-dependent modification of PPARγ alters the balance between adipocyte and osteoblast differentiation and provides checkpoint regulation of the lineage bifurcation of these 2 lineages. Moreover, these findings provide pathophysiological and therapeutic insights regarding MSC participation in adipogenesis and osteogenesis.
Lipid changes in breast cancer patients on exemestane treatment: final results of the TEAM Greek substudy
Authors: C. Markopoulos, A. Polychronis, U. Dafni, D. Koukouras, V. Zobolas, E. Tzorakoleftherakis, G. Xepapadakis, H. Gogas
Journal: Annals of Oncology (2008)
Sensitivity and specificity of clinical signs for assessment of dehydration in endurance athletes
Authors: J McGarvey, J Thompson, C Hanna, T D Noakes, J Stewart, D Speedy
Journal: British Journal of Sports Medicine (2008)

To investigate the diagnostic accuracy of commonly used signs of dehydration in marathon runners.The diagnostic accuracy of 5 clinical signs/symptoms thought to indicate dehydration (altered skin turgor, dry oral mucous membranes, sunken eyes, an inability to spit and the sensation of thirst) was assessed by comparing the presence of these markers with the criterion standard of body weight change over a marathon footrace.2006 Auckland Marathon.606 competitors in the full marathon.Body weight was measured before and immediately after the marathon. The 5 clinical signs/symptoms were assessed immediately after the marathon.Diagnostic accuracy of clinical signs/symptoms to detect dehydration greater than 3% of body weight. Results 606 complete data sets were obtained. 3 clinical signs were associated with greater percentage weight loss: sunken eyes (mean percentage weight loss with symptom 2.6% (standard deviation 1.5), without 2.3% (1.5)); decreased skin turgor (with 3.0% (1.4), without 2.3% (1.5)) and the sensation of thirst (with 2.5% (1.5), without 2.3% (1.5)). The ability to spit and dry oral mucous membranes were unrelated to percentage weight loss. No signs/symptoms showed acceptably high validity for detecting a weight loss equal to or greater than 3% of body weight.The 5 parameters (decreased skin turgor, sensation of thirst, sunken eyes, inability to spit and dry mucous membranes) tested in this study did not precisely identify runners with total weight loss >3% at the end of a marathon.
Increased Atherosclerotic Lesion Calcification in a Novel Mouse Model Combining Insulin Resistance, Hyperglycemia, and Hypercholesterolemia
Authors: Suvi E. Heinonen, Pia Leppänen, Ivana Kholová, Henri Lumivuori, Sanna-Kaisa Häkkinen, Fatima Bosch, Markku Laakso, Seppo Ylä-Herttuala
Journal: Circulation Research (2007)

No mouse model is currently available where the induction of type 2 diabetes on an atherosclerotic background could be achieved without significant concomitant changes in plasma lipid levels. We crossbred 2 genetically modified mouse strains to achieve a model expressing both atherosclerosis and characteristics of type 2 diabetes. For atherosclerotic background we used low-density lipoprotein receptor–deficient mice synthetizing only apolipoprotein B100 (LDLR −/− ApoB 100/100 ). Diabetic background was obtained from transgenic mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells. Thorough phenotypic characterization was performed in 6- and 15-month-old mice on both normal and high-fat Western diet. Results indicated that IGF-II transgenic LDLR −/− ApoB 100/100 mice demonstrated insulin resistance, hyperglycemia, and mild hyperinsulinemia compared with hypercholesterolemic LDLR −/− ApoB 100/100 controls. In addition, old IGF-II/LDLR −/− ApoB 100/100 mice displayed significantly increased lesion calcification, which was more related to insulin resistance than glucose levels, and significantly higher baseline expression in aorta of several genes related to calcification and inflammation. Lipid levels of IGF-II/LDLR −/− ApoB 100/100 mice did not differ from LDLR −/− ApoB 100/100 controls at any time. In conclusion, type 2 diabetic factors induce increased calcification and lesion progression without any lipid changes in a new mouse model of diabetic macroangiopathy.