tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes
Authors: Bruce Neal, Vlado Perkovic, Dick de Zeeuw, Kenneth W. Mahaffey, Greg Fulcher, Kirk Ways, Mehul Desai, Wayne Shaw, George Capuano, Maria Alba, Joel Jiang, Frank Vercruysse, Gary Meininger, David Matthews
Journal: Diabetes Care (2014)

OBJECTIVE There are limited data about the effects of sodium–glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODS The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined. RESULTS Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m2, estimated glomerular filtration rate of 75 mL/min/1.73 m2, fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were −0.62% (95% CI −0.69, −0.54; −6.8 mmol/mol [95% CI −7.5, −5.9]; P &amp;lt; 0.001) and −0.73% (95% CI −0.81, −0.65; −8.0 mmol/mol [95% CI −8.9, −7.1]; P &amp;lt; 0.001) at 18 weeks and −0.58% (95% CI −0.68, −0.48; −6.3 mmol/mol [95% CI −7.4, −5.2]) and −0.73% (95% CI −0.83, −0.63; −8.0 mmol/mol [95% CI −9.1, −6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses. CONCLUSIONS Canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.
Comparison of computed tomography, endosonography, and intraoperative assessment in TN staging of gastric carcinoma.
Authors: K Ziegler, C Sanft, T Zimmer, M Zeitz, D Felsenberg, H Stein, C Germer, C Deutschmann, E O Riecken
Journal: Gut (1993)

From 1986 to 1990 a prospective comparative study was undertaken to compare the relative accuracy of computed tomography, endogastric ultrasonography, and intraoperative surgical assessment in evaluating the depth of invasion (T category) and involvement of lymph nodes (N category) of patients with gastric carcinoma. One hundred and eight consecutive patients, who were treated by total gastrectomy and previously evaluated with computed tomography, endogastric ultrasonography, and intraoperative surgical assessment, entered the study. Results (T and N category) were compared with those of histopathological staging (pT and pN category). T categories were correctly staged in 43% of cases with computed tomography, 86% with endogastric ultrasonography, and 56% with intraoperative surgical assessment. Computed tomography scanning correctly staged 51% of all N1 and N2 lymph nodes compared with 74% for endogastric ultrasonography and 54% for intraoperative surgical assessment. In general, computed tomography was more accurate for advanced stages of cancer and showed a tendency to overstage the T category and understage N category of gastric tumours. By contrast, endogastric ultrasonography was equally accurate for all T categories and showed an understaging for N categories. Intraoperative surgical assessment overstaged early T stages, understaged T4 tumours, and was equally accurate for all grades of N categories. Computed tomography scanning and intraoperative surgical assessment of T and N categories were of little value in staging of gastric carcinoma. Endogastric ultrasonography is more accurate than computed tomography scanning and intraoperative surgical assessment. Therefore endogastric ultrasonography should be introduced in the preoperative assessment of patients with gastric carcinoma.
Selective Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Mediates C-Reactive Protein–Evoked Endothelial Vasodilator Dysfunction in Coronary Arterioles
Authors: Travis W. Hein, Erion Qamirani, Yi Ren, Xin Xu, Naris Thengchaisri, Lih Kuo
Journal: Circulation Research (2013)

Studies in cultured endothelium implicate that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) or Fcγ receptor II (CD32) contributes to the proatherogenic effects of C-reactive protein (CRP). However, the identity of the receptors linking to deleterious actions of CRP in vasomotor regulation remains unknown.We tested the hypothesis that LOX-1 contributes to adverse effects of CRP on endothelium-dependent vasomotor function in resistance arterioles.Porcine coronary arterioles were isolated for vasoreactivity study, dihydroethidium fluorescence staining of superoxide, immunohistochemical localization of receptors, immunoprecipitation of receptor/CRP interaction, and protein blot. Intraluminal treatment of pressurized arterioles with a pathophysiological level of CRP (7 µg/mL; 60 minutes) attenuated endothelium-dependent nitric oxide-mediated and prostacyclin-mediated dilations to serotonin and arachidonic acid, respectively. LOX-1 and CD32 were detected in the endothelium of arterioles. Blockade of LOX-1 with either pharmacological antagonist κ-carrageenan or anti-LOX-1 antibody prevented the detrimental effect of CRP on vasodilator function, whereas anti-CD32 antibody treatment was ineffective. Denudation of endothelium and blockade of LOX-1 but not CD32 prevented CRP-induced elevation of superoxide in the vessel wall. CRP was coimmunoprecipitated with LOX-1 and CD32 from CRP-treated arterioles. Similarly, LOX-1 and CD32 blockade prevented CRP-induced arteriolar expression of plasminogen activator inhibitor-1, a thrombogenic protein.CRP elicits endothelium-dependent oxidative stress and compromises nitric oxide-mediated and prostacyclin-mediated vasomotor function via LOX-1 activation. In contrast, both LOX-1 and CD32 mediate plasminogen activator inhibitor-1 upregulation in arterioles by CRP. Thus, activation of LOX-1 and CD32 may contribute to vasomotor dysfunction and proatherogenic actions of CRP, respectively.
Spontaneous Occurrence of &lt;italic&gt;γ&lt;/italic&gt;-Glutamyl Transpeptidase-Positive Hepatocytic Foci in 105-Week-Old Wistar and 72-Week-Old Fischer 344 Male Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Katsuhiro Ogawa, Tamenori Onoé, Masaya Takeuchi
Journal: JNCI Journal of the National Cancer Institute (1981)

Spontaneous hepatic changes in old male rats of Wistar and F344 inbred strains were studied histochemically. gamma-Glutamyl transpeptidase-positive hepatocytic foci and cholangiolar proliferation associated with fibrosis and inflammatory infiltration were common findings in the old rats of both strains. Histochemical properties of the hepatocytes of the foci were similar to those of hyperplastic foci seen in early stages of liver carcinogenesis due to various chemical carcinogens. The incidence of the foci was 2.52/cm2 of the histochemically stained sections in 105-week-old male Wistar and F344 rats, and the presence of other spontaneous neoplastic and nonneoplastic changes was revealed.
Association of <i>KRAS</i> G13D Tumor Mutations With Outcome in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy With or Without Cetuximab
Authors: Sabine Tejpar, Ilhan Celik, Michael Schlichting, Ute Sartorius, Carsten Bokemeyer, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2012)

Purpose We investigated in the first-line setting our previous finding that patients with chemorefractory KRAS G13D–mutated metastatic colorectal cancer (mCRC) benefit from cetuximab treatment. Methods Associations between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed. Results Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Significant variations in treatment effects were found for tumor response (P = .005) and PFS (P = .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68) in patients with G13D-mutant tumors. Patients with G12V and other mutations did not benefit from this treatment combination. Patients with KRAS G13D–mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P = .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies. Conclusion The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D–mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values.
Assessing the Maximum Contribution from Ancient Populations
Authors: Per Sjödin, Pontus Skoglund, Mattias Jakobsson
Journal: Molecular Biology and Evolution (2014)

Ancestral relationships between populations separated by time represent an often neglected dimension in population genetics, a field which historically has focused on analysis of spatially distributed samples from the same point in time. Models are usually straightforward when two time-separated populations are assumed to be completely isolated from all other populations. However, this is usually an unrealistically stringent assumption when there is gene flow with other populations. Here, we investigate continuity in the presence of gene flow from unknown populations. This setup allows a more nuanced treatment of questions regarding population continuity in terms of "level of contribution" from a particular ancient population to a more recent population. We propose a statistical framework which makes use of a biallelic marker sampled at two different points in time to assess population contribution, and present two different interpretations of the concept. We apply the approach to published data from a prehistoric human population in Scandinavia (Malmström H, Gilbert MTP, Thomas MG, Brandström M, Storå J, Molnar P, Andersen PK, Bendixen C, Holmlund G, Götherström A, et al. 2009. Ancient DNA reveals lack of continuity between Neolithic hunter-gatherers and contemporary Scandinavians. Curr Biol. 19:1758–1762) and Pleistocene woolly mammoth (Barnes I, Shapiro B, Lister A, Kuznetsova T, Sher A, Guthrie D, Thomas MG. 2007. Genetic structure and extinction of the woolly mammoth, Mammuthus primigenius. Curr Biol. 17:1072–1075; Debruyne R, Chu G, King CE, Bos K, Kuch M, Schwarz C, Szpak P, Gröcke DR, Matheus P, Zazula G, et al. 2008. Out of America: ancient DNA evidence for a new world origin of late quaternary woolly mammoths. Curr Biol. 18:1320–1326).
REDOX REGULATION OF CELLULAR ACTIVATION
Authors: Hajime Nakamura, Kazuhiro Nakamura, Junji Yodoi
Journal: Annual Review of Immunology (1997)

▪ Abstract Growing evidence has indicated that cellular reduction/oxidation (redox) status regulates various aspects of cellular function. Oxidative stress can elicit positive responses such as cellular proliferation or activation, as well as negative responses such as growth inhibition or cell death. Cellular redox status is maintained by intracellular redox-regulating molecules, including thioredoxin (TRX). TRX is a small multifunctional protein that has a redox-active disulfide/dithiol within the conserved active site sequence: Cys-Gly-Pro-Cys. Adult T cell leukemia–derived factor (ADF), which we originally defined as an IL-2 receptor α-chain/Tac inducer produced by human T cell lymphotrophic virus-I (HTLV-I)–transformed T cells, has been identified as human TRX. TRX/ADF is a stress-inducible protein secreted from cells. TRX/ADF has both intracellular and extracellular functions as one of the key regulators of signaling in the cellular responses against various stresses. Extracellularly, TRX/ADF shows a cytoprotective activity against oxidative stress–induced apoptosis and a growth-promoting effect as an autocrine growth factor. Intracellularly, TRX/ADF is involved in the regulation of protein-protein or protein–nucleic acid interactions through the reduction/oxidation of protein cysteine residues. For example, TRX/ADF translocates from the cytosol into the nucleus by a variety of cellular stresses, to regulate the expression of various genes through the redox factor-1 (Ref-1)/APEX. Further studies to clarify the regulatory roles of TRX/ADF and its target molecules may elucidate the intracellular signaling pathways in the responses against various stresses. The concept of “redox regulation” is emerging as an understanding of the novel mechanisms in the pathogenesis of several disorders, including viral infections, immunodeficiency, malignant transformation, and degenerative disease.
Wound healing and fibrosis in intestinal disease
Authors: F Rieder, J Brenmoehl, S Leeb, J Scholmerich, G Rogler
Journal: Gut (2006)

Twelve blood parameters were studied in five groups of women totalling 120 subjects--group I: 26 blood donors (average age 45.2 years, range 23-66); group II: 18 patients with various cerebral, cardiovascular, or infectious illnesses (average age 79.9 years, range 66-92); group III: 28 patients with femoral neck fractures (average age 79.4 years, range 56-95); group IV: 12 patients with hip osteoarthrosis (average age 71.7 years, range 60-87); group V: 36 patients with vertebral crush fractures associated with postmenopausal and involutional osteoporosis (average age 63.0 years, range 51-75). The parameters measured were total proteins, albumin, total, alpha 1, alpha 2, beta, and gamma globulins, total calcium, phosphates, alkaline phosphatase, bilirubin, and haemoglobin. Statistical analysis showed that each group differed from the others even with adjustment for age. Among the discriminant parameters, serum albumin had a distinctive position. Significantly high concentrations of serum albumin in the group with osteoarthrosis raise the question of the possible existence of a population prone to osteoarthrosis in whom the serum albumin level may reflect a special nutritional state associated with the well known bone density in subjects with hip osteoarthrosis. Albumin values in patients with femoral neck fractures are lower than normal but non-significantly. The difference between the group with vertebral crush fractures and that with femoral neck fractures seems to be due to age.
Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle.
Authors: B A Lessey, L Damjanovich, C Coutifaris, A Castelbaum, S M Albelda, C A Buck
Journal: Journal of Clinical Investigation (1992)

Integrins are a class of cell adhesion molecules that participate in cell-cell and cell-substratum interactions and are present on essentially all human cells. The distribution of nine different alpha and beta integrin subunits in human endometrial tissue at different stages of the menstrual cycle was determined using immunoperoxidase staining. Glandular epithelial cells expressed primarily alpha 2, alpha 3, and alpha 6 (collagen/laminin receptors), while stromal cells expressed predominantly alpha 5 (fibronectin receptor). The presence of alpha 1 on glandular epithelial cells was cycle specific, found only during the secretory phase. Expression of both subunits of the vitronectin receptor, alpha v beta 3, also underwent cycle specific changes on endometrial epithelial cells. Immunostaining for alpha v increased throughout the menstrual cycle, while the beta 3 subunit appeared abruptly on cycle day 20 on luminal as well as glandular epithelial cells. Discordant luteal phase biopsies (greater than or equal to 3 d "out of phase") from infertility patients exhibited delayed epithelial beta 3 immunostaining. These results demonstrate similarities, as well as specific differences, between endometrium and other epithelial tissues. Certain integrin moieties appear to be regulated within the cycling endometrium and disruption of integrin expression may be associated with decreased uterine receptivity and infertility.
The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells.
Authors: L Rønnov-Jessen, O W Petersen, V E Koteliansky, M J Bissell
Journal: Journal of Clinical Investigation (1995)

The origin of myofibroblasts in stromal reaction has been a subject of controversy. To address this question definitively, we developed techniques for purification and characterization of major stromal cell types. We defined a panel of markers that could, in combination, unequivocally distinguish these cell types by immunocytochemistry, iso-electric focusing, immunoblotting, and two-dimensional gel electrophoresis. We then devised an assay to recapitulate in culture, within two weeks of incubation, critical aspects of the microenvironment in vivo including the typical tissue histology and stromal reaction. When confronted with tumor cells in this assay, fibroblasts readily converted into a graded pattern of myogenic differentiation, strongest in the immediate vicinity of tumor cells. Vascular smooth muscle cells (VSMC), in contrast, did not change appreciably and remained coordinately smooth muscle differentiated. Midcapillary pericytes showed only a slight propensity for myogenic differentiation. Analysis of ten primary tumors implicated converted fibroblasts (10/10), vascular smooth muscle cells (4/10), and pericytes (1/10) in the stromal reaction. Tumor cells were shown to specifically denude the venules both in culture and in vivo, explaining the VSMC phenotype in the stroma. The establishment of this assay and clarification of the origin of these cells pave the way for further analysis of the mechanisms of conversion, and of the consequence of such heterogeneity for diagnosis and treatment.
Is clinical examination dead?
Authors: K. Patel
Journal: BMJ (2013)

“I tried to listen to some heart sounds last week. Couldn’t hear a thing.” So an eminent professor of medicine told me recently. “It’s all quackery, you know.”

This is something I’d thought for a while, but I’d not heard it summed up with such frankness. Although I continue to teach undergraduates the distinction between reverse and fixed splitting of the second heart sound, I have never detected these conditions myself. And I’ve got a strong suspicion that most cardiologists confidently declare “a clear case of a loud …
Overall Survival (OS) and Tumour Shrinkage Outcomes in Patients with Symptomatic/Asymptomatic Metastatic Colorectal Cancer (MCRC): Data From the Prime Study
Authors: Jean-Yves Douillard, Salvatore Siena, Josep Tabernero, Marc Peeters, Chris Davison, Stephan Braun, Roger Sidhu
Journal: Annals of Oncology (2013)
The slow component of the delayed rectifier potassium current in undiseased human ventricular myocytes
Authors: L Virág
Journal: Cardiovascular Research (2001)

The purpose of this study was to investigate the properties of the slow component of the delayed rectifier potassium current (I(Ks)) in myocytes isolated from undiseased human left ventricles.The whole-cell configuration of the patch-clamp technique was applied in 58 left ventricular myocytes from 15 hearts at 37 degrees C. Nisoldipine (1 microM) was used to block inward calcium current (I(Ca)) and E-4031 (1-5 microM) was applied to inhibit the rapid component of the delayed rectifier potassium current (I(Kr)).In 31 myocytes, an E-4031 insensitive, but L-735,821 and chromanol 293B sensitive, tail current was identified which was attributed to the slow component of I(K) (I(Ks)). Activation of I(Ks) was slow (tau=903+/-101 ms at 50 mV, n=14), but deactivation of the current was relatively rapid (tau=122.4+/-11.7 ms at -40 mV, n=19). The activation of I(Ks) was voltage independent but its deactivation showed clear voltage dependence. The deactivation was faster at negative voltages (about 100 ms at -50 mV) and slower at depolarized potentials (about 300 ms at 0 mV). In six cells, the reversal potential was -81.6+/-2.8 mV on an average which is close to the K(+) equilibrium potential suggesting K(+) as the main charge carrier.In undiseased human ventricular myocytes, I(Ks) exhibits slow activation and fast deactivation kinetics. Therefore, in humans I(Ks) differs from that reported in guinea pig, and it best resembles I(Ks) described in dog and rabbit ventricular myocytes.
Duodenal mucosal bicarbonate secretion in man. Stimulation by acid and inhibition by the alpha 2-adrenoceptor agonist clonidine.
Authors: L Knutson, G Flemstrom
Journal: Gut (1989)

A multi-channel small diameter tube was used to study the secretion of bicarbonate by 3 cm long segments of the proximal duodenum isolated between balloons. The tube had an outer diameter of 5.3 mm and two central and four smaller, peripheral channels. Measurements of infused phenol red, 14C-PEG and vitamin B12 and of trypsin activity were performed to rule out contamination of the perfusate by gastric and pancreatic secretions. Basal secretion of bicarbonate by the duodenal mucosa in healthy subjects varied between 135 and 220 mumol/cm of intestine per hour. Perfusion of the lumen with acid (100 mM HCl for five minutes) increased the secretion to greater than 400 mumol/cm/h and the alpha 2-adrenoreceptor agonist clonidine (150 micrograms iv) decreased the HCO3- secretion by 70 mumol/cm/h. Clonidine simultaneously reduced the mean arterial blood pressure and plasma noradrenaline concentration, but did not affect the plasma glucose or adrenaline concentration. Duodenal bicarbonate secretion is important in the protection of this mucosa against acid discharged from the stomach. Increased sympathetic activity may, by inhibiting the bicarbonate secretion, decrease the protection in proximal duodenum in man and facilitate ulceration.