tbuckley/cabot-search huggingface dataset:
Long-Term Titrated-Dose α-Glucosidase Inhibition in Non-Insulin-Requiring Hispanic NIDDM Patients
Authors: Peter S Johnston, Peter U Feig, Robert F Coniff, Alice Krol, Jaime A Davidson, Steven M Haffner
Journal: Diabetes Care (1998)

OBJECTIVE To assess the long-term safety and effectiveness of a titrated dose of the alpha-glucosidase inhibitor miglitol (BAY m 1099) in Hispanic NIDDM patients. RESEARCH DESIGN AND METHODS A 1-year double-blind randomized placebo-controlled study in which diet-treated or diet plus sulfonylurea-treated Hispanic NIDDM patients received either placebo (n = 131) or miglitol in doses of 50, 100, 150, 200 mg t.i.d. (n = 254), up-titrated and down-titrated based on tolerability. Efficacy parameters included changes from baseline in HbA1c, fasting and 2-h postprandial plasma glucose and serum insulin, fasting serum lipids, and urinary albumin-to-creatinine ratio (ACR). Safety assessments consisted primarily of tabulation of adverse events and intercurrent illnesses, and of periodic laboratory determinations. RESULTS Reductions from baseline in HbA1c levels at the 6-month (primary efficacy) endpoint were significantly greater by 0.83% in the miglitol group than in the placebo group. HbA1c reductions in the miglitol treatment group significantly exceeded those in the placebo group by 0.63, 0.73, and 0.92% at 3, 9, and 12 months of treatment, respectively. Reductions in 120-min postprandial glucose and insulin levels were significantly greater in the miglitol group than in the placebo group at all postbaseline visits. There was little difference between treatments for changes in fasting insulin or lipid levels. Miglitol-associated reductions versus placebo in fasting plasma glucose (P = 0.0587 at 6 months) and in ACR (P = 0.0541 at 1-year) were nearly statistically significant. These efficacy results were not notably different between the 6-month endpoint, at which time the mean miglitol dose was 100 mg t.i.d., and the 1-year visit, when the mean miglitol dose was 149 mg t.i.d. Notable adverse events seen significantly more often in the miglitol group than in the placebo group were flatulence and diarrhea (or soft stools). The incidence of these gastrointestinal adverse events appeared to be dose dependent. CONCLUSIONS Miglitol treatment of non-insulin-requiring Hispanic NIDDM patients at doses from 50 to 200 mg t.i.d. produced statistically and clinically significant reductions of HbA1c, primarily associated with reduction of glucose and insulin levels in the postprandial period, which were sustained over a year of treatment. Adverse events related to the drug's mechanism of action were common, but generally well tolerated. Doses above 100 mg t.i.d. were not associated with notably enhanced efficacy in most patients.
Recent Advances in Evaluation of Gonadotropic Hormones
Authors: J L Vaituraitis, G T Ross
Journal: Annual Review of Medicine (1973)

Over the past five years radioimrnunoassays for gonadotropins have been applied extensively in studying control of gonadotropin secretion during physio­ logic and pathophysiologic states of human gonadal function. Results of these studies have been rather fully reviewed (1-3). Despite remarkable contributions to the understanding of endocrine control of gonadotropin secretion, results obtained with different reagents have not always been consistent (4). Further­ more, discrepancies have been noted when immunoassay potency estimates are compared with bioassay estimates, using a single reference preparation in both systems (5, 6). Frequently, it has been impossible to rationalize discrepancies though it has been supposed that they originated in variable structural require­ ments for biologic and immunologic binding sites (5). In the following discussion, recently delineated chemical, biological, and immunological properties giving rise to these disparities will be reviewed. Exploi­ tation of these findings has provided rational explanations for some discrepan­ cies, facilitated the production of specific reagents, and extended the applica­ tions of gonadotropin measurements in humans.
Journal impact factors for 2004: another rise for Thorax
Authors: J A Wedzicha
Journal: Thorax (2005)

In the Rotterdam Study, the authors investigated whether high intake of antioxidants from food is associated with the risk of stroke. Among 5,197 participants who were followed on average for 6.4 years, 227 ischemic strokes occurred. Higher intake of antioxidants was associated with a lower risk of stroke. The relationship was dose-dependent, significant for vitamin C, and most pronounced in smokers. These results agree with the view that high dietary intake of antioxidants, in particular vitamin C and—in smokers—vitamin E, reduces the risk of stroke.
Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme
Authors: M. Kerkhof, J. C. M. Dielemans, M. S. van Breemen, H. Zwinkels, R. Walchenbach, M. J. Taphoorn, C. J. Vecht
Journal: Neuro-Oncology (2013)

To examine the efficacy of valproic acid (VPA) given either with or without levetiracetam (LEV) on seizure control and on survival in patients with glioblastoma multiforme (GBM) treated with chemoradiation.A retrospective analysis was performed on 291 patients with GBM. The efficacies of VPA and LEV alone and as polytherapy were analyzed in 181 (62%) patients with seizures with a minimum follow-up of 6 months. Cox-regression survival analysis was performed on 165 patients receiving chemoradiation with temozolomide of whom 108 receiving this in combination with VPA for at least 3 months.Monotherapy with either VPA or LEV was instituted in 137/143 (95.8%) and in 59/86 (68.6%) on VPA/LEV polytherapy as the next regimen. Initial freedom from seizure was achieved in 41/100 (41%) on VPA, in 16/37 (43.3%) on LEV, and in 89/116 (76.7%) on subsequent VPA/LEV polytherapy. At the end of follow-up, seizure freedom was achieved in 77.8% (28/36) on VPA alone, in 25/36 (69.5%) on LEV alone, and in 38/63 (60.3%) on VPA/LEV polytherapy with ongoing seizures on monotherapy. Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7-67.3) compared with 61 weeks (95% CI: 52.5-69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43-0.92; P = .016), adjusting for age, extent of resection, and O(6)-DNA methylguanine-methyltransferase promoter methylation status.Polytherapy with VPA and LEV more strongly contributes to seizure control than does either as monotherapy. Use of VPA together with chemoradiation with temozolomide results in a 2-months' longer survival of patients with GBM.
The Phosphoinositide 3-Kinase/Akt Pathway: A New Target in Human Renal Cell Carcinoma Therapy
Authors: Carole Sourbier, Véronique Lindner, Hervé Lang, Abdelali Agouni, Eric Schordan, Sabrina Danilin, Sylvie Rothhut, Didier Jacqmin, Jean-Jacques Helwig, Thierry Massfelder
Journal: Cancer Research (2006)

Abstract Metastatic renal cell carcinoma is resistant to current therapies. The phosphoinositide 3-kinase (PI3K)/Akt signaling cascade induces cell growth, cell transformation, and neovascularization. We evaluated whether targeting this pathway could be of therapeutic value against human renal cell carcinoma. The activation of the PI3K/Akt pathway and its role in renal cell carcinoma progression was evaluated in vitro in seven human cell lines by Western blot, cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, terminal deoxyribonucleotide transferase–mediated nick-end labeling assays, and fluorescence-activated cell sorting analysis, using two PI3K inhibitors, LY294002 and wortmannin, as well as by transfection with various Akt constructs and through Akt knockdown by small interfering RNA (siRNA). In vivo nude mice bearing human renal cell carcinoma tumor xenografts were treated with LY294002 (75 mg/kg/wk, 4 weeks, i.p.). Tumor growth was measured and tumors were subjected to Western blot and immunohistochemical analysis. Akt was constitutively activated in all cell lines. Constitutive phosphorylation of glycogen synthase kinase-3 (GSK-3) was observed in all cell lines, whereas forkhead transcription factor and mammalian target of rapamycin, although expressed, were not constitutively phosphorylated. Exposure to LY294002 or wortmannin decreased Akt activation and GSK-3 phosphorylation and reduced cell growth by up to 70% through induction of cell apoptosis. These effects were confirmed by transfection experiments with Akt constructs or Akt siRNA. Importantly, LY294002 induced up to 50% tumor regression in mice through tumor cell apoptosis. Tumor neovascularization was significantly increased by LY294002 treatment. Blood chemistries showed no adverse effects of the treatment. Our results suggest an important role of PI3K/Akt inhibitors as a potentially useful treatment for patients with renal cell carcinoma. (Cancer Res 2006; 66(10): 5130-42)
Baseline Tumor Oxygen Saturation Correlates with a Pathologic Complete Response in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy
Authors: Shigeto Ueda, Darren Roblyer, Albert Cerussi, Amanda Durkin, Anais Leproux, Ylenia Santoro, Shanshan Xu, Thomas D. O'Sullivan, David Hsiang, Rita Mehta, John Butler, Bruce J. Tromberg
Journal: Cancer Research (2012)

Abstract Tissue hemoglobin oxygen saturation (i.e., oxygenation) is a functional imaging endpoint that can reveal variations in tissue hypoxia, which may be predictive of pathologic response in subjects undergoing neoadjuvant chemotherapy. In this study, we used diffuse optical spectroscopic imaging (DOSI) to measure concentrations of oxyhemoglobin (ctO2Hb), deoxy-hemoglobin (ctHHb), total Hb (ctTHb = ctO2Hb + ctHHb), and oxygen saturation (stO2 = ctO2Hb/ctTHb) in tumor and contralateral normal tissue from 41 patients with locally advanced primary breast cancer. Measurements were acquired before the start of neoadjuvant chemotherapy. Optically derived parameters were analyzed separately and in combination with clinical biomarkers to evaluate correlations with pathologic response. Discriminant analysis was conducted to determine the ability of optical and clinical biomarkers to classify subjects into response groups. Twelve (28.6%) of 42 tumors achieved pathologic complete response (pCR) and 30 (71.4%) were non-pCR. Tumor measurements in pCR subjects had higher stO2 levels (median 77.8%) than those in non-pCR individuals (median 72.3%, P = 0.01). There were no significant differences in baseline ctO2Hb, ctHHb, and ctTHb between response groups. An optimal tumor oxygenation threshold of stO2 = 76.7% was determined for pCR versus non-pCR (sensitivity = 75.0%, specificity = 73.3%). Multivariate discriminant analysis combining estrogen receptor staining and stO2 further improved the classification of pCR versus non-pCR (sensitivity = 100%, specificity = 85.7%). These results show that elevated baseline tumor stO2 are correlated with a pCR. Noninvasive DOSI scans combined with histopathology subtyping may aid in stratification of individual patients with breast cancer before neoadjuvant chemotherapy. Cancer Res; 72(17); 4318–28. ©2012 AACR.
Autophagy in Vascular Disease
Authors: Guido R.Y. De Meyer, Mandy O.J. Grootaert, Cédéric F. Michiels, Ammar Kurdi, Dorien M. Schrijvers, Wim Martinet
Journal: Circulation Research (2015)

Autophagy is a reparative, life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. Growing evidence reveals that basal autophagy is an essential in vivo process mediating proper vascular function. Moreover, autophagy is stimulated by many stress-related stimuli in the arterial wall to protect endothelial cells and smooth muscle cells against cell death and the initiation of vascular disease, in particular atherosclerosis. Basal autophagy is atheroprotective during early atherosclerosis but becomes dysfunctional in advanced atherosclerotic plaques. Little is known about autophagy in other vascular disorders, such as aneurysm formation, arterial aging, vascular stiffness, and chronic venous disease, even though autophagy is often impaired. This finding highlights the need for pharmacological interventions with compounds that stimulate the prosurvival effects of autophagy in the vasculature. A large number of animal studies and clinical trials have indicated that oral or stent-based delivery of the autophagy inducer rapamycin or derivatives thereof, collectively known as rapalogs, effectively inhibit the basic mechanisms that control growth and destabilization of atherosclerotic plaques. Other autophagy-inducing drugs, such as spermidine or add-on therapy with widely used antiatherogenic compounds, including statins and metformin, are potentially useful to prevent vascular disease with minimal adverse effects.
Molecular Diagnosis of Sentinel Lymph Node Metastases in Cervical Cancer Using Squamous Cell Carcinoma Antigen
Authors: Song-Hua Yuan, Xue-Fang Liang, Wei-Hua Jia, Jian-Ling Huang, Mei Wei, Ling Deng, Li-Zhi Liang, Xiao-Yun Wang, Yi-Xin Zeng
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To clarify the prognostic value of molecular diagnosis of SLN metastases in cervical cancer using SCCA. Experimental Design: All SLNs and primary tumors, part of non-SLNs, were harvested from 36 patients with cervical cancer. Expression levels of SCCA, cytokeratin 19 (CK19), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in 178 samples (29 primary tumors, 5 histologic positive nodes, 60 histologic negative SLNs, 69 non-SLNs, and 15 normal nodes) were assessed by quantitative reverse transcription-PCR assay. The quantitative value of SCCA or CK19 mRNA was described as each value relative to GAPDH mRNA. The cutoff value was set at the upper limit of the quantitative value of nodes from noncancer patients, and those above this value constituted the molecular metastasis group. Results: The SCCA mRNA expression values were more than 1 × 103 in 28 primary tumors and all histologic positive nodes, and its expression levels in SLNs were higher than in non-SLNs. SLNs from patients with adverse prognostic features had higher SCCA mRNA expression levels. Four histologic negative SLNs were diagnosed molecular metastases based on SCCA mRNA. Two cases with histologically uninvolved pelvic nodes recurred. Survival analysis indicates that molecular lymphatic metastasis based on elevated SCCA mRNA level is the best predictor of recurrence. However, CK19 is not a suitable marker due to its low specificity and relative higher baseline expression in normal nodes. Conclusions: SCCA mRNA levels for molecular diagnosis of SLN metastases in cervical cancer more accurately identifies patients at risk for recurrence than the routine histology does.
The mPTP and its regulatory proteins: final common targets of signalling pathways for protection against necrosis
Authors: T. Miura, M. Tanno
Journal: Cardiovascular Research (2011)

The mitochondrial permeability transition pore (mPTP) is a non-selective, large-conductance channel that is closed under physiological conditions. Opening of the mPTP, leading to abolition of mitochondrial functions, is a major mechanism of myocyte necrosis by ischaemia/reperfusion, and direct inhibition of mPTP opening by use of pharmacological or genetic manipulations limits infarct size in vivo. Multiple pro-survival signal pathways commonly target the mPTP and inhibit its opening. Although the molecular structure of the mPTP has not been established, recent studies have characterized roles of each mPTP subunit and functions of several proteins directly interacting with the mPTP. This article briefly describes the understanding of mPTP regulation and interaction of the mPTP with four proteins (hexokinase II, glycogen synthase kinase-3β, signal transducer and activator of transcription 3, and sirtuin 3) that are downstream of signal pathways relevant to protection from ischaemia/reperfusion injury.
Prourokinase Mutant That Induces Highly Effective Clot Lysis Without Interfering With Hemostasis
Authors: Jian-Ning Liu, Jian-Xia Liu, Bei-fang Liu, Ziyong Sun, Jian-Ling Zuo, Pei-xiang Zhang, Jing Zhang, Yu-hong Chen, Victor Gurewich
Journal: Circulation Research (2002)

Prourokinase (proUK) is a zymogenic plasminogen activator that at pharmacological doses is prone to nonspecific activation to urokinase. This has handicapped therapeutic exploitation of its fibrin-specific physiological properties. To attenuate this susceptibility without compromising specific activation of proUK on a fibrin clot, a Lys300→His mutation (M5) was developed. M5 had a lower intrinsic activity and, therefore, remained stable in plasma at a 4-fold higher concentration than did proUK. M5 had a higher 2-chain activity and induced more rapid plasminogen activation and fibrin-specific clot lysis in vitro. Sixteen dogs embolized with radiolabeled clots were infused with saline, proUK, tissue plasminogen activator, or M5. The lower intrinsic activity allowed a higher infusion rate with M5, which induced the most rapid and efficient clot lysis (50% clot lysis by ≈600 μg/kg M5 versus ≈1200 μg/kg proUK). In association with this, M5 caused neither a significant increase in the primary bleeding time nor secondary bleeding (total blood loss). By contrast, these measurements increased 4-fold and 5-fold, respectively, with proUK and &gt;5-fold and 8-fold, respectively, with tissue plasminogen activator. Clot lysis by M5 and hemostasis were further evaluated in 6 rhesus monkeys. M5 again induced rapid clot lysis without a significant increase in the primary bleeding time, and secondary bleeding did not occur. In conclusion, a site-directed mutation designed to improve the stability of proUK in blood at therapeutic concentrations induced superior clot lysis in vitro and in vivo without causing significant interference with hemostasis.
THE INFLUENCE OF CORTISONE ON EXPERIMENTAL VIRAL INFECTION
Authors: K. Marilyn Smart, Edwin D. Kilbourne
Journal: The Journal of Experimental Medicine (1966)

The initial observations that cortisone may act as an inhibitor of viral interference (11, 4) are now explicable as an inhibitory effect on interferon synthesis. The suggestion that the action of interferon is also inhibited by cortisone or its analogues (6) has not been confirmed in a plaque reduction type of interferon assay system in which autointerference by the challenge inoculum is a lesser problem. In this respect, the present results are in accord with those obtained by DeMaeyer and DeMaeyer (8) with hydrocortisone in a system in which a low multiplicity (0.1) Sindbis virus infection in monolayer culture was employed with cytopathic effect (CPE) as an end-point. It has been shown that hydrocortisone is restrictive to the synthesis of interferon induced by inoculation of either infective or inactivated virus into the chick embryo, and that this inhibitory effect is temporary. However, in another study in the chick embryo, three spaced injections of hydrocortisone (0.25 mg/dose) prevented the appearance of detectable interferon during the entire 64 hr observation period following inoculation of 10(3.3) EID(50) of Lee virus (12). The importance of explicit definition of experimental conditions in assessing hormonal effects on infection is illustrated by the capacity of hydrocortisone either to inhibit or increase interferon synthesis in vitro, depending on the proportion of inactivated and infective virus in the inoculum employed, and the time at which interferon is measured. As suggested previously, it is not unlikely that similar shifts in hormone-virus-interferon balance may operate in vivo to influence the outcome of infection.
Tolerance of the Human Kidney to Isolated Controlled Ischemia
Authors: Dipen J. Parekh, Joel M. Weinberg, Barbara Ercole, Kathleen C. Torkko, William Hilton, Michael Bennett, Prasad Devarajan, Manjeri A. Venkatachalam
Journal: Journal of the American Society of Nephrology (2013)

Tolerance of the human kidney to ischemia is controversial. Here, we prospectively studied the renal response to clamp ischemia and reperfusion in humans, including changes in putative biomarkers of AKI. We performed renal biopsies before, during, and after surgically induced renal clamp ischemia in 40 patients undergoing partial nephrectomy. Ischemia duration was >30 minutes in 82.5% of patients. There was a mild, transient increase in serum creatinine, but serum cystatin C remained stable. Renal functional changes did not correlate with ischemia duration. Renal structural changes were much less severe than observed in animal models that used similar durations of ischemia. Other biomarkers were only mildly elevated and did not correlate with renal function or ischemia duration. In summary, these data suggest that human kidneys can safely tolerate 30-60 minutes of controlled clamp ischemia with only mild structural changes and no acute functional loss.
Increased C5a receptor expression in sepsis
Authors: Niels C. Riedemann, Ren-Feng Guo, Thomas A. Neff, Ines J. Laudes, Katie A. Keller, Vidya J. Sarma, Maciej M. Markiewski, Dimitrios Mastellos, Christoph W. Strey, Carl L. Pierson, John D. Lambris, Firas S. Zetoune, Peter A. Ward
Journal: Journal of Clinical Investigation (2002)

Excessive production of the complement activation product C5a appears to be harmful during the development of sepsis in rodents. Little is known about the role of the C5a receptor (C5aR) and its presence in different organs during sepsis. Using the cecal ligation/puncture (CLP) model in mice, we show here that C5aR immunoreactivity was strikingly increased in lung, liver, kidney, and heart early in sepsis in both control and neutrophil-depleted mice. C5aR mRNA expression in these organs was also significantly increased during sepsis. Immunohistochemical analysis revealed patterns of increased C5aR expression in parenchymal cells in all four organs following CLP. Mice injected at the start of CLP with a blocking IgG to C5aR (αC5aR) showed dramatically improved survival when compared with animals receiving nonspecific IgG, as did mice injected with αC5a. In αC5aR-treated mice, serum levels of IL-6 and TNF-α and bacterial counts in various organs were significantly reduced during CLP when compared with control CLP animals. These studies demonstrate for the first time that C5aR is upregulated in lung, liver, kidney, and heart during the early phases of sepsis and that blockade of C5aR is highly protective from the lethal outcome of sepsis.
Differential pattern of expression of caveolin-1 and AIF-1 in chronic graft-versus-host disease suggests a specific role in the pathogenesis of systemic sclerosis
Authors: I. Tinazzi, D. Biasi, F. Benedetti, C. Colato, P. Emery, F. D. Galdo
Journal: Annals of the Rheumatic Diseases (2010)

The role of the immune system in the pathogenesis of systemic sclerosis (SSc) is still unclear. Chronic allograft rejection and sclerodermoid graft-versus-host disease (Scl-GVHD) show a tissue pathology similar to SSc providing a indirect evidence of this role. We have shown that allograft inflammatory factor-1 (AIF-1) and caveolin-1 (cav-1) play an important role in the pathogenesis of SSc [ Arthritis and Rheumatism , 2006, 54 : 2616–25; Arthritis and Rheumatism , 2007, 56 : 3478–88; Arthritis and …