The morbidity and mortality of diabetes mellitus are mostly attributed to cardiovascular complications. Despite tremendous advancement in glycemic control, anti-diabetic medications have failed to ...revert vascular impairment once triggered by the metabolic disorder. The angiogenic growth factors, Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2), are crucial regulators of vessel formation and maintenance starting with embryonic development and continuing through life. In mature vessels, angiopoietins control vascular permeability, inflammation and remodeling. A crucial role of angiopoietins is to drive vascular inflammation from the active to the quiescent state, enabling restoration of tissue homeostasis. The mechanism is of particular importance for healing and repair after damage, two conditions typically impaired in metabolic disorders. There is an emerging body of evidences suggesting that the imbalance of Ang1 and Ang2 regulation, leading to an increased Ang2/Ang1 ratio, represents a culprit of the vascular alterations of patients with type-2 diabetes mellitus. Pharmacological modulation of Ang1 or Ang2 actions may help prevent or delay the onset of diabetic vascular complications by restoring vessel function, favoring tissue repair and maintaining endothelial quiescence. In this review, we present a summary of the role of Ang1 and Ang2, their involvement in diabetic complications, and novel therapeutic strategies targeting angiopoietins to ameliorate vascular health in metabolic disorders.
Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. To define novel ...pathways that regulate susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioma, we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant glioma cells, levels of different miRs are increased, and in particular, miR-30b/c and -21. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. T98G-sensitive cells treated with miR-21 or -30b/c become resistant to TRAIL. Furthermore, we demonstrate that miR-30b/c and miR-21 target respectively the 3' untranslated region of caspase-3 and TAp63 mRNAs, and that those proteins mediate some of the effects of miR-30 and -21 on TRAIL resistance, even in human glioblastoma primary cells and in lung cancer cells. In conclusion, we show that high expression levels of miR-21 and -30b/c are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets for TRAIL resistance in glioma.
This paper focuses on the understanding of the Random Telegraph Signal (RTS) in Single-Photon Avalanche Diodes (SPAD). We studied the RTS of two different SPAD layouts, designed and implemented in a ...150-nm CMOS process, after proton irradiation. The two structures are characterized by different junction types: the first structure is constituted by a P+/Nwell junction, while the second is formed by a Pwell/Niso junction. RTS occurrence has been measured in about one thousand SPAD pixels and the differences addressed in two layouts are motivated and discussed. Hypotheses on the RTS origin are drawn by analyzing the RTS time constants and the RTS occurrence evolution as a function of the annealing temperature.
Background Meta-analyses of trials of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins for cardiovascular disease prevention have failed to show any statistically significant benefit ...of statins for cancer prevention. However, these trials included relatively young participants, who develop few cancers, and their follow-up periods may have been too short to detect an association between statin use and cancer incidence. We investigated this association in a population of veterans. Methods We identified patients using antihypertensive medications but no cholesterol-lowering medications (n = 25594) and patients using statins (n = 37248) who were enrolled in the Veterans Affairs New England Healthcare System between January 1, 1997, and December 31, 2005. Age- and multivariable-adjusted Cox proportional hazards models were used to calculate the hazard ratio (HR) and its 95% confidence interval (CI) for cancer incidence, excluding nonmelanoma skin cancer, among patients taking statins compared with patients taking antihypertensive medications and among patients grouped by statin dose (as equivalent simvastatin dose). All statistical tests were two-sided. Results The absolute incidence of total cancers was 9.4% among statin users and 13.2% among nonusers (difference = 3.8%, 95% CI = 3.3% to 4.3%, Pdifference < .001). Statin users had a statistically significant lower risk for total cancer than nonusers after adjustment for age (HR = 0.76, 95% CI = 0.73 to 0.80) and multiple potential confounders (HR = 0.74, 95% CI = 0.70 to 0.78). After multivariable adjustment, a statistically significantly decreased risk of all cancers was also associated with increasing statin use (Ptrend < .001). Conclusions Patients using statins may be at lower risk for developing cancer. Additional observational studies and randomized trials of statins for cancer prevention are warranted.
A tri‐federal initiative arising out of the Cancer Moonshot has resulted in the formation of a program to utilize advanced genomic and proteomic expression platforms on high‐quality human ...biospecimens in near‐real‐time in order to identify potentially actionable therapeutic molecular targets, study the relationship of molecular findings to cancer treatment outcomes, and accelerate novel clinical trials with biomarkers of prognostic and predictive value.
This paper concerns an efficient algorithm for the solution of the exterior orientation problem. Orthogonal decompositions are used to first isolate the unknown depths of feature points in the camera ...reference frame, allowing the problem to be reduced to an absolute orientation with scale problem, which is solved using the singular value decomposition (SVD). The key feature of this approach is the low computational cost compared to existing approaches.
Contrast-induced nephropathy accounts for >10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay and represents a powerful predictor of poor early and late ...outcome. Mechanisms of contrast-induced nephropathy are not completely understood. In vitro data suggests that contrast media (CM) induces a direct toxic effect on renal tubular cells through the activation of the intrinsic apoptotic pathway. It is unclear whether this effect has a role in the clinical setting. In this work, we evaluated the effects of CM both in vivo and in vitro. By analyzing urine samples obtained from patients who experienced contrast-induced acute kidney injury (CI-AKI), we verified, by western blot and immunohistochemistry, that CM induces tubular renal cells apoptosis. Furthermore, in cultured cells, CM caused a dose-response increase in reactive oxygen species (ROS) production, which triggered Jun N-terminal kinases (JNK1/2) and p38 stress kinases marked activation and thus apoptosis. Inhibition of JNK1/2 and p38 by different approaches (i.e. pharmacological antagonists and transfection of kinase-death mutants of the upstream p38 and JNK kinases) prevented CM-induced apoptosis. Interestingly, N-acetylcysteine inhibited ROS production, and thus stress kinases and apoptosis activation. Therefore, we conclude that CM-induced tubular renal cells apoptosis represents a key mechanism of CI-AKI.
After the acute coronary syndrome, adding warfarin to standard aspirin therapy decreases myocardial infarction and stroke but increases major bleeding.
To quantify the risks and benefits of warfarin ...therapy after the acute coronary syndrome.
MEDLINE from 1990 to October 2004. Additional data were obtained from study authors. Clinical risk factors were used to classify hypothetical patients into cardiovascular and bleeding risk groups on the basis of published data.
Randomized trials comparing intensive warfarin therapy (international normalized ratio > 2.0) plus aspirin with aspirin alone after the acute coronary syndrome.
Two reviewers independently selected studies and extracted data on study design; quality; and clinical outcomes, including myocardial infarction, stroke, revascularization, death, and major and minor bleeding. Rate ratios for outcomes were calculated and pooled by using the method of DerSimonian and Laird.
Ten trials involving a total of 5938 patients (11,334 patient-years) met the study criteria. Compared with aspirin alone, warfarin plus aspirin was associated with a decrease in the annual rate of myocardial infarction (0.022 vs. 0.041; rate ratio, 0.56 95% CI, 0.46 to 0.69), ischemic stroke (0.004 vs. 0.008; rate ratio, 0.46 CI, 0.27 to 0.77), and revascularization (0.115 vs. 0.135; rate ratio, 0.80 CI, 0.67 to 0.95). Warfarin was associated with an increase in major bleeding (0.015 vs. 0.006; rate ratio, 2.5 CI, 1.7 to 3.7). Mortality did not differ.
Two large studies provided most of the data. Studies did not include coronary stenting, and results should not be applied to patients with stents. Relative risk reductions may not be consistent across risk groups.
For patients with the acute coronary syndrome who are at low or intermediate risk for bleeding, the cardiovascular benefits of warfarin outweigh the bleeding risks.
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