Intravesical Bacillus Calmette-guérin Efficiently Reduces P70s6k1 But Not 4e-bp1 Phosphorylation In Nonmuscle Invasive Bladder Cancer.

We characterized the functional consequences of intravesical bacillus Calmette-Guérin on the molecular mechanism of the AKT/mTOR signaling pathway in nonmuscle invasive bladder cancer. To our knowledge this has not been reported previously. At age 7 weeks female Fischer 344 rats received 1.5 mg/kg MNU intravesically every other week for 6 weeks. They were randomized at 10 per group to MNU (0.2 ml vehicle), bacillus Calmette-Guérin (10(6) cfu Connaught strain), rapamycin (15 μg/ml) and bacillus Calmette-Guérin plus simultaneous rapamycin, each intravesically for 6 weeks. At week 15 the bladders were collected for histopathology, immunohistochemistry and immunoblot to determine p-AKT, Rictor, Raptor, p-4E-BP1, p-p70S6K1, p-AMPK-α, p-mTOR and p-p53. Papillary carcinoma (pTa) and high grade intraepithelial neoplasia (pTis) predominated in the MNU group while normal urothelium, papillary and flat hyperplasia were more common in treated groups. Nonmuscle invasive bladder cancer treated with bacillus Calmette-Guérin showed suppression of p70S6K1 but not 4E-BP1 phosphorylation. This suggests that 4E-BP1 is regulated differently than p70S6K1, escaping the bacillus Calmette-Guérin action that occurs in a mTOR independent manner. The association of bacillus Calmette-Guérin with rapamycin but not rapamycin monotherapy affected p70S6K1 and 4E-BP1 phosphorylation with no features of in situ carcinoma (pTis). The activation status of p70S6K1 and 4E-BP1 might be used to stratify patients who could benefit from targeting such molecular elements with multitarget/multidrug intravesical therapy. In the future 4E-BP1 might be a worthwhile new target for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer.

Jnk And Ikkβ Phosphorylation Is Reduced By Glucocorticoids In Adipose Tissue From Insulin-resistant Rats.

Peripheral insulin resistance (IR) is one of the main side effects caused by glucocorticoid (GC)-based therapies, and the molecular mechanisms of GC-induced IR are not yet fully elucidated. Thus, we aimed to investigate the effects of dexamethasone treatment on the main components of insulin and inflammatory signaling in the adipose tissue of rats. Male Wistar rats received daily injections of dexamethasone (1mg/kg body weight (b.w.), intraperitoneally (i.p.)) for 5 days (DEX), whereas control rats received saline (CTL). The metabolic status was investigated, and the epididymal fat fragments were collected for lipolysis and western blot analyses. The DEX rats became hyperglycemic, hyperinsulinemic, insulin resistant and glucose intolerant, compared with the CTL rats (P<0.05). The basal glycerol release in the fat fragments was 1.5-fold higher in the DEX rats (P<0.05). The phosphorylation of protein kinase B (PKB) at ser(473) decreased by 44%, whereas, the phosphorylation of insulin receptor substrate (IRS)-1 at ser(307) increased by 93% in the adipose tissue of the DEX rats after an oral bolus of glucose (P<0.05). The basal phosphorylation of c-jun-N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B (IKKβ) proteins was reduced by 46% and 58%, respectively, in the adipose tissue of the DEX rats (P<0.05). This was paralleled with a significant reduction (47%) in the glucocorticoid receptor (GR) protein content in the adipose tissue of the DEX rats (P<0.05). The insulin-resistant status of rats induced by dexamethasone administration have PKB and IRS-1 activity attenuated in epididymal fat without increases in the phosphorylation of the proinflammatory signals JNK and IKKβ.

Pseudodifferential operators with C*-algebra-valued symbols: Abstract characterizations

Given a separable unital C*-algebra C with norm parallel to center dot parallel to, let E-n denote the Banach-space completion of the C-valued Schwartz space on R-n with norm parallel to f parallel to(2)=parallel to < f, f >parallel to(1/2), < f, g >=integral f(x)* g(x)dx. The assignment of the pseudodifferential operator A=a(x,D) with C-valued symbol a(x,xi) to each smooth function with bounded derivatives a is an element of B-C(R-2n) defines an injective mapping O, from B-C(R-2n) to the set H of all operators with smooth orbit under the canonical action of the Heisenberg group on the algebra of all adjointable operators on the Hilbert module E-n. In this paper, we construct a left-inverse S for O and prove that S is injective if C is commutative. This generalizes Cordes' description of H in the scalar case. Combined with previous results of the second author, our main theorem implies that, given a skew-symmetric n x n matrix J and if C is commutative, then any A is an element of H which commutes with every pseudodifferential operator with symbol F(x+J xi), F is an element of B-C(R-n), is a pseudodifferential operator with symbol G(x - J xi), for some G is an element of B-C(R-n). That was conjectured by Rieffel.

Exercise Intensity, Inflammatory Signaling, and Insulin Resistance in Obese Rats

DA SILVA, A. S. R., J. R. PAULI, E. R. ROPELLE, A. G. OLIVEIRA, D. E. CINTRA, C. T. DE SOUZA, L. A. VELLOSO, J. B. C. CARVALHEIRA, and M. J. A. SAAD. Exercise Intensity, Inflammatory Signaling, and Insulin Resistance in Obese Rats. Med. Sci. Sports Exerc., Vol. 42, No. 12, pp. 2180-2188, 2010. Purpose: To evaluate the effects of intensity of exercise on insulin resistance and the expression of inflammatory proteins in the skeletal muscle of diet-induced obese (DIO) rats after a single bout of exercise. Methods: In the first exercise protocol, the rats swam for two 3-h bouts, separated by a 45-min rest period (with 6 h in duration-DIO + EXE), and in the second protocol, the rats were exercised with 45 min of swimming at 70% of the maximal lactate steady state-MLSS (DIO + MLSS). Results: Our data demonstrated that both protocols of exercise increased insulin sensitivity and increased insulin-stimulated tyrosine phosphorylation of insulin receptor and insulin receptor substrate 1 and serine phosphorylation of protein kinase B in the muscle of DIO rats by the same magnitude. In parallel, both exercise protocols also reduced protein tyrosine phosphatase 1B activity and insulin receptor substrate 1 serine phosphorylation, with concomitant reduction in c-jun N-terminal kinase and I kappa B kinase activities in the muscle of DIO rats in a similar fashion. Conclusions: Thus, our data demonstrate that either exercise protocols with low intensity and high volume or exercise with moderate intensity and low volume represents different strategies to restore insulin sensitivity with the same efficacy.

Mannan-binding lectin MBL2 gene polymorphism in chronic hepatitis C: association with the severity of liver fibrosis and response to interferon therapy

Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro-Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0.022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0.04) and to the control group (P = 0.011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0.023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment.

The potential role of C-reactive protein in distinguishing cytomegalovirus from tuberculosis and bacterial infections in renal transplant recipients

Introduction: The delay in the diagnosis of infections can be deleterious in renal transplant recipients. Thus, laboratory tests leading to an earlier diagnosis are very useful for these patients. Purpose: To assess the behavior of C-reactive protein (CRP) in renal transplant recipients with a diagnosis of cytomegalovirus (CMV) infection, tuberculosis (TB) and bacterial infection (BI). Methods: A retrospective analysis of 129 patients admitted at our hospital, from 2006 to 2008 because of CMV, TB or BI, was carried out. Appropriate statistical analysis was done and values were expressed as medians, range. Results: When CRP levels were compared among the groups with CMV disease, TB or BI, the group with CMV disease presented lower levels of CRP (18.4 mg/L, 0.28-44 mg/L) than the TB and BI (p < 0.05) groups. The area under the receiver-operating characteristics curve, distinguishing CMV disease from TB/BI, was 0.96 (p < 0.0001), resulting in 100% sensitivity and 90.63% specificity to detect CMV disease when CRP < 44.5 mg/L. The subgroup analysis of CMV infection showed increasing levels of CRP (0.28, 16 and 29.5 mg/L) in the asymptomatic, symptomatic and invasive disease subgroups, respectively (p < 0.05). Conclusion: The measurement of CRP levels may be a useful tool for differentiating CMV infection from the other types (bacterial or TB) of infection in kidney transplant recipients.

Abnormal cell-cycle expression of the proteins p27, mdm2 and cathepsin B in oral squamous-cell carcinoma infected with human papillomavirus

Since the role of human papillomavirus (HPV) infection in oral carcinogenesis is still unclear, the purpose of this study was to verify the association between the expression of p27, mdm2 and cathepsin B and by HPV-related oral lesions. Fifty-five oral biopsies were studied and HPV detection and typing (6/11, 16, 18, 31 and 33) were performed using polymerase chain reaction techniques. The distribution p27, mdm2 and cathepsin B was determined by immunohistochemistry. Twenty-one (38%) out of the 55 oral lesions tested positive for HPV, of which 6(33%) were HPV 6/11, 1 (5%) was HPV 16,14 (72%) were HPV 18 and none was HPV 33/31. Among the 55 biopsies, immunopostivity for p27, mdm2 and cathepsin B was observed in 17 (30.9%), 37 (67.2%) and 37 (67.2%), respectively. Among 21 HPV-positive oral lesions, immunopostivity of mdm2, p27 and cathepsin B was found, respectively, in 6 (33%) out of 18 benign lesions (BL), 4(22%) out of 18 potential malignant epithelial lesions (PMEL) and 11(57.9%) out of 19 malignant lesions (ML). High-risk HPV types may be associated with oral carcinoma, by cell-cycle control dysregulation, contributing to oral carcinogenesis and the overexpression of mdm2, p27 and cathepsin B. (C) 2009 Elsevier GmbH. All rights reserved.

Exploring through cover - the integrated interpretation of high resolution aeromagnetic, airborne electromagnetic and ground gravity data from the Grant's Patch area, Eastern Goldfields Province, Archaean Yigarn Craton Part B; Gravity inversion as a

The cost and risk associated with mineral exploration in Australia increases significantly as companies move into deeper regolith-covered terrain. The ability to map the bedrock and the depth of weathering within an area has the potential to decrease this risk and increase the effectiveness of exploration programs. This paper is the second in a trilogy concerning the Grant's Patch area of the Eastern Goldfields. The recent development of the VPmg potential field inversion program in conjunction with the acquisition of high-resolution gravity data over an area with extensive drilling provided an opportunity to evaluate three-dimensional gravity inversion as a bedrock and regolith mapping tool. An apparent density model of the study area was constructed, with the ground represented as adjoining 200 m by 200 m vertical rectangular prisms. During inversion VPmg incrementally adjusted the density of each prism until the free-air gravity response of the model replicated the observed data. For the Grant's Patch study area, this image of the apparent density values proved easier to interpret than the Bouguer gravity image. A regolith layer was introduced into the model and realistic fresh-rock densities assigned to each basement prism according to its interpreted lithology. With the basement and regolith densities fixed, the VPmg inversion algorithm adjusted the depth to fresh basement until the misfit between the calculated and observed gravity response was minimised. The resulting geometry of the bedrock/regolith contact largely replicated the base of weathering indicated by drilling with predicted depth of weathering values from gravity inversion typically within 15% of those logged during RAB and RC drilling.

GB virus C/Hepatitis G virus and other putative hepatitis non A-E viruses

The identification of the major agents causing human hepatitis (Hepatitis A, B, C, D and E Viruses) was achieved during the last 30 years. These viruses are responsible for the vast majority of human viral hepatitis cases, but there are still some cases epidemiologically related to infectious agents without any evidence of infection with known virus, designated as hepatitis non A - E. Those cases are considered to be associated with at least three different viruses: 1 - Hepatitis B Virus mutants expressing its surface antigen (HBsAg) with altered epitopes or in low quantities; 2 - Another virus probably associated with enteral transmitted non A-E hepatitis, called Hepatitis F Virus. Still more studies are necessary to better characterize this agent; 3 - Hepatitis G Virus or GB virus C, recently identified throughout the world (including Brazil) as a Flavivirus responsible for about 10% of parenteral transmitted hepatitis non A-E. Probably still other unknown viruses are responsible for human hepatitis cases without evidence of infection by any of these viruses, that could be called as non A-G hepatitis.

Intestinal helminthes and/or Toxocara infection are unrelated to anti-HBs titers in seven-year-old children vaccinated at birth with recombinant hepatitis B vaccine

The aim of this investigation was to evaluate the possible effect of nematode infection on anti-HBs antibody levels in the serum of seven-year-old schoolchildren vaccinated at birth with the recombinant hepatitis B vaccine. Anti-HBs and anti HBc antibodies were evaluated in the sera of 100 schoolchildren with at least one intestinal nematode and/or a positive serological reaction for anti-Toxocara antibodies and in 95 schoolchildren without intestinal helminthiasis or serum anti-Toxocara antibodies. Both groups were from public elementary schools located on the urban periphery of Vitória, ES, Brazil. Among these 195 children, the median anti-HBs antibody titer was 31.3IU/ml and the frequency of titers less than 10IU/ml was 33.8% (95% CI: 27.1-40.4%). There were no significant differences between the medians of anti-HBs titers or the frequency of titers less than 10IU/ml between the groups with or without helminthes (29.5 and 32.9IU/ml and 33 and 34.7%, respectively; p>0.05). Even when the children with intestinal nematodes and/or anti-Toxocara antibodies and with blood eosinophil counts over 600/mm³ were compared with children without infection from intestinal nematodes and without anti-Toxocara antibodies, with blood eosinophil counts less than 400 eosinophils/mm³, these differences were not significant. None of the children presented anti-HBc antibodies. In conclusion, infections with intestinal nematodes and/or the presence of anti-Toxocara antibodies did not interfere with the anti-HBs antibody titers in seven-year-old children vaccinated at birth with the recombinant hepatitis B vaccine.