Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection

We examined a rational approach to therapy of chronic hepatitis B virus (HBV) infection that utilized the reduction of viral load combined with appropriately timed immune modulation/stimulation. In a placebo-controlled study, chronic woodchuck hepatitis virus (WHV) carrier woodchucks received clevudine (L-FMAU), previously shown to have especially potent and sustained antiviral activity in woodchucks, for 32 weeks followed by WHV surface antigen (WHsAg) alum-adjuvanted vaccine at 32, 36, 40 and 48 weeks. Clevudine induced significant reductions in viraemia, surface antigenaemia, hepatic WHV nucleic acids, and hepatic core and surface antigens. Viral replication markers remained markedly suppressed in 75% of the clevudine-treated woodchucks following drug withdrawal, but remained at high levels in the vaccine monotherapy and placebo groups. Combination drug and vaccine therapy had benefits based on sustained reduction of viraemia, antigenaemia, and hepatic WHV DNA and RNA; inhibition of progression of chronic hepatitis; reduced frequency of chronic liver injury; and delayed onset of hepatocellular carcinoma (HCC). Combination therapy contributed to prevention of HCC in up to 38% of treated carriers, although the growth rate of established HCC was not affected. This study demonstrates enhanced benefits of combination chemo-immunotherapy against viral load and disease progression in chronic hepadnaviral infection, and provides a platform for further development of such treatment regimens.     

The 6-min walk distance: change over time and value as a predictor of survival in severe COPD.

The 6-min walk distance (6MWD) is used to evaluate the functional capacity of patients with chronic obstructive pulmonary disease (COPD). The change in 6MWD over time and its correlation with changes in spirometry and survival are unclear. Patients (n=198) with severe COPD and 41 age-matched controls were followed for 2 yrs, and anthropometrics, spirometry, 6MWD and comorbidities were measured. The 6MWD decreased in the COPD group from 238 +/- 107 m to 218 +/- 112 m (-26 +/- 37 m x yr(-1)), and increased in the control group from 532 +/- 82 m to 549 +/- 86 m (12 +/- 25 m x yr(-1)). In both groups, there was a poor correlation with changes in forced expiratory volume in one second (FEV1). Nonsurvivors in the COPD group (42%) had a more pronounced change in the 6MWD (-40 versus -22 m x yr(-1)) but a similar change in FEV1 (118 versus 102 mL x yr(-1)). The 6MWD independently predicted survival, after accounting for age, body mass index, FEV1 and comorbidities. In severe chronic obstructive pulmonary disease, the 6-min walk distance predicts mortality better than other traditional markers of disease severity. Its measurement is useful in the comprehensive evaluation of patients with severe disease.     

Predicting Recurrence and Progression of Noninvasive Papillary Bladder Cancer at Initial Presentation Based on Quantitative Gene Expression Profiles

Background

Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based on specific tumor biology, are yet to be identified.

Objective

To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach.

Design, setting, and participants

Retrospective study of patients with Ta G2/3 bladder tumors at initial presentation with three distinct clinical outcomes: absence of recurrence (n = 16), recurrence without progression (n = 16), and progression to carcinoma in situ or invasive disease (n = 16).

Measurements

Expressions of 24 genes that feature in relevant pathways that are deregulated in bladder cancer were quantified by real-time polymerase chain reaction on tumor biopsies from the patients at initial presentation.

Results and limitations

CCND3 (p = 0.003) and HRAS (p = 0.01) were predictive for recurrence by univariate analysis. In a multivariable model based on CCND3 expression, sensitivity and specificity for recurrence were 97% and 63%, respectively. HRAS (p < 0.001), E2F1 (p = 0.017), BIRC5/Survivin (p = 0.038), and VEGFR2 (p = 0.047) were predictive for progression by univariate analysis. Multivariable analysis based on HRAS, VEGFR2, and VEGF identified progression with 81% sensitivity and 94% specificity. Since this is a small retrospective study using medium-throughput profiling, larger confirmatory studies are needed.

Conclusions

Gene expression profiling across relevant cancer pathways appears to be a promising approach for Ta bladder tumor outcome prediction at initial diagnosis. These results could help differentiate between patients who need aggressive versus expectant management.     

Dissociable learning-dependent changes in REM and non-REM sleep in declarative and procedural memory systems

Sleep spindles and rapid eye movements have been found to increase following an intense period of learning on a combination of procedural memory tasks. It is not clear whether these changes are task specific, or the result of learning in general. The current study investigated changes in spindles, rapid eye movements, K-complexes and EEG spectral power following learning in good sleepers randomly assigned to one of four learning conditions: Pursuit Rotor (n=9), Mirror Tracing (n=9), Paired Associates (n=9), and non-learning controls (n=9). Following Pursuit Rotor learning, there was an increase in the duration of Stage 2 sleep, spindle density (number of spindles/min), average spindle duration, and an increase in low frequency sigma power (12-14Hz) at occipital regions during SWS and at frontal regions during Stage 2 sleep in the second half of the night. These findings are consistent with previous findings that Pursuit Rotor learning is consolidated during Stage 2 sleep, and provide additional data to suggest that spindles across all non-REM stages may be a mechanism for brain plasticity. Following Paired Associates learning, theta power increased significantly at central regions during REM sleep. This study provides the first evidence that REM sleep theta activity is involved in declarative memory consolidation. Together, these findings support the hypothesis that brain plasticity during sleep does not involve a unitary process; that is, different types of learning have unique sleep-related memory consolidation mechanisms that act in dissociable brain regions at different times throughout the night.     

Molecular signatures that predict nodal metastasis in bladder cancer: does the primary tumor tell tales?

Evaluation of: Smith SC, Baras AS, Dancik G et al. A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol. 12, 137-143 (2011). Accurate identification of nodal status in patients with bladder cancer is important in determining their prognosis and administration of perioperative chemotherapy. In this article, we review the study by Smith and colleagues, documenting the identification of a 20-gene model that can predict nodal stage in patients with bladder cancer based on the profiles of their primary tumors. The gene-expression model generated in this study was able to identify node-positive disease based on tumor tissues obtained from patients in a Phase III bladder cancer trial cohort. The model was able to predict nodal status independent of standard clinicopathologic prognostic criteria. This study adds the agnostic profiling dimension to prior investigations that have attempted to define molecular signatures that predict nodal metastasis in bladder cancer patients based on the primary tumors' gene-expression profiles.     

Food deprivation modifies corticosterone-dependent behavioural shifts in the common lizard

Stressful events typically induce glucocorticoid production that suppresses unnecessary physiological and behavioural functions. The glucocorticoid production also temporally activates alternative behavioural and physiological pathways. These responses are generally adaptive changes to avoid the negative effects of stressors. However, under low food availability, these behavioural and physiological modifications might lead to energetic costs. We therefore predict that these responses should not be activated when there are energetic constraints (e.g., low food availability). We experimentally tested whether food deprivation modifies corticosterone-induced behavioural and physiological responses in captive male common lizards. We measured corticosterone-induced responses in terms of body mass, metabolic rate, activity level and basking behaviour. We found that corticosterone-induced various behavioural and physiological responses which were dependent on food availability. Well-fed lizards treated with corticosterone were active earlier, and increased their basking behaviour. These behavioural modifications did not occur in food-deprived lizards. This inactivation of stress-related behavioural changes probably allows the lizard to save energy.     

Antiviral effects of lamivudine, emtricitabine, adefovir dipivoxil, and tenofovir disoproxil fumarate administered orally alone and in combination to woodchucks with chronic woodchuck hepatitis virus infection

Adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) are nucleotide analogs that inhibit the replication of wild-type hepatitis B virus (HBV) and lamivudine (3TC)-resistant virus in HBV-infected patients, including those who are coinfected with human immunodeficiency virus. The combination of ADV or TDF with other nucleoside analogs is a proposed strategy for managing antiviral drug resistance during the treatment of chronic HBV infection. The antiviral effect of oral ADV or TDF, alone or in combination with 3TC or emtricitabine (FTC), against chronic woodchuck hepatitis virus (WHV) infection was evaluated in a placebo-controlled study in the woodchuck, an established and predictive model for antiviral therapy. Once-daily treatment for 48 weeks with ADV plus 3TC or TDF plus FTC significantly reduced serum WHV viremia levels from the pretreatment level by 6.2 log₁₀ and 6.1 log₁₀ genome equivalents/ml serum, respectively, followed by TDF plus 3TC (5.6 log₁₀ genome equivalents/ml), ADV alone (4.8 log₁₀ genome equivalents/ml), ADV plus FTC (one survivor) (4.4 log₁₀ genome equivalents/ml), TDF alone (2.9 log₁₀ genome equivalents/ml), 3TC alone (2.7 log₁₀ genome equivalents/ml), and FTC alone (2.0 log₁₀ genome equivalents/ml). Individual woodchucks across all treatment groups also demonstrated pronounced declines in serum WHV surface antigen, characteristically accompanied by declines in hepatic WHV replication and the hepatic expression of WHV antigens. Most woodchucks had prompt recrudescence of WHV replication after drug withdrawal, but individual woodchucks across treatment groups had sustained effects. No signs of toxicity were observed for any of the drugs or drug combinations administered. In conclusion, the oral administration of 3TC, FTC, ADV, and TDF alone and in combination was safe and effective in the woodchuck model of HBV infection.     

Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects

Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.     

p53 and retinoblastoma pathways in bladder cancer

A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma genes and pathways. Examination of the alterations in the molecules in these pathways that regulate the cell cycle and their effects on the prognosis of bladder cancer are areas of active research. While defects in the p53-Mdm2-p14 axis have been implicated in urothelial cancer, perturbations in the cyclin-dependent kinases and their inhibitors have also been extensively studied in this context. Genetic alterations of the retinoblastoma gene and aberrant post-translational modifications of its protein have also been incriminated in invasive bladder cancer. This article reviews the individual prognostic roles of alterations in these molecules in the context of bladder cancer. Additionally, we review findings from recent studies that are attempting to analyze these markers in combination in an effort to construct molecular panels that can serve as more robust outcome predictors. More importantly, alterations in these molecules are now becoming enticing targets for novel therapeutics. We also review some of these agents that can restore the tumor cells’ altered homeostatic mechanisms, thereby having potential in transitional cell carcinoma therapy. Future management of bladder cancer will employ validated marker panels for outcome prediction, and novel genetic and pharmacologic agents that will be able to target molecular alterations in individual tumors based on their respective profiles. A.P. Mitra and M. Birkhahn contributed equally to this paper.