In vivo pharmacodynamics of indole-3-carbinol in the inhibition of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: involvement of Nrf2 and cell cycle/apoptosis signaling pathways

Indole‐3‐carbinol (I3C) found abundantly in crucifers has been shown to possess anti‐cancer effects. The present study aims to examine the chemopreventive effects and the molecular mechanism of I3C, particularly the anti‐oxidative stress pathway regulated by nuclear erythroid related factor 2 (Nrf2). HepG2‐C8‐ARE‐luciferase cells were used for Nrf2‐ARE activity. TRAMP C1 cells were used to investigate the effects of I3C on Nrf2‐mediated genes. To test the chemopreventive efficacy of I3C, transgenic adenocarcinoma of mouse prostate (TRAMP) mice were fed with 1% I3C supplemented diet for 12 or 16 wk. The expression of Nrf2 and its downstream target genes, cell cycle and apoptosis genes were investigated using quantitative real‐time polymerase chain reaction (qPCR). The protein expressions of these biomarkers were also investigated using Western blotting. I3C induced antioxidant response element (ARE)‐luciferase activity in a dose‐dependent manner. Treatments of TRAMP C1 cells with I3C also resulted in the induction of Nrf2‐mediated genes. I3C significantly suppressed the incidence of palpable tumor and reduced the genitourinary weight in TRAMP mice. Western blots and qPCR analyses of prostate tissues showed that I3C induced the expression of Nrf2, NAD(P)H quinine oxidoreductase 1 (NQO‐1) as well as cell cycle and apoptosis related biomarkers in I3C‐fed TRAMP mice. This study demonstrated that the effectiveness of I3C as prostate cancer chemoprevention agent via up‐regulation of a novel Nrf2‐mediated anti‐oxidative stress pathway. © 2011 Wiley Periodicals, Inc.     

Outpatient thromboprophylaxis with low-molecular-weight heparin in solid tumors: Where do we stand today?

Journal of Thrombosis and Thrombolysis -     

Randomized placebo-controlled clinical trial of immunoglobulin Y as adjunct to standard supportive therapy for rotavirus-associated diarrhea among pediatric patients

This study aims to evaluate the effect of hyperimmune immunoglobulin Y (IgY) against human rotavirus (HRV) among pediatric patients receiving standard supportive treatment for rotavirus-associated diarrhea mostly with an enteric non-cholera co-pathogen in a hospital setting. Two natural HRV reassortant clinical strains ATCC VR 2273 and ATCC VR 2274 were used as mixed immunizing antigens in poultry hens to generate anti-HRV IgY (Rotamix IgY). The Rotamix IgY was used in laboratory and clinical studies against control or placebo IgY. The control or placebo IgY was prepared using tissue culture medium from mock-infected MA104 cell line as antigen for poultry immunization. In vitro, Rotamix IgY exhibited multi-serotypic cross neutralization activities along with synergistic effects against major global serotypes G1, G2, G3, G4 and other human or animal rotavirus strains when compared with mono-specific IgY. Suckling mice (ICR strain) pre-treated orally once with Rotamix IgY and then challenged with rotavirus 3h later showed a significant dose-dependent reduction in frequency (p<0.05) and duration (p<0.05) of diarrhea compared to placebo IgY-treated mice. Out of 114 children aged between 3 and 14 months and with diarrhea upon admission in a Myanmar hospital, 54 dehydrated and rotavirus-positive children were randomized into Rotamix IgY group and placebo IgY group. Of these, only 52 children had complete data with n=26 children per study group. Ninety-two percent of patients in each of these groups were positive for co-infecting enteric non-cholera pathogen and all patients received standard supportive therapy for diarrhea. The patients were monitored for volume and duration of oral rehydration fluid (ORF) and intravenous fluid (IVF) intake, daily stool frequency and overall duration of diarrhea, and frequency and duration of rotavirus shedding. Compared to placebo IgY group, the Rotamix IgY group had statistically significant reduction in mean ORF intake (p=0.004), mean duration of intravenous fluid administration (p=0.03), mean duration of diarrhea from day of admission (p<0.01) and mean duration of rotavirus clearance from stool from day of admission (p=0.05). Overall, our novel approach using oral Rotamix IgY for rotavirus-infected children mostly with non-cholera enteric pathogen co-infection appears to be a promising, safe and effective adjunct to management of acute diarrhea in pediatric patients.     

Knob antigen deposition in cerebral malaria

Plasmodium falciparum-infected erythrocytes attach to the endothelial cells via electron-dense knobs and this attachment has been suggested as one of the contributing factors in the development of cerebral malaria. Monoclonal antibodies against an 80-95 Kd knob protein were prepared and applied to brain tissue from cerebral malaria patients. The deposition of the 80-95 Kd knob protein antibodies was observed in the basement membrane of cerebral capillaries by the peroxidase anti-peroxidase method. This result indicates involvement of knob protein deposition in the pathogenesis of cerebral malaria.     

Impact of Primary Ambulatory Thromboprophylaxis (PATP) with Low-Molecular Weight Heparins (LMWHs) on Survival in Patients with Lung Cancer Receiving Chemotherapy

Lung cancer (LC) is the leading cause of cancer mortality. PATP was provided in experimental trials to decrease the venous thromboembolism (VTE), with ultimate aim to improve overall survival (OS). We undertook an updated systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the impact of PATP with LMWHs on OS and VTE in patients with LC. 5443 patients with LC from nine RCTs were included. The pooled hazard ratio (HR) for OS was 1.02 (95% CI 0.83 to 1.26; P = 0.83) and for progression or metastasis-free survival was 1.03 (95% CI 0.86 to 1.24; P = 0.74). The pooled risk ratio (RR) for VTE was 0.54 (95% CI 0.43 to 0.69; P < 0.00001) and the risk difference (RD) was—0.03 (− 0.05 to − 0.02; P < 0.00001). Our analysis showed no survival advantage with the addition of PATP with LMWHs to standard chemotherapy in patients with LC, regardless of histology or stages of small cell LC.

     

Renal effects of cadmium intake of a Japanese general population in two areas unpolluted by cadmium

Renal effects of cadmium exposure (i.e., in food products) on people living in two areas unpolluted by cadmium in Japan were investigated. The population comprised 875 inhabitants (i.e., 346 males and 529 females) and 635 inhabitants (i.e., 222 males and 413 females), all of whom in each area were 50+ y of age. The authors used urinary cadmium concentration as an indicator of internal dose, and total urinary protein, beta2-microglobulin, and N-acetyl-beta-glucosaminidase were indicators of renal dysfunction. The authors used multiple-regression and logistic-regression analyses to study the relationship between urinary cadmium excretion and the above indicators of renal dysfunction. In the two geographic areas, both analyses revealed that urinary cadmium concentrations were associated significantly with indicators of renal dysfunction. The results suggest that renal dysfunction is related significantly with environmental cadmium exposure in areas of Japan that are not polluted by cadmium.