Hesperidin inhibits cyclophosphamide-induced tumor growth delay in mice

Hesperidin is a natural compound that has chemoprotective effects in tumor cell lines and protective effects against hematotoxicity induced by cyclophosphamide. The aim of this study was to evaluate the effect of hesperidin on the antitumor effect of cyclophosphamide in tumor-bearing mice. Administration of hesperidin reduced the leukopenia induced by cyclophosphamide in normal mice. White blood cell counts were increased in mice treated with hesperidin at a dose 200 mg/kg prior to cyclophosphamide injection. This significant protective effect was observed at 4 and 7 days after cyclophosphamide injection. Coadministration of hesperidin with cyclophosphamide in colon carcinoma (CT-26)-bearing mice was found to significantly inhibit cyclophosphamide-induced tumor growth delay. Tumor-bearing mice treated with hesperidin had increased tumor development compared with control animals that did not receive any treatment. These results show that hesperidin interacts with cyclophosphamide to inhibit its antitumor effect. In this study, estrogen receptor was negative for the development of CT-26 tumor. These results imply that fruits containing hesperidin, such as citrus, might have side effects on the efficacy of cyclophosphamide in the treatment of patients with colon cancer.     

Local Expression of Indoleamine 2,3 Dioxygenase in Syngeneic Fibroblasts Significantly Prolongs Survival of an Engineered Three-Dimensional Islet Allograft

OBJECTIVE

The requirement of systemic immunosuppression after islet transplantation is of significant concern and a major drawback to clinical islet transplantation. Here, we introduce a novel composite three-dimensional islet graft equipped with a local immunosuppressive system that prevents islet allograft rejection without systemic antirejection agents. In this composite graft, expression of indoleamine 2,3 dioxygenase (IDO), a tryptophan-degrading enzyme, in syngeneic fibroblasts provides a low-tryptophan microenvironment within which T-cells cannot proliferate and infiltrate islets.

RESEARCH DESIGN AND METHODS

Composite three-dimensional islet grafts were engineered by embedding allogeneic mouse islets and adenoviral-transduced IDO–expressing syngeneic fibroblasts within collagen gel matrix. These grafts were then transplanted into renal subcapsular space of streptozotocin diabetic immunocompetent mice. The viability, function, and criteria for graft take were then determined in the graft recipient mice.

RESULTS

IDO-expressing grafts survived significantly longer than controls (41.2 ± 1.64 vs. 12.9 ± 0.73 days; P < 0.001) without administration of systemic immunesuppressive agents. Local expression of IDO suppressed effector T-cells at the graft site, induced a Th2 immune response shift, generated an anti-inflammatory cytokine profile, delayed alloantibody production, and increased number of regulatory T-cells in draining lymph nodes, which resulted in antigen-specific impairment of T-cell priming.

CONCLUSIONS

Local IDO expression prevents cellular and humoral alloimmune responses against islets and significantly prolongs islet allograft survival without systemic antirejection treatments. This promising finding proves the potent local immunosuppressive activity of IDO in islet allografts and sets the stage for development of a long-lasting nonrejectable islet allograft using stable IDO induction in bystander fibroblasts.Endocrine replacement therapy by islet transplantation represents a feasible and attractive alternative therapeutic approach for treating type 1 diabetes (1,2). Despite improvement of allogeneic islet engraftment using systemic immunosuppression, islet transplantation is still limited by high rates of rejection. Furthermore, some immunosuppressive agents are prodiabetogenic and associated with adverse side effects (3–6). Finding more efficient and less harmful strategies to protect islet graft is therefore required for improving islet transplantation outcome.Localized expression of immunoregulatory factors using gene transfer to graft is a feasible method to provide an immunoprivileged microenvironment and consequently improves graft survival. Such an on-site delivery system results in more potent local immunosuppression with less systemic side effects (7–9).IDO is a cytosolic enzyme that catalyzes essential amino acid l-tryptophan to kynurenine (10) and has profound effects on T-cell proliferation, differentiation, effector functions, and viability (11). Both the reduction in local tryptophan concentration and the production of immunomodulatory tryptophan metabolites contribute to immunosuppressive effects of IDO (12,13). Broad evidence implicates IDO and the tryptophan catabolic pathway in generation of immune tolerance to antigens in tissue microenvironments. In particular, the role of IDO in fetal tolerance in mammalian pregnancy (14,15), immunologic tolerance to tumors (16,17), and self-tolerance has been documented (18,19). The unique immunoregulatory function of IDO substantiates the application of this enzyme as a strategy to suppress alloimmune responses in transplantation.Our research group has shown that overexpression of IDO in fibroblasts suppresses immune response and improves outcome of skin grafts (20–25) and that bystander IDO-expressing fibroblasts suppress immune response to allogeneic mouse islets in vitro (26). Furthermore, in a recent study we showed that mouse islets and fibroblasts are selectively resistant to IDO-mediated activation of nutrient deficiency stress (27). Here, we engineered a three-dimensional composite islet allograft equipped with IDO-expressing fibroblasts and examined whether local expression of IDO, conferred by adenoviral-mediated gene transfer to bystander syngeniec fibroblasts, prevents the rejection of islet allograft. Our approach here is novel compared with other studies that examined the suppressive effect of IDO in islet transplantation (28,29) because 1) bystander syngeneic fibroblasts were used as the target of gene transfer instead of islets to avoid deleterious effects of adenovirus infection on islets (30–32), 2) islets were embedded within an extracellular matrix that by itself improves islet function and viability (33,34), and 3) cotransplanted fibroblasts are more than just a source of IDO and can enhance islet physiological competence (35,36).     

Psychological adjustment of survivors of localised prostate cancer: investigating the role of dyadic adjustment, cognitive appraisal and coping style

OBJECTIVES: The aim of this study was to identify the factors that contribute to psychological adjustment in prostate cancer patients two or more years post-treatment. METHOD: One hundred and sixty-seven men who had undergone treatment for localised prostate cancer participated in this study. In the sample 63 participants had undergone external beam radiotherapy (EBRT), 55 radical prostatectomy (RP), 27 EBRT plus hormone therapy (EBRT/HT), and the remainder a combination of treatments. Patients completed the UCLA-PCI, the POMS, CISS, DAS and a threat appraisal questionnaire. RESULTS: The majority of patients reported relatively positive adjustment in most domains except sexual functioning. For those who reported ongoing psychological difficulty mood disturbance was associated with sexual bother, dyadic adjustment, threat appraisal, self-efficacy appraisal and emotion-focussed coping. Lower levels of urinary bother were associated with the use of more task-focussed coping. Emotion-focussed coping and threat appraisal mediated the relationship between sexual bother and mood disturbance. Emotion-focussed coping moderated the influence of dyadic adjustment on mood disturbance. CONCLUSIONS: Dyadic adjustment, threat appraisal and coping style play a significant role in the long-term psychological adjustment of prostate cancer patients. The results of the current study indicate that the use of emotion-focussed coping to manage sexual bother appears to result in poor psychological adjustment, which indicates the need for further education or intervention to manage sexual dysfunction. ETHICS CLEARANCE: Human ethics approval was granted from Southern Health, Peter MacCallum Cancer Centre and the Monash University Ethics Committee before commencement of data collection.     

An increased lung cancer risk associated with codon 72 polymorphism in the TP53 gene and human papillomavirus infection in Mazandaran province, Iran

The TP53 gene has a polymorphism in exon 4 at codon 72 that presents the arginine or proline genotype. The association of TP53 codon 72 polymorphism with lung cancer risk has been studied by several groups, although with inconsistent results. Our previous study showed that the human papillomavirus (HPV) infection is associated with the development of lung cancer in Mazandaran, north part of Iran (cases=25.6% versus controls=9.0%, P=0.002). The frequency of TP53 codon 72 polymorphism was studied in a north part Iranian group of 92 healthy controls and 141 lung cancer patients. The allelic distribution of the three genotypes (ArgArg, ArgPro, ProPro) in healthy normal controls was 46.1, 32.6 and 21.3%, respectively, which differs from that of lung cancer patients showing genotype frequency as 42.6, 49.6 and 7.8%. A relation between the presence of the Arg allele and lung cancer risk was observed. Our study reveals that Arg allele, active smoking and HPV infection are the important risk factors in lung cancer development in the north part of Iran, Mazandaran province.     

Relationship between lung cancer and human papillomavirus in north of Iran, Mazandaran province

Lung cancer is a major health problem and the leading cause of cancer deaths in the world. The pathogenesis of lung cancer is complex, and is believed to be due to the interaction between environmental and genetic factors. Various evidences show that HPV might be involved in bronchial carcinogenesis. In this study, 141 lung cancer patients and 92 non-cancer control subjects were enrolled to examine whether HPV DNA existed in lung tumor and normal tissues in Mazandaran, north part of Iran by nested PCR. Our data showed that 33 of 129 lung tumors had HPV DNA compared with 8 of 90 non-cancer control subjects (25.6% vs. 9.0%, P=0.002). The infection of HPV had an OR of 3.48 (95% CI 1.522-7.958; P=0.002). Meanwhile infection of high risk HPV types (16 and 18) had a significantly high OR of lung cancer incidence as 8.00 (95% CI 1.425-44.920; P=0.021) compared with 4.423 (95% CI 2.407-8.126; P0.0001) of smoking status. This result suggests that HPV infection is associated with lung cancer development in Mazandaran, Iran.     

Suppressive effect of sustained low-contrast adaptation followed by transient high-contrast on peripheral target detection

We observed that presenting a low-contrast Gabor patch (2 cpd, 5 degrees eccentricity, contrast=4%) for 8 s and then flashing a 20-30 ms high-contrast patch over it could elicit the perceptual disappearance of a subsequent low-contrast stimulus, whereas neither low-contrast adaptation nor high-contrast flash alone had any considerable effect (p<0.00001). In other experiments we found (a) suppressive components are phase-insensitive, (b) the effect transfers between eyes, (c) suppression is selective for orientation, and (d) the induction by the transient high-contrast Gabor patch could be transferred to another previously adapted location up to a few degrees. Results indicate synergy between contrast and adaptation through a non-linear interaction between rapid gain adjustment to transient change and adaptation to sustained spatial patterns. Findings are compatible with non-local mechanisms presumably at the cortical level.     

Cutaneous delivery of a live, attenuated chimeric flavivirus vaccine against Japanese encephalitis (ChimeriVax)-JE) in non-human primates

Flaviviral diseases such as yellow fever, Japanese encephalitis (JE) and dengue hemorrhagic fever cause enormous morbidity and mortality worldwide. There is an urgent need for alternative technologies for mass vaccination against these and other diseases, particularly in the developing world. Here, we administered a live attenuated, chimeric JE vaccine (ChimeriVax)-JE) to nonhuman primates by skin microabrasion and intradermal delivery using microneedles. Both cutaneous delivery methods induced mild viremia similar in magnitude to that observed following subcutaneous (SC) injection. The duration of viremia induced by cutaneous delivery (5-7 days), however, was substantially longer than via SC (0-3 days). In addition, mean neutralizing antibody titers in cutaneous delivery groups were up to 7-fold greater than via SC injection. There were no safety issues identified and both cutaneous delivery methods appeared to be well tolerated. Thus, cutaneous delivery may represent a minimally-invasive alternative approach for flavivirus vaccines that more closely resembles the natural route of viral infection.