Developmental and behavioral effects in neonatal and adult mice following prenatal activation of endocannabinoid receptors by capsaicin.

Despite the apparent abundance of ligand-gated transient receptor potential vanilloid type 1 (TRPV1) and possible cross talk between the endocannabinoid and endovanilloid systems in the central nervous system (CNS), it is unclear what role TRPV1 receptor activation in CNS plays in neurobehavioral development. We previously reported that capsaicin or WIN55212-2 induces risk aversion in the plus-maze test, which was dependent on the gender and mouse strain used. In this study, pregnant BALBc mice were administered capsaicin (1.0 or 4.0 mg/kg, i.p.) during the second week of gestation. Developmental effects of prenatal exposure to capsaicin were assessed in neonates, and behavioral effects were assessed in adult offspring. Gender- and dose-specific variations in ultrasonic vocalizations, weight gain, righting reflex, and general activity of the pups were observed. Prenatal exposure to capsaicin altered plus-maze performance, especially with further exogenous capsaicin challenge. Furthermore, dose- and gender-specific effects were evident in the conditioned place preference/aversion paradigm following conditioning with capsaicin in adult animals. The capsaicin-induced aversion in the plus-maze test was enhanced by WIN55212-2 and blocked by pretreatment with vanilloid antagonist capsazepine or the CB1 receptor antagonist rimonabant, demonstrating an interaction between the endocannabinoid and endovanilloid systems in CNS. Taken together, the interaction between the endocannabinoid and endovanilloid signaling systems can be exploited for therapeutic applications in health and disease.

The physical and mental health problems of refugee and migrant fathers: findings from an Australian population-based study of children and their families.

OBJECTIVES: The aim of this study was to report on the physical and mental health of migrant and refugee fathers participating in a population-based study of Australian children and their families. DESIGN: Cross-sectional survey data drawn from a population-based longitudinal study when children were aged 4-5 years. SETTING: Population-based study of Australian children and their families. PARTICIPANTS: 8137 fathers participated in the study when their children were aged 4-5 years. There were 131 (1.6%) fathers of likely refugee background, 872 (10.7%) fathers who migrated from English-speaking countries, 1005 (12.4%) fathers who migrated from non-English-speaking countries and 6129 (75.3%) Australian-born fathers. PRIMARY OUTCOME MEASURES: Fathers' psychological distress was assessed using the self-report Kessler-6. Information pertaining to physical health conditions, global or overall health, alcohol and tobacco use, and body mass index status was obtained. RESULTS: Compared with Australian-born fathers, fathers of likely refugee background (adjusted OR(aOR) 3.17, 95% CI 2.13 to 4.74) and fathers from non-English-speaking countries (aOR 1.79, 95%CI 1.51 to 2.13) had higher odds of psychological distress. Refugee fathers were more likely to report fair to poor overall health (aOR 1.95, 95% CI 1.06 to 3.60) and being underweight (aOR 3.49, 95% CI 1.57 to 7.74) compared with Australian-born fathers. Refugee fathers and those from non-English-speaking countries were less likely to report light (aOR 0.25, 95% CI 0.15 to 0.43, and aOR 0.30, 95% CI 0.24 to 0.37, respectively) and moderate to harmful alcohol use (aOR 0.04, 95% CI 0.10 to 0.17, and aOR 0.14, 95% CI 0.10 to 0.19, respectively) than Australian-born fathers. Finally, fathers from non-English-speaking and English-speaking countries were less likely to be overweight (aOR 0.62, 95% CI 0.51 to 0.75, and aOR 0.84, 95% CI 0.68 to 1.03, respectively) and obese (aOR 0.43, 95% CI 0.32 to 0.58, and aOR 0.77, 95% CI 0.61 to 0.98, respectively) than Australian-born fathers. CONCLUSION: Fathers of refugee background experience poorer mental health and poorer general health than Australian-born fathers. Fathers who have migrated from non-English-speaking countries also report greater psychological distress than Australian-born fathers. This underscores the need for primary healthcare services to tailor efforts to reduce disparities in health outcomes for refugee populations that may be vulnerable due to circumstances and sequelae of forced migration and to recognise the additional psychological stresses that may accompany fatherhood following migration from non-English-speaking countries. It is important to note that refugee and migrant fathers report less alcohol use and are less likely to be overweight and obese than Australian-born fathers.

Prostate-specific membrane antigen-based therapeutics.

Prostate cancer (PC) is the most common noncutaneous malignancy affecting men in the US, leading to significant morbidity and mortality. While significant therapeutic advances have been made, available systemic therapeutic options are lacking. Prostate-specific membrane antigen (PSMA) is a highly-restricted prostate cell-surface antigen that may be targeted. While initial anti-PSMA monoclonal antibodies were suboptimal, the development of monoclonal antibodies such as J591 which are highly specific for the external domain of PSMA has allowed targeting of viable, intact prostate cancer cells. Radiolabeled J591 has demonstrated accurate and selective tumor targeting, safety, and efficacy. Ongoing studies using anti-PSMA radioimmunotherapy with (177)Lu-J591 seek to improve the therapeutic profile, select optimal candidates with biomarkers, combine with chemotherapy, and prevent or delay the onset of metastatic disease for men with biochemical relapse. Anti-PSMA monoclonal antibody-drug conjugates have also been developed with completed and ongoing early-phase clinical trials. As PSMA is a selective antigen that is highly overexpressed in prostate cancer, anti-PSMA-based immunotherapy has also been studied and utilized in clinical trials.

Activities of SYK and PLCgamma2 predict apoptotic response of CLL cells to SRC tyrosine kinase inhibitor dasatinib.

PURPOSE: B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL. EXPERIMENTAL DESIGN: Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors. RESULTS: Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cgamma2, correlate well with the apoptotic response of CLL cells to dasatinib. CONCLUSIONS: Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cgamma2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathogenic perspective, our study suggests the existence of alternative mechanisms or pathways that activate SYK, independent of SRC kinase activities. The study further implicates that SYK might serve as a more effective therapeutic target in CLL treatment.