Nimbolide Inhibits SOD2 to Control Pancreatic Ductal Adenocarcinoma Growth and Metastasis.

Reactive oxygen species are frequently associated with various cancers including pancreatic ductal adenocarcinomas (PDACs). Superoxide dismutase 2 (SOD2) is an enzyme that plays an important role in reactive oxygen species (ROS) signaling. Investigating the molecular function and biological functions of SOD2 can help us develop new therapeutic options and uncover new biomarkers for PDAC diagnosis and prognosis. Here, we show that nimbolide (NB), a triterpene limonoid, effectively blocks the growth and metastasis of PDACs by suppressing the expression and activity of SOD2. To identify the role of SOD2 in NB-induced anticancer activity, we used RNA interference to silence and plasmid transfection to overexpress it. Silencing SOD2 significantly reduced the growth and metastatic characteristics like epithelial-to-mesenchymal transition, invasion, migration, and colony-forming capabilities of PDACs, and NB treatment further reduced these characteristics. Conversely, the overexpression of SOD2 enhanced these metastatic characteristics. ROS signaling has a strong feedback mechanism with the PI3K/Akt signaling pathway, which could be mediated through SOD2. Finally, NB treatment to SOD2-overexpressing PDAC xenografts resulted in significant inhibition of tumor growth and metastasis. Overall, this work suggests that NB, a natural and safe phytochemical that silences SOD2 to induce high levels of ROS generation, results in increased apoptosis and reduced growth and progression of PDACs. The role of SOD2 in regulating NB-induced ROS generation presents itself as a therapeutic option for PDACs.

Augmented Parkin-dependent mitophagy underlies the hepatoprotective effect of remote ischemic conditioning used prior to hemorrhagic shock.

BACKGROUND AND AIMS: Hemorrhagic shock-resuscitation (HSR) following trauma contributes to organ dysfunction by causing ischemia-reperfusion injury (IRI). We previously showed that 'remote ischemic preconditioning' (RIPC) exerted multi-organ protection from IRI. Maintenance of mitochondrial quality by clearance of dysfunctional mitochondria via mitophagy is vital in restoring organ integrity. We hypothesized that parkin-dependent mitophagy played a role in RIPC-induced hepatoprotection following HSR. METHODS: The hepatoprotective effect of RIPC in a murine model of HSR-IRI was investigated in wild type and parkin-/- animals. Mice were subjected to HSR ± RIPC and blood and organs were collected, followed by cytokine ELISAs, histology, qPCR, Western blots, and transmission electron microscopy. RESULTS: HSR increased hepatocellular injury, as measured by plasma ALT and liver necrosis, while antecedent RIPC prevented this injury; in parkin-/- mice, RIPC failed to exert hepatoprotection. The ability of RIPC to lessen HSR-induced rises in plasma IL-6 and TNFα, was lost in parkin-/- mice. While RIPC alone did not induce mitophagy, the application of RIPC prior to HSR caused a synergistic increase in mitophagy, this increase was not observed in parkin-/- mice. RIPC induced shifts in mitochondrial morphology favoring mitophagy in WT but not in parkin-/- animals. CONCLUSIONS: RIPC was hepatoprotective in WT mice following HSR but not in parkin-/- mice. Loss of protection in parkin-/- mice corresponded with the failure of RIPC plus HSR to upregulate the mitophagic process. Improving mitochondrial quality by modulating mitophagy, may prove to be an attractive therapeutic target in disease processes caused by IRI.

Caring for children with mental health or developmental and behavioural disorders: Perspectives of family health teams on roles and barriers to care.

OBJECTIVE: To inform a shared care model between developmental and behavioural (DB) and mental health specialists and primary care physicians by having members of primary care family health teams (FHTs) report on strengths of and barriers to providing care for children with DB disorders and mental health concerns. DESIGN: Qualitative study using semistructured focus groups. SETTING: Academic and community-based FHTs in Toronto, Ont. PARTICIPANTS: Primary care physicians, nurses, allied health professionals, and family medicine trainees within the participating FHTs. METHODS: Nine focus groups were conducted with FHT members, and transcripts were analyzed for key themes using an inductive thematic analysis approach. MAIN FINDINGS: Eighty-four participants across 9 sites were interviewed. Six sites were academically affiliated and 3 were community based. Participants described their roles in the care of children with DB disorders as primarily "referral agent" but also as "long-term supporter" and "health care coordinator." Family health team members expressed the desire to "learn" and "do more" for these children but noted numerous barriers to providing care, captured in 4 overarching themes: limited training beyond how to screen, lack of service knowledge, limited time and communication, and cumbersome access to mental health and dual diagnosis services. CONCLUSION: Primary care physicians are in the unique position of being able to provide longitudinal care for children with DB and mental health disorders. However, they perceive barriers to providing care that can affect access to services, service quality, and health outcomes for these children and their families. The health system might benefit from addressing these barriers by providing more training for primary care physicians in the longitudinal care of children with mental health and DB disorders, and by improving communication between FHTs and DB and mental health specialists regarding service navigation and emerging comorbidities. A shared care model integrating DB and mental health specialists into primary care might be one approach that warrants implementation and research.

Transient Motor Asymmetry Among Infants With Congenital Torticollis-Description, Characterization, and Results of Follow-Up.

AIM: The purpose of this study was to assess the prevalence of transient functional motor asymmetry in infants with congenital postural torticollis. METHODS: This was a retrospective review of the medical records of infants with postural torticollis. We analyzed epidemiological, obstetric, perinatal data, physical therapy, physician assessments, and clinical follow-up for two years after diagnosis. RESULTS: Of 173 children, 44 (25.4%, 95% confidence interval = 19.5 to 32.4) demonstrated functional asymmetry. Demographic and obstetrical data did not differ between the asymmetry/nonasymmetry groups. Delayed motor development (P = 0.01) and plagiocephaly (P = 0.032) were more common in infants with motor asymmetry. No difference was observed in the frequency of referral for further neurological diagnosis between the group with functional asymmetry and that without asymmetry. Among the 44 patients with functional asymmetry, 78% depicted no evidence of torticollis by age two years, and the motor asymmetry had disappeared in 82%. CONCLUSION: Benign, transient functional motor asymmetry occurred in a quarter of infants with congenital postural torticollis. Transient motor delay was also significantly more common in the asymmetry group. In most instances, motor asymmetry and motor delay disappeared by age two years. Plagiocephaly was more common in the asymmetry group. Clinician awareness of this transient asymmetry may have avoided unnecessary diagnostic tests in these infants.

Contribution of the addition of anti-ß2-glycoprotein to the classification of antiphospholipid syndrome in predicting adverse pregnancy outcome.

OBJECTIVES: Anti-ß2 glycoprotein 1 (a-ß2GP1) was added to the criteria for antiphospholipid syndrome (APS) in 2005. However, its clinical significance with respect to complications of pregnancy is not well established. The aim of this study was to evaluate the association of laboratory findings of a-ß2GP1 with events of thromboembolism or obstetric complications (pregnancy loss, placental dysfunction, intrauterine growth restriction, preeclampsia, fetal death, and preterm delivery) in women with clinical and laboratory evidence of APS. METHODS: A retrospective cohort design was used. Ninety-one patients (total 394 pregnancies) referred to a tertiary medical center for evaluation of clinical features consistent with APS were divided into three groups: group A (n = 34), two positive tests for anticardiolipin (ACL) or lupus anticoagulant (LAC), in accordance with original APS classification (1998); group B (n = 18), two positive tests for a-ß2GP1, in accordance with the revised APS criteria; and group C (n = 39), only one positive test for ACL or LAC. RESULTS: Of the 52 women with APS (group A or B), 36 had primary disease, and 16 had secondary disease. On comparison of the groups, group B was characterized by a significantly higher rate of complicated pregnancy (83.3%) than groups A (47.1%) and C (76.9%), P = 0.007, and a higher rate of fetal loss (72.2%) than groups A + C (28.8%, P = 0.001). CONCLUSIONS: The findings suggest that the revised APS criteria are preferable to the original classification for the prediction of complicated pregnancy.