WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) infection is associated with adult T-cell leukemia/lymphoma (ATLL), a lymphoproliferative malignancy with a dismal prognosis and limited therapeutic options. Recent evidence shows that HTLV-1-transformed cells present defects in both DNA replication and DNA repair, suggesting that these cells might be particularly sensitive to treatment with a small helicase inhibitor. Because the "Werner syndrome ATP-dependent helicase" encoded by the WRN gene plays important roles in both cellular proliferation and DNA repair, we hypothesized that inhibition of WRN activity could be used as a new strategy to target ATLL cells. METHODS: Our analysis demonstrates an apoptotic effect induced by the WRN helicase inhibitor in HTLV-1-transformed cells in vitro and ATL-derived cell lines. Inhibition of cellular proliferation and induction of apoptosis were demonstrated with cell cycle analysis, XTT proliferation assay, clonogenic assay, annexin V staining, and measurement of mitochondrial transmembrane potential. RESULTS: Targeted inhibition of the WRN helicase induced cell cycle arrest and apoptosis in HTLV-1-transformed leukemia cells. Treatment with NSC 19630 (WRN inhibitor) induces S-phase cell cycle arrest, disruption of the mitochondrial membrane potential, and decreased expression of anti-apoptotic factor Bcl-2. These events were associated with activation of caspase-3-dependent apoptosis in ATL cells. We identified some ATL cells, ATL-55T and LMY1, less sensitive to NSC 19630 but sensitive to another WRN inhibitor, NSC 617145. CONCLUSIONS: WRN is essential for survival of ATL cells. Our studies suggest that targeting the WRN helicase with small inhibitors is a novel promising strategy to target HTLV-1-transformed ATL cells.

Medication education program for Indian children with asthma: A feasibility stud.

OBJECTIVE: It is postulated that children with asthma who receive an interactive, comprehensive, culturally relevant education program would improve their asthma knowledge (AK), asthma control, and adherence compared with children receiving usual care. The aim of this study was to develop, implement, and evaluate the efficacy of a culturally relevant asthma education intervention for children with asthma and their parents in India. METHODS: Children with asthma (7-12 years) and their parents were recruited from an outpatient clinic in a Chest Diseases Hospital in New Delhi, and were randomly assigned to either an intervention or usual care group. At baseline, outcome data collected included pediatric asthma caregiver quality of life (PACQL, primary outcome), AK, asthma control, adherence, inhaler technique, action plan ownership, and goal achievement. These data were collected again at 1 and 6 months after baseline. Outcomes were compared within and between groups using ANOVA techniques. RESULTS: Forty parent-child pairs were recruited. Of these, 24 pairs of children with asthma and their parents received the educational intervention. The PACQL significantly improved from baseline to 6 months in the intervention (5.87 ± 0.94-7.00 ± 0.03) versus the usual care group (5.90 ± 0.52-6.34 ± 0.56) (P < 0.001). Other outcomes such as the parents' and child's AK, child's asthma control and inhaler technique were significantly improved in the intervention group across the study. All the participants possessed a written asthma action plan at the end of the intervention. Eighty-five goals were set by children with asthma across all the visits and were achieved by completion. CONCLUSION: An asthma educator delivered interactive program simultaneously involving children with asthma and their parents, improved quality of life, empowered and promoted better self-management skills.

Impact of flow path length and flow rate on phosphorus loss in simulated overland flow from a humic gleysol grassland soil.

In this overland flow simulation experiment, the relationships between flow path length, flow rate and the concentration of different P fractions were investigated. Overland flow was simulated using a 3 mx0.12 m laboratory flume. To remove the impact of rainfall on P lost in overland flow, simulated rainfall was not used during these experiments. Instead overland flow was generated by pumping water into the flume at the surface of the grass sod. The experimental setup allowed for the variation in flow path length and flow rate between and during experimental runs. The results demonstrated that an increase in flow path length caused an increase in Total Dissolved P (TDP), Dissolved Reactive P (DRP) and Total Reactive P (TRP) concentration in overland flow (p<0.01) while an increase in flow rate resulted in a decrease in the concentration of these P fractions in overland flow due to dilution (p<0.01). Total P (TP), Particulate P (PP) and Dissolved Organic P were not affected by the variables tested during this study. When flow path length was increased in conjunction with flow rate, there was an increase in TDP, DRP, and TRP concentrations despite the impact of greater dilution. The results indicate that variations in flow path length during a rainfall event may play a role in determining the concentration of dissolved P fractions in overland flow at field scale.

Mandibular skeletal and dental asymmetry in Class II subdivision malocclusions.

Mandibular symmetry was compared between a group of 28 subjects exhibiting Class II subdivision malocclusions and 30 subjects with Class I malocclusions who served as the control group. With submentovertex radiographs, symmetry was assessed by measuring the relative difference in spatial position of mandibular landmarks in both anteroposterior and transverse dimensions as determined by coordinate systems representing the cranial floor, mandible, and mandibular dentition. Only those variables representing the anteroposterior difference between right and left mandibular molar positions showed a statistically significant difference between the groups. Whether the position of the mandibular molars was measured relative to the cranial floor or within the mandible itself, the mandibular first molar was located more posteriorly on the Class II side of the subdivision malocclusion within a mandible that exhibited no other unusual asymmetry.