Interplay of Polarity Proteins and GTPases in T-Lymphocyte Function

Polarity refers to the asymmetric distribution of different cellular components within a cell and is central to many cell functions. In T-cells, polarity regulates the activation, migration, and effector function of cytotoxic T-cells (CTLs) during an immune response. The regulation of asymmetric cell division by polarity proteins may also dictate CTL effector and memory differentiation following antigen presentation. Small GTPases, along with their associated polarity and adaptor proteins, are critical for mediating the polarity changes necessary for T-cell activation and function, and in turn, are regulated by guanine exchange factors (GEFS) and GTPase activating proteins (GAPS). For example, a novel GEF, dedicator of cytokinesis 8 (DOCK8) was recently identified as a regulator of immune cell function and mutations in DOCK8 have been detected in patients with severe combined immunodeficiency. Both B and T-cells from DOCK8 mutant mice form defective immunological synapses and have abnormal functions, in addition to impaired immune memory development. This paper will discuss the interplay between polarity proteins and GTPases, and their role in T-cell function

Interplay of Polarity Proteins and GTPases in T-Lymphocyte Function

Polarity refers to the asymmetric distribution of different cellular components within a cell and is central to many cell functions. In T-cells, polarity regulates the activation, migration, and effector function of cytotoxic T-cells (CTLs) during an immune response. The regulation of asymmetric cell division by polarity proteins may also dictate CTL effector and memory differentiation following antigen presentation. Small GTPases, along with their associated polarity and adaptor proteins, are critical for mediating the polarity changes necessary for T-cell activation and function, and in turn, are regulated by guanine exchange factors (GEFS) and GTPase activating proteins (GAPS). For example, a novel GEF, dedicator of cytokinesis 8 (DOCK8) was recently identified as a regulator of immune cell function and mutations in DOCK8 have been detected in patients with severe combined immunodeficiency. Both B and T-cells from DOCK8 mutant mice form defective immunological synapses and have abnormal functions, in addition to impaired immune memory development. This paper will discuss the interplay between polarity proteins and GTPases, and their role in T-cell function

Healthcare Barriers of Residents at a Subsidized Housing Community

Introduction: Despite expanded healthcare programs, the low income and elderly lack coverage of vision, hearing, and dental services. Community services are often asked to fill these gaps. To evaluate the situation in Burlington, VT, we surveyed staff and residents in Burlington Housing Authority (BHA) subsidized housing to (1) identify gaps in healthcare coverage and (2) assess barriers to accessing those services in this population.https://scholarworks.uvm.edu/comphp_gallery/1207/thumbnail.jp

Feasibility trial evaluation of a physical activity and screen-viewing course for parents of 6 to 8 year-old children : Teamplay

Background: Many children spend too much time screen-viewing (watching TV, surfing the internet and playing video games) and do not meet physical activity (PA) guidelines. Parents are important influences on children’s PA and screen-viewing (SV). There is a shortage of parent-focused interventions to change children’s PA and SV. Methods: Teamplay was a two arm individualized randomized controlled feasibility trial. Participants were parents of 6–8 year old children. Intervention participants were invited to attend an eight week parenting program with each session lasting 2 hours. Children and parents wore an accelerometer for seven days and minutes of moderate-to-vigorous intensity PA (MVPA) were derived. Parents were also asked to report the average number of hours per day that both they and the target child spent watching TV. Measures were assessed at baseline (time 0) at the end of the intervention (week 8) and 2 months after the intervention had ended (week 16). Results: There were 75 participants who provided consent and were randomized but 27 participants withdrew post-randomization. Children in the intervention group engaged in 2.6 fewer minutes of weekday MVPA at Time 1 but engaged in 11 more minutes of weekend MVPA. At Time 1 the intervention parents engaged in 9 more minutes of weekday MVPA and 13 more minutes of weekend MVPA. The proportion of children in the intervention group watching ≥ 2 hours per day of TV on weekend days decreased after the intervention (time 0 = 76%, time 1 = 39%, time 2 = 50%), while the control group proportion increased slightly (79%, 86% and 87%). Parental weekday TV watching decreased in both groups. In post-study interviews many mothers reported problems associated with wearing the accelerometers. In terms of a future full-scale trial, a sample of between 80 and 340 families would be needed to detect a mean difference of 10-minutes of weekend MVPA. Conclusions: Teamplay is a promising parenting program in an under-researched area. The intervention was acceptable to parents, and all elements of the study protocol were successfully completed. Simple changes to the trial protocol could result in more complete data collection and study engagement

Vemurafenib-resistant BRAF-V600E-mutated melanoma is regressed by MEK-targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model.

Melanoma is a recalcitrant disease. The present study used a patient-derived orthotopic xenograft (PDOX) model of melanoma to test sensitivity to three molecularly-targeted drugs and one standard chemotherapeutic. A BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 50 PDOX nude mice were divided into 5 groups: G1, control without treatment; G2, vemurafenib (VEM) (30 mg/kg); G3; temozolomide (TEM) (25 mg/kg); G4, trametinib (TRA) (0.3 mg/kg); and G5, cobimetinib (COB) (5 mg/kg). Each drug was administered orally, daily for 14 consecutive days. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, TRA, an MEK inhibitor, was the only agent of the 4 tested that caused tumor regression (P < 0.001 at day 14). In contrast, another MEK inhibitor, COB, could slow but not arrest growth or cause regression of the melanoma. First-line therapy TEM could slow but not arrest tumor growth or cause regression. The patient in this study had a BRAF-V600E-mutant melanoma and would be considered to be a strong candidate for VEM as first-line therapy, since VEM targets this mutation. However, VEM was not effective. The PDOX model thus helped identify the very-high efficacy of TRA against the melanoma PDOX and is a promising drug for this patient. These results demonstrate the powerful precision of the PDOX model for cancer therapy, not achievable by genomic analysis alone

Process evaluation of the Teamplay parenting intervention pilot : implications for recruitment, retention and course refinement

Background Parenting programs could provide effective routes to increasing children’s physical activity and reducing screen-viewing. Many studies have reported difficulties in recruiting and retaining families in group parenting interventions. This paper uses qualitative data from the Teamplay feasibility trial to examine parents’ views on recruitment, attendance and course refinement. Methods Semi-structured interviews were conducted with 16 intervention and 10 control group parents of 6–8 year old children. Topics discussed with the intervention group included parents’ views on the recruitment, structure, content and delivery of the course. Topics discussed with the control group included recruitment and randomization. Interviews were digitally recorded, transcribed and thematically analyzed. Results Many parents in both the intervention and control group reported that they joined the study because they had been thinking about ways to improve their parenting skills, getting ideas on how to change behavior, or had been actively looking for a parenting course but with little success in enrolling on one. Both intervention and control group parents reported that the initial promotional materials and indicative course topics resonated with their experiences and represented a possible solution to parenting challenges. Participants reported that the course leaders played an important role in helping them to feel comfortable during the first session, engaging anxious parents and putting parents at ease. The most commonly reported reason for parents returning to the course after an absence was because they wanted to learn new information. The majority of parents reported that they formed good relationships with the other parents in the group. An empathetic interaction style in which leaders accommodated parent’s busy lives appeared to impact positively on course attendance. Conclusions The data presented indicate that a face-to-face recruitment campaign which built trust and emphasized how the program was relevant to families positively affected recruitment in Teamplay. Parents found the parenting component of the intervention attractive and, once recruited, attendance was facilitated by enjoyable sessions, empathetic leaders and support from fellow participants. Overall, data suggest that the Teamplay recruitment and retention approaches were successful and with small refinements could be effectively used in a larger trial

Parental modelling, media equipment and screen-viewing among young children : cross-sectional study

Objective: To examine whether parental screenviewing, parental attitudes or access to media equipment were associated with the screen-viewing of 6-year-old to 8-year-old children. Design: Cross-sectional survey. Setting: Online survey. Main outcome: Parental report of the number of hours per weekday that they and, separately, their 6- year-old to 8-year-old child spent watching TV, using a games console, a smart-phone and multiscreen viewing. Parental screen-viewing, parental attitudes and pieces of media equipment were exposures. Results: Over 75% of the parents and 62% of the children spent more than 2 h/weekday watching TV. Over two-thirds of the parents and almost 40% of the children spent more than an hour per day multiscreen viewing. The mean number of pieces of media equipment in the home was 5.9 items, with 1.3 items in the child’s bedroom. Children who had parents who spent more than 2 h/day watching TV were over 7.8 times more likely to exceed the 2 h threshold. Girls and boys who had a parent who spent an hour or more multiscreen viewing were 34 times more likely to also spend more than an hour per day multiscreen viewing. Media equipment in the child’s bedroom was associated with higher TV viewing, computer time and multiscreen viewing. Each increment in the parental agreement that watching TV was relaxing for their child was associated with a 49% increase in the likelihood that the child spent more than 2 h/day watching TV. Conclusions: Children who have parents who engage in high levels of screen-viewing are more likely to engage in high levels of screen-viewing. Access to media equipment, particularly in the child’s bedroom, was associated with higher levels of screen-viewing. Family-based strategies to reduce screen-viewing and limit media equipment access may be important ways to reduce child screen-viewing

Interplay of Polarity Proteins and GTPases in T-Lymphocyte Function

Polarity refers to the asymmetric distribution of different cellular components within a cell and is central to many cell functions. In T-cells, polarity regulates the activation, migration, and effector function of cytotoxic T-cells (CTLs) during an immune response. The regulation of asymmetric cell division by polarity proteins may also dictate CTL effector and memory differentiation following antigen presentation. Small GTPases, along with their associated polarity and adaptor proteins, are critical for mediating the polarity changes necessary for T-cell activation and function, and in turn, are regulated by guanine exchange factors (GEFS) and GTPase activating proteins (GAPS). For example, a novel GEF, dedicator of cytokinesis 8 (DOCK8) was recently identified as a regulator of immune cell function and mutations in DOCK8 have been detected in patients with severe combined immunodeficiency. Both B and T-cells from DOCK8 mutant mice form defective immunological synapses and have abnormal functions, in addition to impaired immune memory development. This paper will discuss the interplay between polarity proteins and GTPases, and their role in T-cell function

Reducing Disparities in Tobacco Retailer Density by Banning Tobacco Product Sales Near Schools

This study examined whether a policy of banning tobacco product retailers from operating within 1000 feet of schools could reduce existing socioeconomic and racial/ethnic disparities in tobacco retailer density

Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600E mutation in a patient-derived orthotopic xenograft (PDOX) model.

Melanoma is a recalcitrant disease in need of transformative therapuetics. The present study used a patient-derived orthotopic xenograft (PDOX) nude-mouse model of melanoma with a BRAF-V600E mutation to determine the efficacy of temozolomide (TEM) combined with tumor-targeting Salmonella typhimurium A1-R. A melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 40 PDOX nude mice were divided into 4 groups: G1, control without treatment (n = 10); G2, TEM (25 mg/kg, administrated orally daily for 14 consecutive days, n = 10); G3, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, n = 10); G4, TEM combined with S. typhimurium A1-R (25 mg/kg, administrated orally daily for 14 consecutive days and 5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, respectively, n = 10). Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, all treatments significantly inhibited tumor growth compared to untreated control (TEM: p < 0.0001; S. typhimurium A1-R: p < 0.0001; TEM combined with S. typhimurium A1-R: p < 0.0001). TEM combined with S. typhimurium A1-R was significantly more effective than either S. typhimurium A1-R (p = 0.0004) alone or TEM alone (p = 0.0017). TEM combined with S. typhimurium A1-R could regress the melanoma in the PDOX model and has important future clinical potential for melanoma patients