STAT5 activation promotes progression and chemotherapy-resistance in early T-cell precursor acute lymphoblastic leukemia

IL-7 supports the growth and chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL), particularly the early T-cell precursor subtype (ETP-ALL), which frequently has activating mutations of IL-7 signaling. STAT5 is an attractive therapeutic target because it is almost universally activated in ETP-ALL, even in the absence of mutations of upstream activators such as the IL-7R, JAK and FLT3. To examine the role of activated STAT5 in ETP-ALL, we have used a Lmo2-transgenic (Lmo2Tg) mouse model in which we can monitor chemoresistant pre-leukemia (pre-LSCs) and leukemia stem cells (LSCs) that drive T-ALL development and relapse following chemotherapy. Using IL-7R-deficient Lmo2Tg mice, we show that IL-7 signaling was not required for the formation of pre-LSCs but essential for their expansion and clonal evolution into LSCs to generate T-ALL. Activated STAT5B was sufficient for the development of T-ALL in IL-7R; Lmo2Tg mice, indicating that inhibition of STAT5 is required to block the supportive signals provided by IL-7. To further understand the role of activated STAT5 in LSCs of ETP-ALL, we developed a new transgenic mouse that enables T-cell specific and doxycycline-inducible expression of the constitutively activated STAT5B1∗6 mutant. Expression of STAT5B1∗6 in T-cells had no effect alone but promoted expansion and chemoresistance of LSCs in Lmo2Tg mice. Pharmacologic inhibition of STAT5 with Pimozide induced differentiation and loss of LSCs, whilst enhancing response to chemotherapy. Furthermore, Pimozide significantly reduced leukemia burden in vivo and overcame chemoresistance of patient-derived ETP-ALL xenografts. Overall, our results demonstrate that STAT5 is an attractive therapeutic target for eradicating LSCs in ETP-ALL

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Mujeres Fuertes y Corazones Saludables: Adaptation of the StrongWomen—Healthy Hearts (SWHH) Program for Rural Latinas Using an Intervention Mapping Approach

Objectives: To adapt Strong Women, Healthy Hearts (SWHH), an evidence-based physical activity and nutrition program to reflect the needs of rural Latinas. Methods: Using a community-based participatory approach and an intervention mapping process, we partnered with a community advisory board of rural Latinas to identify and adapt a nutrition and physical activity program. A needs assessment and a logic model determined which program best aligned with community objectives and most fit for adaptation. SWHH was adapted; using feedback from the community advisory board to reflect the community’s culture, resources, and needs. We collaborated with one of developers of SWHH in the adaptation process to ensure evidence-based elements were retained. Intervention strategies, program curriculum, materials, and structure were adapted. An example adaptation was changing recipes to include similar nutritional content that align with the culture and local resources. Another example was training community members to lead the class instead of extension agents which were leaders in SWHH. Results/Findings: Through this adaptation process the adapted program, Mujeres Fuertes, Corazones Saludables was formed. We have translated all participant materials into Spanish and have revised the curriculum to reflect changes made. A pilot study is being conducted with overweight, sedentary, middle-aged, Spanish-speaking, rural Latinas to assess feasibility and effectiveness of adapted program. We are measuring weight, cardiorespiratory fitness, physical activity and nutrition behavior before and after the 12-week program. The data has been collected at the two time points and evaluation is underway. Conclusions: The intervention mapping process was appropriate and collaboration with the community advisory board ensured culturally appropriate and relevant adaptations to the local community context

Exploration of the Experience of Care Home Managers of COVID-19 Vaccination Programme Implementation and Uptake by Residents and Staff in Care Homes in Northern Ireland

The Coronavirus 2019 (COVID-19) pandemic disproportionately affected people living and working in care homes. This study aimed to explore the experience of care home managers on the implementation and uptake of the COVID-19 vaccination programme by residents and staff in care homes in Northern Ireland. An exploratory mixed methods approach was used, i.e., semi-structured interviews to design the cross-sectional survey and content analysis of statements using open ended questions. Care home managers were approached and sixty-seven valid quantitative and forty-nine descriptive responses were analysed. The study identified eight themes which described factors that motivated residents (family visits and relationship with managers and staff), and staff vaccine uptake (return to normal life at work and trust in care home managers). The identified themes also confirmed that vaccine uptake is negatively influenced by perceived side effects. The findings indicated that social media can promote or decelerate the uptake of vaccine despite the accessibility to a successful vaccination programme. The study highlights the important role of managers in handling the challenges through building trust and establishing relationships with staff and residents. The findings identified challenges to the uptake of the COVID-19 vaccine by staff and residents that can inform the implementation of future vaccination programmes