Low income, multi-ethnic communities in Main South/Piedmont neighborhoods of Worcester, Massachusetts are exposed to cumulative, chronic built-environment stressors, and have limited capacity to respond, magnifying their vulnerability to adverse health outcomes. “Neighborhood STRENGTH”, our community based participatory research (CBPR) project, comprised four partners: a youth center; an environmental non-profit; a community based health center; and a university. Unlike most CBPR projects that are single topic-focused, our ‘holistic’, systems-based project targeted five priorities. The three research-focused/action-oriented components were: 1) participatory monitoring of indoor and outdoor pollution; 2) learning about health needs and concerns of residents through community based listening sessions; and 3) engaging in collaborative survey work, including a household vulnerability survey and an asthma prevalence survey for schoolchildren. The two action-focused/research-informed components were: 4) tackling persistent street trash and illegal dumping strategically; and 5) educating and empowering youth to promote environmental justice. We used a coupled CBPR-capacity building approach to design, vulnerability theory to frame, and mixed methods: quantitative environmental testing and qualitative surveys. Process and outcomes yielded important lessons: vulnerability theory helps frame issues holistically; having several topic-based projects yielded useful information, but was hard to manage and articulate to the public; access to, and engagement with, the target population was very difficult and would have benefited greatly from having representative residents who were paid at the partners' table. Engagement with residents and conflict burden varied highly across components. Notwithstanding, we built enabling capacity, strengthened our understanding of vulnerability, and are able to share valuable experiential knowledge.

Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT)responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL + T cells into mouse models of allo-HSCT. We found that murine TRAIL + T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL + T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL + T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL + precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.

Highlights d Bistability and hysteresis are dynamically controlled by BCR clustering d Mathematical modeling predicts enhanced BCR clustering in CLL d Super-resolution microscopy confirms CLL BCRs autoaggregate at steady state d CLL B cell signaling varies between patients and predicts disease severity

PurposeChronic Lymphocytic Leukemia (CLL) is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation.Experimental DesignWe developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR). Results from multidimensional modeling were validated using an independent test cohort of 38 patients.ResultsWe identified a dynamic and variable imbalance between proximal (pSYK, pBTK) and distal (pPLCγ2, pBLNK, ppERK) phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCγ2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness.ConclusionSingle-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to-cell. Disruption of the pSYK/pPLCγ2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets.

As part of the System Linkages and Access to Care Initiative, 12 HIV service delivery organizations in New York implemented one of the following three interventions to improve linkage to and retention in HIV care at their site: Peer Support, Appointment Procedures, and Anti-Retroviral Treatment and Access to Services. Aggregate process measure data describing intervention delivery, in conjunction with qualitative findings to help explain barriers and facilitators to achieving full implementation were examined. Process data from the interventions showed shortcomings in the percentage of eligible patients who went on to be enrolled, and the number of enrollees who ultimately received the components of the interventions. Factors identified in qualitative interviews that facilitated implementation and intervention delivery included: concerted buy-in and coordination of staff, building upon existing infrastructure including ensuring sufficient staff capacity, and allowing adaptability of certain parts of the intervention to better fit patient needs and clinical settings.