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"Devine, S."
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CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma
Multiple myeloma (MM) is an incurable hematological malignancy. Chimeric antigen receptor (CAR)-expressing T cells have been demonstrated successfully in the clinic to treat B-lymphoid malignancies. However, the potential utility of antigen-specific CAR-engineered natural-killer (NK) cells to treat MM has not been explored. In this study, we determined whether CS1, a surface protein that is highly expressed on MM cells, can be targeted by CAR NK cells to treat MM. We successfully generated a viral construct of a CS1-specific CAR and expressed it in human NK cells.
In vitro
, CS1-CAR NK cells displayed enhanced MM cytolysis and interferon-γ (IFN-γ) production, and showed a specific CS1-dependent recognition of MM cells.
Ex vivo
, CS1-CAR NK cells also showed similarly enhanced activities when responding to primary MM tumor cells. More importantly, in an aggressive orthotopic MM xenograft mouse model, adoptive transfer of NK-92 cells expressing CS1-CAR efficiently suppressed the growth of human IM9 MM cells and also significantly prolonged mouse survival. Thus, CS1 represents a viable target for CAR-expressing immune cells, and autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat MM.
Journal Article
Drowning prevention strategies for migrant adults in Australia: a qualitative multiple case study
Drowning is a global public health issue, with minority populations, including migrants, experiencing significant disparities in drowning. The World Health Organization recommends learning to swim as a strategy to reduce drowning. In Australia, migrants are identified as a priority population for drowning prevention, accounting for approximately one-third of all drowning deaths.
This study aimed to identify swimming and water safety programs aimed at adult migrant populations in Australia and to explore how these programs are meeting the needs of migrant adults.
Using a qualitative multiple case study methodology a desktop review was conducted of 30 publicly accessible swimming and water safety programs across Australia aimed at migrant communities. From this review, six programs were purposively selected for in-depth analysis. Interviews and focus groups with 63 participants (program, managers, swim teachers and program participants), were conducted, guided by the Health Belief Model and Theory of Planned Behaviour. Data was thematically analysed using a deductive approach.
Four overlapping key themes with 14 sub-themes were identified: (1) Motivations for establishing programs for migrant adults, (2) Perceived barriers to participation, (3) Addressing cultural and socio-economic determinants of health and (4) Factors and challenges to program success. Findings revealed that drowning among migrant communities was the catalyst for establishing programs, and that staff consciously design these swim programs to make programs accessible and relevant to migrants. This includes offering single-gender programs, providing culturally appropriate swimwear, having bilingual teachers, low or no cost participation fees and ensuring training pathways to employment in the aquatic industry.
Swimming and water safety programs that acknowledge and respond to migrants’ needs and characteristics offer multiple benefits beyond drowning prevention, including improved physical, social and mental health, and positive settlement experiences. These programs highlight the importance of acquiring water safety awareness, knowledge and skills, and how this can influence generational attitudes and behaviour towards drowning risk and water engagement. Drowning is a complex public health issue, with collaboration among multisectoral stakeholders required to create an impact and reduce inequities, especially for vulnerable populations such as migrant adults.
Journal Article
The information requirements of complex biological and economic systems with algorithmic information theory
This article interprets the natural laws creating and maintaining a complex system, such as an ecology or an economy, distant from equilibrium, as computations on a real world Universal Turing Machine (UTM). As a laboratory, UTM can simulate the real world UTM, from the perspective of algorithmic information theory, the number of bits in the shortest, appropriately coded binary algorithm that specifies a real world system on a laboratory UTM defines its algorithmic entropy and its information content. As only algorithmic entropy differences matter, and differences are UTM- independent, differences measured on the laboratory UTM align with entropy changes in the real world. The system’s distance from equilibrium in bits defines its order. Computations require energy. Landauer’s principle identifies the minimum energy per bit (or the real world equivalent) to drive the computation that creates and sustains a real world system in a homeostatic state distant from equilibrium. This high-grade energy carries the computational instructions that do work on the system, ejecting disorder as heat and waste. While replication algorithms drive the emergence of complex ecological systems (doi:10.1016/j.biosystems.2015.11.008), in economic systems, individual agent behaviour can be captured by computer algorithms akin to the perspective of an adaptive system paradigm. Rather than specifying detailed behavioural routines for an economy, a narrative is used to identify the information drivers that create an ordered far-from-equilibrium economic system. The narrative shows that, somewhat like the interdependence of species in a vibrant ecology, agents trade, utilise technology, and amalgamate to form more complex structures creating order and driving the economy further from equilibrium. An ordered economy is a better economy. Order-creating investments (infrastructure, machines etc.) enhance economic performance, in contrast to non-ordering investments that extract wealth from others, adding nothing.
Journal Article
Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF?
Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.
Journal Article
Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden?
Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and have important roles in hematopoietic engraftment, GvHD and graft-versus-leukemia responses following allogeneic hematopoietic cell transplantation (HCT). In addition, pDCs mediate antiviral immunity, particularly as they are the body’s primary cellular source of type I interferon. Given their pleiotropic roles, pDCs have emerged as cells that critically impact transplant outcomes, including overall survival. In this article, we will review the pre-clinical and clinical literature, supporting the crucial roles that pDCs assume as key immune effector cells during HCT.
Journal Article
How we approach patient evaluation for hematopoietic stem cell transplantation
The evaluation of patients for hematopoietic stem cell transplantation is a complex process. The decision to recommend transplantation is not simply dependent on patient diagnosis; instead it is a specialized analytic decision process intricately dependent on a number of variables including patient age, performance status, medical comorbidities, family support structure, socioeconomic viability and motivation to participate in self-care, to name a few. The process of pre-transplant patient evaluation has substantial variability across different transplant centers, owing to lack of formal published guidelines. This review summarizes the process of pre-transplant patient evaluation and workup, and aims to describe components of a well-organized and evidenced-based patient selection process for SCT
Journal Article
The hematopoietic stem cell transplant comorbidity index can predict for 30-day readmission following autologous stem cell transplant for lymphoma and multiple myeloma
Patients who undergo autologous stem cell transplant (ASCT) for hematologic malignancies frequently have multiple comorbidities. The hematopoietic cell transplantation comorbidity index (HCT-CI), a transplant-specific modification of the Charlson comorbidity index, can predict risk of readmission following allogeneic stem cell transplant. Its utility in the autologous setting is unknown. We evaluated 620 patients who underwent ASCT at the Ohio State University from 2007 to 2012 for lymphoma or multiple myeloma (MM) to identify factors associated with readmission. Univariable and multivariable logistic regression were used to estimate the odds of readmission within 30 days of discharge following ASCT. A Cox proportional hazards model was used to evaluate OS. Sixty-four patients were readmitted within 30 days; the most common indications were fever and prolonged gastrointestinal toxicity. MM compared with lymphoma (odds ratio (OR) 1.89, 95% confidence interval (95% CI): 1.06–3.38,
P
=0.03), HCT-CI⩾3 (OR 1.74, 95% CI: 1.03–2.96,
P
=0.04) and length of hospitalization ⩾28 days (OR 3.14, 95% CI: 1.26–7.83,
P
=0.01) remained significantly associated with 30-day readmission in a multivariable model. While the model had excellent fit (
P
>0.75), its ability to predict individual patients who would be readmitted was less than acceptable (receiver-operator curve=0.64, 95% CI: 0.57–0.71). In a multivariable proportional hazards model, 30-day readmission (hazards ratio (HR) 1.81, 95% CI: 1.04–3.18,
P
=0.04), length of hospitalization ⩾28 days (HR 4.93, 95% CI: 2.65–9.18,
P
<0.001) and chemorefractory disease (HR 3.08, 95% CI: 1.74–5.43,
P
<0.001) were independently associated with inferior OS, but HCT-CI was not. Evaluation of other assessment tools may allow better prediction of outcomes following ASCT.
Journal Article