The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/ß-catenin signaling.

Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/ß-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of ß-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.

Muscle Stem Cell-Derived Extracellular Vesicles Reverse Hydrogen Peroxide-Induced Mitochondrial Dysfunction in Mouse Myotubes.

Muscle stem cells (MuSCs) hold great potential as a regenerative therapeutic but have met numerous challenges in treating systemic muscle diseases. Muscle stem cell-derived extracellular vesicles (MuSC-EVs) may overcome these limitations. We assessed the number and size distribution of extracellular vesicles (EVs) released by MuSCs ex vivo, determined the extent to which MuSC-EVs deliver molecular cargo to myotubes in vitro, and quantified MuSC-EV-mediated restoration of mitochondrial function following oxidative injury. MuSCs released an abundance of EVs in culture. MuSC-EVs delivered protein cargo into myotubes within 2 h of incubation. Fluorescent labeling of intracellular mitochondria showed co-localization of delivered protein and mitochondria. Oxidatively injured myotubes demonstrated a significant decline in maximal oxygen consumption rate and spare respiratory capacity relative to untreated myotubes. Remarkably, subsequent treatment with MuSC-EVs significantly improved maximal oxygen consumption rate and spare respiratory capacity relative to the myotubes that were damaged but received no subsequent treatment. Surprisingly, MuSC-EVs did not affect mitochondrial function in undamaged myotubes, suggesting the cargo delivered is able to repair but does not expand the existing mitochondrial network. These data demonstrate that MuSC-EVs rapidly deliver proteins into myotubes, a portion of which co-localizes with mitochondria, and reverses mitochondria dysfunction in oxidatively-damaged myotubes.

Trade law and alcohol regulation: what role for a global Alcohol Marketing Code?

BACKGROUND AND AIMS: Following calls for restrictions and bans on alcohol advertising, and in light of the tobacco industry's challenge to Australia's tobacco plain packaging measure, a tobacco control measure finding support in the World Health Organization (WHO) Framework Convention on Tobacco Control, this paper considers what role, if any, an international alcohol marketing code might have in preventing or reducing the risk of challenges to domestic alcohol marketing restrictions under trade rules. METHODS: Narrative review of international trade and health instruments and international trade court judgements regarding alcohol products and marketing restrictions. FINDINGS: The experience of European trade courts in the litigation of similar measures suggests that World Trade Organization rules have sufficient flexibility to support the implementation of alcohol marketing restrictions. However, the experience also highlights the possibility that public health measures have disproportionate and unjustifiable trade effects and that the ability of a public health measure to withstand a challenge under trade rules will turn on its particular design and implementation. CONCLUSION: Measures implemented pursuant to international public health instruments are not immune to trade law challenges. Close collaboration between health policymakers, trade officials and lawyers, from as early as the research stage in the development of a measure to ensure a robust evidence base, will ensure the best chance of regulatory survival for an international marketing code.

Health worker densities and immunization coverage in Turkey: a panel data analysis.

BACKGROUND: Increased immunization coverage is an important step towards fulfilling the Millennium Development Goal of reducing childhood mortality. Recent cross-sectional and cross-national research has indicated that physician, nurse and midwife densities may positively influence immunization coverage. However, little is known about relationships between densities of human resources for health (HRH) and vaccination coverage within developing countries and over time. The present study examines HRH densities and coverage of the Expanded Programme on Immunization (EPI) in Turkey during the period 2000 to 2006. METHODS: The study is based on provincial-level data on HRH densities, vaccination coverage and provincial socioeconomic and demographic characteristics published by the Turkish government. Panel data regression methodologies (random and fixed effects models) are used to analyse the data. RESULTS: Three main findings emerge: (1) combined physician, nurse/midwife and health officer density is significantly associated with vaccination rates--independent of provincial female illiteracy, GDP per capita and land area--although the association was initially positive and turned negative over time; (2) HRH-vaccination rate relationships differ by cadre of health worker, with physician and health officers exhibiting significant relationships that mirror those for aggregate density, while nurse/midwife densities are not consistently significant; (3) HRH densities bear stronger relationships with vaccination coverage among more rural provinces, compared to those with higher population densities. CONCLUSION: We find evidence of relationships between HRH densities and vaccination rates even at Turkey's relatively elevated levels of each. At the same time, variations in results between different empirical models suggest that this relationship is complex, affected by other factors that occurred during the study period, and warrants further investigation to verify our findings. We hypothesize that the introduction of certain health-sector policies governing terms of HRH employment affected incentives to provide vaccinations and therefore relationships between HRH densities and vaccination rates. National-level changes experienced during the study period--such as a severe financial crisis--may also have affected and/or been associated with the HRH-vaccination rate link. While our findings therefore suggest that the size of a health workforce may be associated with service provision at a relatively elevated level of development, they also indicate that focusing on per capita levels of HRH may be of limited value in understanding performance in service provision. In both Turkey and elsewhere, further investigation is needed to corroborate our results as well as gain deeper understanding into relationships between health worker densities and service provision.

Does social capital enhance health and well-being? Evidence from rural China.

Despite increasing acknowledgement that social capital is an important determinant of health and overall well-being, empirical evidence regarding the direction and strength of these linkages in the developing world is limited and inconclusive. This paper empirically examines relationships between social capital and health and well-being-as well as the suitability of commonly used social capital measures-in rural China, where rapid economic growth coexists with gradual and fundamental social changes. To measure social capital, we adopt a structural/cognitive distinction, whereby structural social capital is measured by organizational membership and cognitive social capital is measured by a composite index of trust, reciprocity, and mutual help. Our outcome measures included self-reported general health, psychological health, and subjective well-being. We adopt multi-level estimation methods to account for our conceptualization of social capital as both an individual- and contextual-level resource. Results indicate that cognitive social capital (i.e., trust) is positively associated with all three outcome measures at the individual level and psychological health/subjective well-being at the village level as well. We further find that trust affects health and well-being through pathways of social network and support. In contrast, there is little statistical association or consistent pattern between structural social capital (organizational membership) and the outcome variables. Furthermore, although organizational membership is highly correlated with collective action, neither is associated with health or well-being. Our results suggest that policies aimed at producing an environment that enhances social networks and facilitates the exchange of social support hold promise for improving the health and well-being of the rural Chinese population. In addition, China may not have fully taken advantage of the potential contribution of structural social capital in advancing health and well-being. A redirection of collective action from economic to social activities may be worth considering.