Regenerative Medicine Strategies for Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS), the most severe and common form of single ventricle congenital heart lesions, is characterized by hypoplasia of the mitral valve, left ventricle (LV), and all LV outflow structures. While advances in surgical technique and medical management have allowed survival into adulthood, HLHS patients have severe morbidities, decreased quality of life, and a shortened lifespan. The single right ventricle (RV) is especially prone to early failure because of its vulnerability to chronic pressure overload, a mode of failure distinct from ischemic cardiomyopathy encountered in acquired heart disease. As these patients enter early adulthood, an emerging epidemic of RV failure has become evident. Regenerative medicine strategies may help preserve or boost RV function in children and adults with HLHS by promoting angiogenesis and mitigating oxidative stress. Rescuing a RV in decompensated failure may also require the creation of new, functional myocardium. Although considerable hurdles remain before their clinical translation, stem cell therapy and cardiac tissue engineering possess revolutionary potential in the treatment of pediatric and adult patients with HLHS who currently have very limited long-term treatment options.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140239/1/ten.teb.2016.0136.pd

Strategies to rescue the consequences of inducible arginase-1 deficiency in mice

Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken beta-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies

A collaboration platform for enabling industrial symbiosis : towards creating a self-learning waste-to-resource database for recommending industrial symbiosis transactions using text analytics

Industrial Symbiosis (IS) adopts a collaborative approach, which aims to re-channel resources – traditionally considered spent and non-productive – towards alternative value-adding pathways. Empirically, the concept of IS has been rapidly implemented in practice through a facilitated approach, whereby businesses are engaged and “match-made” via a facilitating body. While recommending alternative pathways for companies to establish IS-based transactions is a long-standing practice, recent technological advancement has shifted the nature of this task from one that is based purely on human intellect and reasoning, towards one which leverages intelligent recommendation algorithms to provide relevant suggestions. Traditionally, these recommendation engines rely on manually populated knowledge bases that are not only labor-intensive to build but also costly to maintain. This work presents the creation of a self-learning waste-to-resource database supporting an IS recommendation system by utilizing text analytics techniques. We further demonstrate its practical application to support IS facilitating bodies in their core activity

Impact Assessment of Biomass Burning on Air Quality in Southeast and East Asia During BASE-ASIA

A synergy of numerical simulation, ground-based measurement and satellite observation was applied to evaluate the impact of biomass burning originating from Southeast Asia (SE Asia) within the framework of NASA's 2006 Biomass burning Aerosols in Southeast Asia: Smoke Impact Assessment (BASE-ASIA). Biomass burning emissions in the spring of 2006 peaked in MarcheApril when most intense biomass burning occurred in Myanmar, northern Thailand, Laos, and parts of Vietnam and Cambodia. Model performances were reasonably validated by comparing to both satellite and ground-based observations despite overestimation or underestimation occurring in specific regions due to high uncertainties of biomass burning emission. Chemical tracers of particulate K(+), OC concentrations, and OC/EC ratios showed distinct regional characteristics, suggesting biomass burning and local emission dominated the aerosol chemistry. CMAQ modeled aerosol chemical components were underestimated at most circumstances and the converted AOD values from CMAQ were biased low at about a factor of 2, probably due to the underestimation of biomass emissions. Scenario simulation indicated that the impact of biomass burning to the downwind regions spread over a large area via the Asian spring monsoon, which included Southern China, South China Sea, and Taiwan Strait. Comparison of AERONET aerosol optical properties with simulation at multi-sites clearly demonstrated the biomass burning impact via longrange transport. In the source region, the contribution from biomass burning to AOD was estimated to be over 56%. While in the downwind regions, the contribution was still significant within the range of 26%-62%

Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells.

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments

Understanding patient-provider communication entered via a patient portal system

ABSTRACT Our study examines patient-provider communication via a patient portal in a large medical center. Our study is based on 1172 interactions made among stakeholders concerning 100 patients who are randomly selected from the 2009 MyHealthAtVanderbilt.com (a patient portal at the Vanderbilt Medical Center) patient pool; among which, 35 use the patient portal for messages. The findings show a wide range of topics discussed and ways in which patients provide and seek information as well as express psychosocial and emotional needs. In addition, while the patient portal has advantages over traditional communication technologies, it was not the primary communication media for our study sample. More research is needed to better elucidate barriers to the use of patient portals and the optimal methods of communication in differing contexts

Sex differences in cancer mechanisms

We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab- and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients