While moderate calorie restriction did not significantly decrease VAT in older adults at high risk for cardiometabolic disease, it did reduce total body fat and cardiometabolic risk factors without significantly more adverse events and lean mass loss.

Hypoxia plays a critical role in the tumor microenvironment of high-grade gliomas by promoting the glioma stem cell (GSC)-like phenotype, which displays resistance to standard therapies. We tested three glioblastoma multiforme xenograft lines (xenolines) against γ(1)34.5-deleted recombinant oncolytic herpes simplex virus (oHSV) C101 under 1% (hypoxia) and 20.8% (normoxia) oxygen tension for effects on oHSV infectivity, replication, and cytotoxicity in all tumor cells and CD133(+) GSCs. Expression levels of CD133, a putative GSC marker, and CD111 (nectin-1), an adhesion molecule that is the most efficient method for HSV entry, increased significantly under hypoxia in all three xenolines. Despite increased CD111 expression under hypoxic conditions, oHSV infectivity, cytotoxicity and viral recovery were not improved or were diminished in all three xenolines under hypoxia. In contrast, wild-type HSV-1 equally infected xenoline cells in normoxia and hypoxia, suggesting that the 34.5 mutation plays a role in the decreased C101 infectivity in hypoxia. Importantly, CD133(+) cells were not more resistant to oHSV than CD133(-) tumor cells regardless of oxygen tension. Furthermore, CD133 expression decreased as viral dose increased in two of the xenolines suggesting that up-regulation of CD133 in hypoxia was not the cause of reduced viral efficacy. Our findings that oHSV infectivity and cytotoxicity were diminished under hypoxia in several GBM xenolines likely have important implications for clinical applications of oHSV therapies, especially considering the vital role of hypoxia in the microenvironment of GBM tumors.

Pathophysiological hypoxia, which fosters the glioma stem-like cell (GSC) phenotype, is present in high-grade gliomas and has been linked to tumor development, invasiveness, and resistance to chemotherapy and radiation. Oncolytic virotherapy with engineered herpes simplex virus-1 (HSV-1) is a promising therapy for glioblastoma; however efficacy of γ134.5-deleted HSVs, which have been used in clinical trials, was diminished in hypoxia. We investigated the ability of a chimeric HCMV/HSV-1 virus, which expresses the human CMV PKR evasion gene IRS1 and is in preparation for clinical trials, to infect and kill adult and pediatric patient-derived glioblastoma xenografts in hypoxia and normoxia. Infectivity, cytotoxicity and viral recovery were significantly greater with the chimeric virus compared to the γ134.5-deleted virus, regardless of oxygen tension. The chimeric virus infected and killed CD133+ GSCs similarly to wild-type HSV-1. Increased activation of mitogen-activated protein kinase (MAPK) p38 and its substrate heat shock protein 27 (Hsp27) was seen after viral infection in normoxia compared to hypoxia. Hsp27 knockdown or p38 inhibition reduced virus recovery indicating that the p38 pathway plays a role in the reduced efficacy of the γ134.5-deleted virus in hypoxia. Together these findings demonstrate chimeric HCMV/HSV-1 efficiently targets both CD133+ GSCs and glioma cells in hypoxia.

Background Rhabdomyosarcoma (RMS) is characterized by features of skeletal muscle and is comprised of two major histological subtypes, embryonal (E-RMS) and alveolar (A-RMS). Subsets of each RMS subtype demonstrate resistance to multimodal therapy leading to treatment failure. Cancer stem cells or cancer-initiating cells (CIC) represent a theorized population of cells that give rise to tumors and are responsible for treatment resistance. Procedure We investigated the ability of CD133, a putative CIC marker, to distinguish a chemoresistant, myogenically primitive population in alveolar (RH30) and embryonal (RD) RMS cell lines. We tested CD133+/- cells for sensitivity to engineered herpes simplex virus (oHSV) Results Relative to CD133- cells, CD133+ A-RMS and E-RMS cells demonstrate an enhanced colony-forming ability, are less differentiated myogenically, and are more resistant to cytotoxic chemotherapy but equally sensitive to oHSV oncolysis. Compared to CD133- RD cells, CD133+ cells express relatively high levels of genes typically expressed in skeletal muscle progenitor satellite cells including PAX7, c-MET, and the GLI effectors of the hedgehog signaling pathway. In contrast, CD133+ RH30 cells were not associated with enhanced expression of satellite cell markers or Hh targets. Conclusions Our findings demonstrate that CD133+ cells from A-RMS and E-RMS cell lines are characterized by a myogenically primitive phenotype. These cells have the capacity to form colonies in vitro and are more resistant to chemotherapy than CD133- cells. CD133 expression may denote a subset of RMS cells with an important role in tumorigenesis and treatment failure. These resistant cells may be effectively targeted by oHSV therapy.

We conducted a study designed to evaluate whether the benefits of intentional weight loss exceed the potential risks in a group of community-dwelling, obese, older adults who were at increased risk for cardiometabolic disease. The CROSSROADS trial used a prospective randomized controlled design to compare the effects of changes in diet composition alone or combined with weight loss with an exercise only control intervention on body composition and adipose tissue deposition (Specific Aim #1: To compare the effects of changes in diet composition alone or combined with weight loss with an exercise only control intervention on body composition, namely visceral adipose tissue (VAT)), cardiometabolic disease risk (Specific Aim #2: To compare the effects of a change in diet composition alone or combined with weight loss with an exercise only control intervention on cardiometabolic disease risk), functional status and quality of life (Specific Aim #3: To compare the effects of a change in diet composition alone or combined with weight loss with an exercise only control intervention on functional status and quality of life). Participants were randomly assigned to one of three groups: Exercise Only (Control) Intervention, Exercise + Diet Quality + Weight Maintenance Intervention, or Exercise + Diet Quality + Weight Loss Intervention. CROSSROADS utilized a lifestyle intervention approach consisting of exercise, dietary, and behavioral components. The development and implementation of the CROSSROADS protocol, including a description of the methodology, detailing specific elements of the lifestyle intervention, assurances of treatment fidelity, and participant retention; outcome measures and adverse event monitoring; as well as unique data management features of the trial results, are presented in this article.