Epidermal growth factor‐induced COX‐2 regulates metastasis of head and neck squamous cell carcinoma through upregulation of angiopoietin‐like 4

Epidermal growth factor receptor (EGFR) expression and activation are the major causes of metastasis in cancers such as head and neck squamous cell carcinoma (HNSCC). However, the reciprocal effect of EGF‐induced COX‐2 and angiopoietin‐like 4 (ANGPTL4) on HNSCC metastasis remains unclear. In this study, we revealed that the expression of ANGPTL4 is essential for COX‐2‐derived prostaglandin E₂ (PGE₂)‐induced tumor cell metastasis. We showed that EGF‐induced ANGPTL4 expression was dramatically inhibited with the depletion and inactivation of COX‐2 by knockdown of COX‐2 and celecoxib treatment, respectively. Prostaglandin E₂ induced ANGPTL4 expression in a time‐ and dose‐dependent manners in various HNSCC cell lines through the ERK pathway. In addition, the depletion of ANGPTL4 and MMP1 significantly impeded the PGE₂‐induced transendothelial invasion ability of HNSCC cells and the binding of tumor cells to endothelial cells. The induction of molecules involved in the regulation of epithelial‐mesenchymal transition was also dependent on ANGPTL4 expression in PGE₂‐treated cells. The depletion of ANGPTL4 further blocked PGE₂‐primed tumor cell metastatic seeding of lungs. These results indicate that the EGF‐activated PGE₂/ANGPTL4 axis enhanced HNSCC metastasis. The concurrent expression of COX‐2 and ANGPTL4 in HNSCC tumor specimens provides insight into potential therapeutic targets for the treatment of EGFR‐associated HNSCC metastasis.     

Transamniotic stem cell therapy (TRASCET) in a rabbit model of spina bifida

Purpose

Transamniotic stem cell therapy (TRASCET) with select mesenchymal stem cells (MSCs) has been shown to induce partial or complete skin coverage of spina bifida in rodents. Clinical translation of this emerging therapy hinges on its efficacy in larger animal models. We sought to study TRASCET in a model requiring intra-amniotic injections 60 times larger than those performed in the rat.

Myopathy associated with homozygous PYROXD1 pathogenic variants detected by genome sequencing

Biallelic pathogenic variants in the gene PYROXD1 have recently been described to cause early-onset autosomal recessive myopathy. Myopathy associated with PYROXD1 pathogenic variants is rare and reported in only 17 individuals. Known pathogenic variants in PYROXD1 include missense, insertion and essential splice-site variants. Here we describe a consanguineous family of individuals affected with late-onset myopathy and homozygous PYROXD1 missense variants (NM_024854.5:c.464A>G [p.Asn155Ser]) expanding our understanding of the possible disease phenotypes of PYROXD1-associated myopathy.     

JPC-2997, a New Aminomethylphenol with High In Vitro and In Vivo Antimalarial Activities against Blood Stages of Plasmodium

4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly active in vitro against the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2B Plasmodium falciparum lines, with 50% inhibitory concentrations (IC_50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC₅₀s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more active in vitro against P. falciparum lines and 3-fold less cytotoxic. The compound possesses potent in vivo suppression activity against Plasmodium berghei, with a 50% effective dose (ED₅₀) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing three Aotus monkeys infected with a chloroquine- and pyrimethamine-resistant strain of Plasmodium vivax at a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The high in vivo potency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.     

Association of Self-Efficacy and Self-Regulation with Nutrition and Exercise Behaviors in a Community Sample of Adults

This study examined the association of self-efficacy and self-regulation with nutrition and exercise behaviors. The study used a cross-sectional design and included 108 participants (54 men, 54 women). Nutrition behaviors (fruit/vegetable consumption, dinner cooking, and restaurant eating) and exercise were measured using total days in last week a behavior was reported. Instruments measuring self-efficacy and self-regulation demonstrated excellent Cronbach’s alphas (.93–.95). Path analysis indicated only fruit/vegetable consumption and exercise were associated with self-efficacy and self-regulation. Self-regulation showed direct association with fruit/vegetable consumption and exercise, but self-efficacy had direct association only with exercise. Self-efficacy and self-regulation should be strategically used to promote health behaviors.