Drug penetration in pediatric brain tumors: Challenges and opportunities.

Larger clinical trial enrollments and a greater understanding of biological heterogeneity have led to improved survival rates for children diagnosed with brain tumors in the last 50 years. However, reducing long-term morbidities and improving survival rates of high-risk tumors remain major challenges. Chemotherapy can reduce tumor burden, but effective drug penetration at the tumor site is limited by barriers in the route of drug administration and within the tumor microenvironment. Bioavailability of drugs is impeded by the blood-brain barrier, plasma protein binding, and structural components by the tumor including the matrix and vasculature contributing to increased interstitial fluid pressure, hypoxia, and acidity. Designing drug delivery systems to circumvent these barriers could lead to improved drug penetration at the tumor site and reduce adverse systemic side effects. In this review, we expand on how systemic and local barriers limit drug penetration and present potential methods to enhance drug penetration in pediatric brain tumors.

The lifelong impact of fetal growth restriction on cardiac development.

BACKGROUND: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. METHODS: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. RESULTS: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR-FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR-FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR-FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. CONCLUSIONS: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development.

Sex-related differences in matrix remodeling and early osteogenic markers in aortic valvular interstitial cells.

Calcific aortic valve disease (CAVD) is a major cardiovascular disorder in the developed countries. Male is a known risk factor in this disease; unfortunately, how sex contributes to CAVD is mostly unknown. The objective of this study is to determine whether valvular interstitial cells (VICs) isolated from male versus female aortic valves demonstrate difference in osteogenic differentiation and/or extracellular matrix (ECM) remodeling. VICs were isolated from male and female rat or porcine aortic valves and cultured in osteogenic media for 10, 15 and 20 days. The proliferation among male and female VICs was assessed by a cell growth assay. The matrix remodeling of the VIC samples was quantified using glycosaminoglycan (GAG), collagen type I and gelatin zymography assays. Early osteogenic marker expression was assessed using alkaline phosphatase (ALP) staining and enzyme activity assay and Alizarin Red S staining. Our result showed that proliferation of VICs was significantly greater in female than male after 12 days of culture in regular media. Additionally, male VICs showed elevated amounts of normalized GAG, collagen I, and activated matrix metallopreoteniase-2 expression compared to female. Similarly, ALP content was greater in male VICs than female at all time points. In addition, male VICs formed calcific nodules with greater size, % area and integrated density than females. The results from this research suggest that there is a sex-related difference in the events associated with osteogenic differentiation of the aortic VICs, where male VICs are more prone to calcification.

A diagnostic quandary: Rotavirus vaccine associated diarrhea.

The patient is an otherwise healthy two-month-old boy who received the recommended vaccinations for his age group, which included the rotavirus pentavalent vaccine (RV5; RotaTeq) at his two-month well child visit. Three days later, he developed prolonged non-bloody diarrhea and was found to have persistently positive rotavirus antigen in his stool. Subsequent workup revealed mild defects in his functional T-cell immunocompetence. Genetic testing was obtained through the Invitae panel and was negative for hereditary forms of primary immunodeficiencies. The rotavirus antigen was found to have cleared from his stool around four months after receiving the RV5. Unfortunately, the source of the rotavirus infection was unable to be determined. The caregivers had misconceptions about the vaccine and the child's immune system function which led to refusal of any further vaccinations. Healthcare providers should strive to develop honest and respectful relationships with parents to have thoughtful dialogues regarding vaccine safety and efficacy.

Articulatory effects on perceptions of men's status and attractiveness.

Research on heterosexual mating has demonstrated that acoustic parameters (e.g., pitch) of men's voices influence their attractiveness to women and appearance of status and formidability to other men. However, little is known about how men's tendency to clearly articulate their speech influences these important social perceptions. In the current study, we used a repeated-measures design to investigate how men's articulatory clarity or conformity influenced women's (N = 45) evaluations of men's attractiveness for both short- and long-term relationships, and men's (N = 46) evaluations of physical formidability and prestige. Results largely supported our hypotheses: men who enunciated phonemes more distinctly were more attractive to women for long-term relationships than short-term relationships and were perceived by other men to have higher prestige than physical dominance. These findings suggest that aspects of articulatory behavior that influence perceptions of prestige and long-term mating attractiveness may indicate an early social history characterized by high socioeconomic status, likely owing to crystallization of articulatory patterns during the critical period of language development. These articulatory patterns may also be honest signals of condition or disposition owing to the nature of complex, multicomponent traits, which deserve further empirical attention.

Novel multinutrient human milk-based human milk fortifier promotes growth and tolerance in premature infants.

BACKGROUND: The objective of this study was to determine whether human milk supplemented with a novel human milk-based human milk fortifier (Novel HMF), compared with a bovine milk-based HMF (Bovine HMF), supports preterm infant growth through 36 weeks' postmenstrual age (PMA). METHODS: This single-center, prospective trial compared growth and nutrition outcomes of preterm infants provided a human milk-based diet (mother's own milk or donor milk) supplemented with a Novel HMF with historic controls provided Bovine HMF. Preterm infants with an estimated gestational age (EGA) between 23 and 33 weeks' PMA and birth weight between 750 and 1800 g were eligible for study inclusion. Weight, length, and head circumference (HC) were monitored weekly. The occurrence of late-onset sepsis, nil per os (NPO) days, necrotizing enterocolitis, metabolic acidosis, and serious adverse events were monitored. RESULTS: Birth weight, length, HC, and EGA were similar between the Novel HMF (n = 37) and Bovine HMF (n = 49) groups. The days to regain birth weight was shorter in the Novel HMF group (9.4 ± 4.0 vs 11.4 ± 4.8, P = .0343), with similar weight gain (g/day) from birth to 36 weeks' PMA. Adjusted weight growth velocity (g/kg/day) was significantly higher in the Novel HMF group at 14 and 21 days but similar at 36 weeks' PMA. The Novel HMF group experienced fewer NPO days with a similar total number of feeding days. CONCLUSIONS: A novel, multinutrient, human milk-based HMF is well tolerated and meets the nutrition needs of preterm infants.

Competition-Based Cell Assay Employing Soluble T Cell Receptors to Assess MHC Class II Antigen Processing and Presentation.

Accurate assessment of antigen-specific immune responses is critical in the development of safe and efficacious biotherapeutics and vaccines. Endosomal processing of a protein antigen followed by presentation on major histocompatibility complex (MHC) class II constitute necessary steps in the induction of CD4+ T cell immune responses. Current preclinical methods for assessing immunogenicity risk consist of in vitro cell-based assays and computational prediction tools. Cell-based assays are time and labor-intensive while in silico methodologies have limitations. Here, we propose a novel cell-based assay capable of investigating an antigen's endosomal processing and MHC class II presentation capabilities. This novel assay relies on competition between epitopes for MHC class II binding and employs labeled soluble T cell receptors (sTCRs) as detectors of epitope presentation.

Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles.

We previously reported low sensitivity of the hepatitis B virus (HBV) ribonuclease H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compounds. Subsequently, our biochemical RNaseH assay was found to have a high false negative rate for predicting HBV replication inhibition, leading to underestimation of the number of HIDs that inhibit HBV replication. Here, 39 HID compounds and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the positive-polarity DNA strand and causes accumulation of RNA:DNA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV positive-polarity DNA strand accumulation. EC50s ranged from 0.69 µM to 19 µM with therapeutic indices from 2.4 to 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNA:DNA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors.