Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Pediatric Solid Tumors

Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ₁34.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.     

Neuronal expression of fibroblast growth factor receptors in zebrafish

Fibroblast growth factor (FGF) signaling is important for a host of developmental processes such as proliferation, differentiation, tissue patterning, and morphogenesis. In vertebrates, FGFs signal through a family of four fibroblast growth factor receptors (FGFR 1-4), one of which is duplicated in zebrafish (FGFR1). Here we report the mRNA expression of the five known zebrafish fibroblast growth factor receptors at five developmental time points (24, 36, 48, 60, and 72 h postfertilization), focusing on expression within the central nervous system. We show that the receptors have distinct and dynamic expression in the developing zebrafish brain, eye, inner ear, lateral line, and pharynx. In many cases, the expression patterns are similar to those of homologous FGFRs in mouse, chicken, amphibians, and other teleosts.     

Binding of Sulfamethazine to β-cyclodextrin and Methyl-β-cyclodextrin

β-cyclodextrin (βCD) and methyl-β-cyclodextrin (MβCD) complexes with sulfamethazine (SMT) were prepared and characterized by different experimental techniques, and the effects of βCD and MβCD on drug solubility were assessed via phase-solubility analysis. The phase-solubility diagram for the drug showed an increase in water solubility, with the following affinity constants calculated: 40.4 ± 0.4 (pH 2.0) and 29.4 ± 0.4 (pH 8.0) M⁻¹ with βCD and 56 ± 1 (water), 39 ± 3 (pH 2.0) and 39 ± 5 (pH 8.0) M⁻¹ with MβCD. According to ¹H NMR and 2D NMR spectroscopy, the complexation mode involved the aromatic ring of SMT included in the MβCD cavity. The complexes obtained in solid state by freeze drying were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and thermal analysis. The amorphous complexes obtained in this study may be useful in the preparation of pharmaceutical dosage forms of SMT.     

TRIM5 alpha Drives SIVsmm Evolution in Rhesus Macaques

The antagonistic interaction with host restriction proteins is a major driver of evolutionary change for viruses. We previously reported that polymorphisms of the TRIM5α B30.2/SPRY domain impacted the level of SIVsmm viremia in rhesus macaques. Viremia in macaques homozygous for the non-restrictive TRIM5α allele TRIM5^Q was significantly higher than in macaques expressing two restrictive TRIM5alpha alleles TRIM5^TFP/TFP or TRIM5^Cyp/TFP. Using this model, we observed that despite an early impact on viremia, SIVsmm overcame TRIM5α restriction at later stages of infection and that increasing viremia was associated with specific amino acid substitutions in capsid. Two amino acid substitutions (P37S and R98S) in the capsid region were associated with escape from TRIM5^TFP restriction and substitutions in the CypA binding-loop (GPLPA87-91) in capsid were associated with escape from TRIM5^Cyp. Introduction of these mutations into the original SIVsmE543 clone not only resulted in escape from TRIM5α restriction in vitro but the P37S and R98S substitutions improved virus fitness in macaques with homozygous restrictive TRIM^TFP alleles in vivo. Similar substitutions were observed in other SIVsmm strains following transmission and passage in macaques, collectively providing direct evidence that TRIM5α exerts selective pressure on the cross-species transmission of SIV in primates.     

The bioenergetic fuel for non-feeding larval development in an endemic palaemonid shrimp from the Iberian Peninsula,Palaemonetes zariquieyi

Palaemonetes zariquieyi, an endemic palaemonid species of shrimp that lives in freshwater and brackish coastal habitats in eastern Spain, shows an abbreviated, non-feeding larval development comprising only three zoeal stages. To identify the endogenous bioenergetic fuel that allows for food-independent development from hatching to metamorphosis, larvae were reared under controlled laboratory conditions, and ontogenetic changes in dry weight (W), elemental (CHN), and lipid composition (total lipids, principal lipid classes, and fatty acids [FA]) were quantified at the onset of each zoeal stage and in the first juvenile. Values of W, C, and H per larva and per mass unit of W decreased throughout the time of larval development, while the N content showed only a weak decline (suggesting strong lipid but only little protein degradation). Correspondingly, directly measured values of total lipids (both in μg/larva and in % of W) decreased gradually, with neutral lipids (NL) consistently remaining the predominant and most strongly used fraction; sterol esters and waxes were not detected. In contrast to the NL, the fraction of polar lipids (PL) per larva remained stable and, as a consequence, tended to increase as a percentage of total lipids. Likewise, other important lipid fractions such as free FA and cholesterol remained stable throughout the time of larval development. Among the FA, palmitic (16:0), oleic (18:1n–9), linoleic (18:2n–6), and eicosapentaenoic (20:5n–3) acid were predominant, showing a significant decrease during larval development; stearic (18:0), vaccenic (18:1n–7), and arachidonic acid (20:4n–6) were found only in small amounts. Our results indicate that the lecithotrophic development of P. zariquieyi is primarily fuelled by the utilization of lipids (especially triacylglycerides and other NL), which is reflected by a decreasing carbon content. Proteins and PL, by contrast, are preserved as structurally indispensable components (nerve and muscle tissues, cell membranes). The abbreviated and non-feeding mode of larval development of P. zariquieyi may have an adaptive value in land-locked freshwater habitats, where planktonic food limitation is likely to occur. The patterns of reserve utilization are similar to those previously observed in other palaemonid shrimps and various other groups of decapod crustaceans with lecithotrophic larvae. This suggests a multiple convergent evolution of bioenergetic traits allowing for reproduction in food-limited aquatic environments.     

Genetic Characterization of a Fusarium Head Blight Resistance QTL from Triticum turgidum ssp. dicoccoides

Plant Molecular Biology Reporter - Qfhs.ndsu-3AS in wild emmer wheat (Triticum turgidum L. ssp. dicoccoides) is a major quantitative trait locus associated with type II resistance to Fusarium head...