2-Hexyl-4-Pentylenic Acid (HPTA) Stimulates the Radiotherapy-induced Abscopal Effect on Distal Tumor through Polarization of Tumor-associated Macrophages.

OBJECTIVE: The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid (HPTA) in combination with radiotherapy (RT) on distant unirradiated breast tumors. METHODS: Using a rat model of chemical carcinogen (7,12-dimethylbenz[a]anthracene,DMBA)-induced breast cancer, tumor volume was monitored and treatment response was evaluated by performing HE staining, immunohistochemistry, immunofluorescence, qRT-PCR, and western blot analyses. RESULTS: The results demonstrated that HPTA in combination with RT significantly delayed the growth of distant, unirradiated breast tumors. The mechanism of action included tumor-associated macrophage (TAM) infiltration into distant tumor tissues, M1 polarization, and inhibition of tumor angiogenesis by IFN-γ. CONCLUSION: The results suggest that the combination of HPTA with RT has an abscopal effect on distant tumors via M1-polarized TAMs, and HPTA may be considered as a new therapeutic for amplifying the efficacy of local RT for non-targeted breast tumors.The graphical abstract was available in the web of www.besjournal.com.

Identification of a novel CHN1 p.(Phe213Val) variant in a large Han Chinese family with congenital Duane retraction syndrome.

Duane retraction syndrome (DRS) is a neuromuscular dysfunction of the eyes. Although many causative genes of DRS have been identified in Europe and the United States, few reports have been published in regard to Chinese DRS. The aim of the present study was to explore the genetic defect of DRS in a Chinese family. Exome sequencing was used to identify the disease-causing gene for the two affected family members. Ophthalmic and physical examinations, as well as genetic screenings for variants in chimerin 1 (CHN1), were performed for all family members. Functional analyses of a CHN1 variant in 293T cells included a Rac-GTP activation assay, α2-chimaerin translocation assay, and co-immunoprecipitation assay. Genetic analysis revealed a NM_001822.7: c.637T > G variant in the CHN1 gene, which resulted in the substitution of a highly conserved C1 domain with valine at codon 213 (NP_001813.1: p.(Phe213Val)) (ClinVar Accession Number: SCV001335305). In-silico analysis revealed that the p.(Phe213Val) substitution affected the protein stability and connections among the amino acids of CHN1 in terms of its tertiary protein structure. Functional studies indicated that the p.(Phe213Val) substitution reduced Rac-GTP activity and enhanced membrane translocation in response to phorbol-myristoyl acetate (PMA). Together with previous studies, our present findings demonstrate that CHN1 may be an important causative gene for different ethnicities with DRS.

Nonhuman Primate Model of Oculocutaneous Albinism with TYR and OCA2 Mutations.

Human visual acuity is anatomically determined by the retinal fovea. The ontogenetic development of the fovea can be seriously hindered by oculocutaneous albinism (OCA), which is characterized by a disorder of melanin synthesis. Although people of all ethnic backgrounds can be affected, no efficient treatments for OCA have been developed thus far, due partly to the lack of effective animal models. Rhesus macaques are genetically homologous to humans and, most importantly, exhibit structures of the macula and fovea that are similar to those of humans; thus, rhesus macaques present special advantages in the modeling and study of human macular and foveal diseases. In this study, we identified rhesus macaque models with clinical characteristics consistent with those of OCA patients according to observations of ocular behavior, fundus examination, and optical coherence tomography. Genomic sequencing revealed a biallelic p.L312I mutation in TYR and a homozygous p.S788L mutation in OCA2, both of which were further confirmed to affect melanin biosynthesis via in vitro assays. These rhesus macaque models of OCA will be useful animal resources for studying foveal development and for preclinical trials of new therapies for OCA.

Phenotypic variability of SLC7A14 mutations in patients with inherited retinal dystrophy.

BACKGROUND: Inherited retinal dystrophy (IRD) is a group of retinal disorders that are both clinically and genetically diverse, typically with loss of photoreceptor function. Herein, we aimed to identify the underlying genetic defect in IRD patients with mutations in the SLC7A14 gene. METHODS: A targeted exome capture panel was applied for mutational screening of SLC7A14. Targeted exome sequencing (TES) was performed on 200 non-syndromic and unrelated autosomal recessive or sporadic IRD families. Candidate variants were validated by direct sequencing and further examined using bioinformatics analyses for determination of their potential effect. RESULTS: We identified compound heterozygous missense mutations (c.988G>A, p.G330R; c.1970G>A, p.R657Q) in an autosomal recessive retinitis pigmentosa (RP) case and a homozygous mutation (c.988G>A, p.G330R) in a simplex case with Leber congenital amaurosis (LCA) in the SLC7A14 gene. Both G330R and R657Q were deleterious based on in silico predictive tools. Our proposed topological model of the SLC7A14 polypeptide suggested that both G330R and R657Q affected evolutionarily highly conserved amino acid residues in SLC7A14 that occurred in transmembrane helixes. Structural modeling revealed a broken arginine and aspartic acid connection between residues 657 and 406. CONCLUSIONS: We applied TES to the molecular diagnosis of patients with IRD and for the first time identified SLC7A14 mutations in two unrelated families with RP and LCA separately. Our findings uniquely add the knowledge of the phenotypic variability of SLC7A14 mutations.