Familial focal segmental glomerulosclerosis associated with a WT1 gene missense mutation: A case report.

Focal s egmental glomerulosclerosis (F SGS) can cause protei nuria and loss o f k idney fun ction, leading to e ndstage renal di s ease (ESRD). Podocyte injury is the ce ntral pathophysiologi cal mechanis m of hereditary FSGS. Numerous mutations in genes e ncoding or affe cting the transcriptional regulation of podocyte cell compar tments have been detected in patients with genetic FSGS. Herein, we report a rare case of familial FSGS with an autosomal dominant WT1 mutation. A 63-year- old man developed pro teinuri a; his reading showed over 1g prote in/day. A pa thological diagn osis of FSG S was made after rena l biops y. H is elder brother an d a 36-year- old son also had ESRD. Heterozygous variant of WT1 (NM_024426.4) c.1373G>A (p.Arg458Gln ) mi s sense was dete cted in the patient a nd his son , by whole-exome sequen cing. Although genetic screening is not a par t of routine practice, it s hould be per for med in such cases to a id a ppropriate tre atment options sel ecting, revealing extra ren al symptoms, and family planning.

Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells.

BACKGROUND: Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of non-small cell lung cancer (NSCLC). Although the discovery of driver mutations and their targeted drugs has remarkably improved the treatment outcomes for lung adenocarcinoma, currently no such molecular target is clinically available for SqCLC. The CDKN2A locus at 9p21 encodes two alternatively spliced proteins, p16INK4a (p16) and p14ARF (p14), which function as cell cycle inhibitors. The Cancer Genome Atlas (TCGA) project revealed that CDKN2A is inactivated in 72% of SqCLC cases. In addition, it was found that CDKN2A mutations are significantly more common in SqCLC than in adenocarcinoma. Down-regulation of p16 and p14 by CDKN2A gene inactivation leads to activation of cyclin-dependent kinases (CDKs), thereby permitting constitutive phosphorylation of Rb and subsequent cell cycle progression. Here, we hypothesized that CDK inhibition may serve as an attractive strategy for the treatment of CDKN2A-defective SqCLC. METHODS: We investigated whether the CDK inhibitors flavopiridol and dinaciclib may exhibit antitumor activity in CDKN2A-defective SqCLC cells compared to control cells. The cytotoxic effect of the CDK inhibitors was evaluated using cell viability assays, and the induction of apoptosis was assessed using TUNEL assays and Western blot analyses. Finally, anti-tumor effects of the CDK inhibitors on xenografted cells were investigated in vivo. RESULTS: We found that flavopiridol and dinaciclib induced cytotoxicity by enhancing apoptosis in CDKN2A-defective SqCLC cells, and that epithelial to mesenchymal transition (EMT) decreased and autophagy increased during this process. In addition, we found that autophagy had a cytoprotective role. CONCLUSION: Our data suggest a potential role of CDK inhibitors in managing CDKN2A-defective SqCLC.

Analysis of Taurine's Anti-Down Syndrome Potential in Caenorhabditis elegans.

Down syndrome (DS) patients overexpress human DS critical region gene 1 (hDSCR-1), whose translational product inhibits calcineurin-dependent signaling pathways of genetic transcription. Compared to hDSCR-1, C. elegans rcn-1 has 40% sequence similarity and its proteins share an analogous function with hDSCR-1 in regulating calcineurin. Taurine has had a positive effect on DS patients. According to animal research studies, taurine reduces the expression of MCIP1, a calcineurin inhibitory protein, on C2C12 myotubes and fibroblast in mouse. This study utilizes two C. elegans models for DS: rcn-1 overexpression model, displaying a calcineurin-deficient phenotype, and calcineurin loss-of function mutants. C. elegans larvae were treated with taurine to characterize its effect and mechanism in helping DS patients. RCN-1 expression and behavioral changes were examined in rcn-1 overexpression and calcineurin-deficient models at different concentrations of taurine. When treated with taurine, transgenic worms harboring an rcn-1 reporter (RCN-1::GFP) showed a reduced level of rcn-1 mRNA expression and improved behaviors that were comparable to those in the wild type. These results indicate that taurine exerts a down-regulating effect on the expression of rcn-1 and, consequently, a positive effect on the expression of calcineurins. In summary, taurine may improve the DS symptoms by prompting a positive interaction between RCN-1 and calcineurin. Furthermore, these results suggest that novel mechanisms may regulate interactions among taurine, RCN-1 and calcineurin.

Microscopical observation of inhibition-behaviors against Diaporthe citri by pre-treated with Pseudomonas putida strain THJ609-3 on the leaves of citrus plants.

Citrus melanose is one of the most important diseases in orchards cultivating citrus in the world. Although the disease does not cause yield loss, the profitability of the infected fruits is often reduced in the fresh-market, resulting in economic loss. In this study, disease reduction was proven by pre-treatment with Pseudomonas putida strain THJ609-3. In order to illustrate mechanism of the disease reduction by the bacterial strain, the infection behaviors of Diaporthe citri and necrosis deposit of plant tissue were observed using a fluorescence microscope. On the leaves pre-treated with the strain THJ609-3, germination rates of D. citri conidia were significantly decreased compared to those of the untreated control. Scanning electron microscopical observations showed that bacterial cells were attached to the surface of fungal hyphae. Furthermore, morphological change of germ tubes of the conidia was detected. These results suggest that the disease reduction may be caused by the direct antifungal activity of the bacterial strain on the leaf surfaces.

Synthesis and conformational analysis of novel 2',3'-didehydo-2',3'-dideoxy-4'-selenonucleosides.

The structure of 2',3'-didehydro-2',3'-dideoxynucleosides (d4Ns) was applied to design the novel bioisosteric 4'-seleno-d4Ns as potential inhibitors of human immunodeficiency virus reverse transcriptase (HIV RT). Conversion of 2',3'-dihydroxyl groups of 4'-selenoribofuranosyl pyrimidines into the olefin was accomplished by treatment of cyclic 2',3'-thiocarbonate with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine.