Nesprins-1 and -2 are highly expressed in skeletal and cardiac muscle and together with SUN (Sad1p/UNC84)-domain containing proteins and lamin A/C form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) bridging complex at the nuclear envelope (NE). Mutations in nesprin-1/2 have previously been found in patients with autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). In this study, three novel rare variants (R8272Q, S8381C and N8406K) in the C-terminus of the SYNE1 gene (nesprin-1) were identified in seven DCM patients by mutation screening. Expression of these mutants caused nuclear morphology defects and reduced lamin A/C and SUN2 staining at the NE. GST pull-down indicated that nesprin-1/lamin/SUN interactions were disrupted. Nesprin-1 mutations were also associated with augmented activation of the ERK pathway in vitro and in hearts in vivo. During C2C12 muscle cell differentiation, nesprin-1 levels are increased concomitantly with kinesin light chain (KLC-1/2) and immunoprecipitation and GST pull-down showed that these proteins interacted via a recently identified LEWD domain in the C-terminus of nesprin-1. Expression of nesprin-1 mutants in C2C12 cells caused defects in myoblast differentiation and fusion associated with dysregulation of myogenic transcription factors and disruption of the nesprin-1 and KLC-1/2 interaction at the outer nuclear membrane. Expression of nesprin-1α2 WT and mutants in zebrafish embryos caused heart developmental defects that varied in severity. These findings support a role for nesprin-1 in myogenesis and muscle disease, and uncover a novel mechanism whereby disruption of the LINC complex may contribute to the pathogenesis of DCM.

Our study suggests that each population may have a unique and prevalent set of FLG mutations.

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A man complained of upper abdominal pain and early satiety for one month. An upper gastrointestinal endoscopy showed nothing special. A CT scan of the abdomen was performed, which demonstrated a huge heterogeneous retroperitoneal mass close to the dorsal wall of the stomach and surrounding the abdominal aortic and celiac trunk. The resected specimen suggested that an irregular tumor invaded the dorsal wall of the stomach. Postoperative histological examination confirmed that it was a gastric squamous cell carcinoma.

Currently, serum biomarkers might usually be thought not to be used for early detection of lung cancer by some researchers. In this study, we used a highly optimized ClinProt-matrix-assisted laser desorption/ionization time-of flight mass spectrometer (MALDI-TOF-MS) to screen non-small cell lung carcinoma (NSCLC) markers in serum. A training set of spectra derived from 45 NSCLC patients, 24 patients with benign lung diseases (BLDs) and 21 healthy individuals, was used to develop a proteomic pattern that discriminated cancer from non-cancer effectively. A test set, including 74 cases (29 NSCLC patients and 45 controls), was used to validate this pattern. After cross-validation, the classifier showed sensitivity and specificity, 86.20% and 80.00%, respectively. Remarkably, 100% of early stage serum samples could be correctly classified as lung cancer. Furthermore, the differential peptides of 1865Da and 4209Da were identified as element of component 3 and eukaryotic peptide chain release factor GTP-binding subunit ERF, respectively. The patterns we described and peptides we identified may have clinical utility as surrogate markers for detection and classification of NSCLC.

Human papillomavirus (HPV) is closely related with many kinds of cancers such as cervical, lung, and skin cancers, etc. HPV 16 showed intratypic variations that were known to differ in oncogenic potential and geographic distribution. This study was designed to analyze sequence variants in oncogenes E6, E7 and L1 of HPV 16 in cervical, lung, and skin cancers in Sichuan, China. Materials from 138 non-malignant controls, 122 cervical cancer patients, 104 lung cancer patients and 104 skin cancer patients were analyzed by PCR and direct sequencing. The infection rates of HPV 16 in cervical, lung, skin cancers were respectively 68.9%, 17.3%, 5.8%. The Asian prototype was the most prevalent variant in cervical cancer in Sichuan (40%). Compared with that detected in cervical cancer, lung and skin cancers showed more monotonous variations, but several mutations on L1 genes existed only in lung or skin cancers such as G6818C, C7011A, and C7017A. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A25.

Cryptorchidism is one of the most common congenital anomalies in newborn boys. There are various risk factors that have been verified to have relationship with cryptorchidism, including exogenous and genetic, but the pathogenesis of cryptorchidism remains unclear. PFKM gene is a critical gene encodes for a regulatory enzyme, which limits the rate in the pathway of glycolysis. In order to investigate the possible association between PFKM gene polymorphisms and cryptorchidism risk, 3 tag SNPs of PFKM gene, rs2228500 (A/G), rs4075913(A/G), and rs11168417(C/T) were selected and genotyped in a hospital-based case-control study involving 140 cryptorchidism patients and 227 healthy controls. The frequency of allele G of SNP rs2228500 is increased in cryptorchidism patients compared to that in controls (p < 0.05). Genotypic frequencies of rs2228500 are associated with the susceptibility of cryptorchidism in the codominant model (p < 0.05). And compared with G/G genotype in the dominant model, notable decreased frequencies of A carriers (A/G-A/A genotypes) were observed in cryptorchidism patients (p = 0.0069, OR = 1.80, 95% CI =1.17-2.75). This research firstly revealed that PFKM gene polymorphisms were associated with cryptorchidism in a Chinese Han population.

To explore the potential molecular mechanism of Oxoglaucine(OG) in the treatment of Breast Cancer(BC) based on network pharmacology and bioinformatics. TCMSP and SwissTargetPrediction databases search for OG Related targets, and GeneCards database finds all BC-related targets. Take the intersection of OG and BC as all potential targets that inhibit BC. All potential targets are topologically analyzed by Cytoscape 3.7.1 software, and finally the core target is obtained. The start analysisi function in the DAVID database performs bioinformatics analysis on all core targets, and further visualizes them with the help of R language tools. As a result, 104 potential targets were obtained, of which SRC, PIK3CA, EGFR, MTOR, ESR1, MAPK1, PTGS2, AR, and NOS3 were the main core targets. OG inhibits the occurrence of BC through Pathways in cancer, PI3K-Akt signaling pathway, Proteoglycans in cancer, ErbB signaling pathway, HIF-1 signaling pathway related pathways, mainly involving signal transduction, protein phosphorylation, negative regulation of apoptotic process, positive regulation of transcription from RNA polymerase II promoter, phosphatidylinositol-mediated signaling biological processes. This study initially reveals the molecular mechanism of OG inhibiting BC, which provides a reference for further research.