No abstract

Cavernous malformations (CMs) affecting the central nervous system occur in approximately 0.16% to 0.4% of the general population. The majority (85%) of the CMs are in a sporadic form, but the genetic background of sporadic CMs remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in 2 genes: MAP3K3 and PIK3CA by whole-exome sequencing (WES). The mutation spectrum correlated with lesion size (P = 0.001), anatomical distribution (P < 0.001), MRI appearance (P = 0.004) and haemorrhage events (P = 0.006). PIK3CA mutation was a significant predictor of overt haemorrhage events (P = 0.003, OR = 11.252, 95% CI = 2.275-55.648). Enrichment of endothelial cell (EC) population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of EC models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic CMs were identified by single-cell RNA-sequencing (scRNA-seq) and verified by pathological staining. Significant apoptosis in MAP3K3 mutation carriers and overexpression of GDF15 and SERPINA5 in PIK3CA mutation carriers contributed to their phenotype. We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic CMs and PIK3CA mutations could confer a higher risk for overt haemorrhage. Our data provide insights into genomic landscapes, propose a mechanistic explanation and underscore the possibility of a molecular classification for sporadic CMs.

This meta-analysis provides an updated and comprehensive estimate of the effects of obesity on metabolic disorders in adolescent polycystic ovary syndrome (PCOS). Relevant articles consistent with the search terms published up to 31 January 2014 were retrieved from PubMed, EMBASE, PsycINFO and CENTRAL. Thirteen articles (16 independent studies) conformed to the inclusion criteria. The evaluated outcomes were the metabolic parameters of obese adolescents with PCOS (case group) relative to normal-weight adolescents with PCOS, or obese adolescents without PCOS. Compared with normal-weight adolescents with PCOS, the case group had significantly lower sex hormone-binding globulin and high-density lipoprotein cholesterol, and significantly higher triglycerides, leptin, fasting insulin, low-density lipoprotein cholesterol and free testosterone levels. Relative to obese adolescents without PCOS, the case group had significantly higher fasting insulin, low-density lipoprotein cholesterol, free testosterone levels and 2-h glucose during the oral glucose tolerance test. These results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Impact statement What is already known about this subject: Obesity and PCOS share many of the same metabolic disorders, for example, hyperandrogenism and hyperinsulinemia with subsequent insulin resistance. Knowledge regarding metabolic features in obese adolescents with PCOS is limited, and there is concern whether obesity and PCOS are related. What do the results of this study add: Relative to PCOS adolescents of normal weight, obese adolescents with PCOS (the case group) had significantly lower SHBG and HDL-C, and significantly higher triglycerides, leptin, fasting insulin, LDL-C and free testosterone levels. The results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. What are the implications of these findings for clinical practice and/or further research: Obesity, metabolic disorders and PCOS in adolescents are associated. Obesity exacerbates metabolic disorders in adolescent PCOS. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Therapeutic intervention combined with lifestyle modification may provide better treatment for adolescent PCOS. The aetiologies of PCOS combined with obesity in adolescents require further investigation.

The present study explored the use of methylated NDRG4 gene as a candidate biomarker for diagnosis of colorectal cancer (CRC). Methylated NDRG4 gene expression from colorectal carcinoma tissue, paracarcinoma tissues, stools, blood and urine were detected successfully in DNA samples from 84 patients, by nested methylation-specific polymerase chain reaction and denaturing high-performance liquid chromatography. The sensitivity and specificity of methylated NDRG4 gene expression for us as a biomarker in colorectal cancer was analyzed and compared with 16 age-matched healthy controls. The positive detection rate of methylated NDRG4 was 81% in carcinoma tissue, 8.3% in paracarcinoma tissues, 54.8% in blood, 72.6% in urine and 76.2% in stools. Considering the convenience of the acquisition of urine samples, an additional group of 76 patients with CRC were recruited for verification of detecting methylated NDRG4 in the urine. The positive detection rate of methylated NDRG4 was 72.4% (55/76) in this cohort. The detection of methylated NDRG4 in stools and urine could be used as a novel diagnostic technique for highly sensitive and specific detection of CRC. Due to the ease of collecting urine samples, this novel method could be a potential biomarker for early diagnosis of CRC.

SDF-1 and CXCR4 are a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of CXCR4 is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin’s lymphoma, and generally correlates with a poor prognosis. In this study, we developed a humanized anti-CXCR4 monoclonal antibody, LY2624587 as a potent CXCR4 antagonist that was advanced into clinical study for cancer. LY2624587 blocked SDF-1 binding to CXCR4 with an IC50 of 0.26 nM, and inhibited SDF-1-induced GTP binding with a Kb of 0.66 nM. In human lymphoma U937 and leukemia CCRF-CEM cells expressing endogenous CXCR4, LY2624587 inhibited SDF-1-induced cell migration with IC50 values of 3.7 and 0.26 nM, respectively. This antibody also inhibited CXCR4 and SDF-1 mediated cell signaling including activation of MAPK and AKT in tumor cells expressing CXCR4. Bifocal microscopic and flow cytometry analyses revealed that LY2624587 mediated receptor internalization and caused CXCR4 down-regulation on the cell surface. In human hematologic cancer cells, LY2624587 caused dose dependent apoptosis in vitro and in vivo. In mouse xenograft models developed with human leukemia and lymphoma cells expressing high levels of CXCR4, LY2624587 exhibited dose-dependent tumor growth inhibition and provided significant survival benefit in a disseminated lymphoma model. Collectively, we have demonstrated that CXCR4 inhibition by LY2624587 has the potential for the treatment of human hematological malignancies.