Citations

Abstract Background: Epithelial Ovarian Cancer (EOC) is a lethal gynecologic malignancy and the fifth cause of cancer mortality in women in the US. Normal ovarian physiology is intricately connected to tightly regulated small GTP binding proteins of the Ras superfamily (Ras, Rac, Rho, Rab, Arf, and Ran) which regulate key cellular processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. These proteins function in a highly coordinated manner through signaling cascades and feedback loops within and among the small GTPase subfamilies. We hypothesized that single nucleotide polymorphisms (SNPs) in small GTPase genes are associated with epithelial ovarian cancer (EOC) risk and aberrant expression of these genes correlates with tumor characteristics including overall survival (OS). Methods: In a discovery set of 7931 EOC cases and 9206 controls we investigated 9,356 SNPs from 112 genes, 657 of which showed associations up to the significance level of p<0.05. We genotyped 407 of the most significant SNPs from 112 genes in a combined dataset (discovery and replication) which consisted of 18,736 EOC cases and 23,448 controls (of European ancestry) from 43 studies in the Ovarian Cancer Association Consortium (OCAC), using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression under log-additive models. A False Discovery Rate (FDR) q<0.2 was applied. Pearson's correlation tests were performed on the expression of genes with tumor characteristics and OS in 561 ovarian tumors: serous (n=464); endometrioid (n=52); clear cell carcinoma (n=28) and mucinous (n=17) subtypes. Results: The most significantly associated SNP associations with EOC were: AKAP6 rs1955513, (OR=0.9, p=3.3x10-4) in all invasive; ARGHEF10L rs10788679, (OR=1.05, p=2.6x10-4) in serous; RAB31 rs1166373, (OR=1.25, p=4.0x10-3) in endometrioid; KRAS rs4963872, (OR=1.35, P=4.5x10-4) in mucinous EOC and TNIK rs6780532, (OR=0.88, p=7.7x10-3) in clear cell carcinoma. Increased expression of AKAP6 and TNIK was marginally correlated with advanced EOC stage (p<0.05) while high KRAS expression was correlated with OS (HR=1.18, p=0.038). Conclusions: Genetic variation in the small GTPase genes appears to be associated with ovarian cancer risk and aberrant expression of these genes correlates with tumor characteristics and OS. Citation Format: Hui-Yi Lin, Yin Xiong, Jonathan Tyrer, Douglas C. Marchion, Alvaro NA Monteiro, Andrew Berchuck, Joellen M. Schildkraut, Ellen L. Goode, Susan J. Ramus, Simon A. Gayther, Paul DP Pharoah, Steven A. Narod, Thomas A. Sellers, Catherine M. Phelan. Investigation of small GTPase genes in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B27.

Summary Background and Purpose Sprawling ( Swl ) is a radiation‐induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1 ). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant. Methods and Results To display the phenotype of Swl mutant mice, we examined the embryos of homozygous ( Swl/Swl ) and heterozygous ( Swl /+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl /+ mice. The Swl /+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/ + DRG neurons was revealed during E11.5–E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein‐driven nerve growth factor (NGF). Mitochondria, another dynein‐driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild‐type (WT) neurons. Nevertheless, the Swl , Loa, and Cra mutations did not affect homodimerization of DYNC1H1. Conclusion The Swl/Swl mutation of Dync1h1 gene led to embryonic mal‐development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein‐driven cargos and excessive apoptosis during mid‐ to late‐developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1.

BackgroundMicrosurgical free flaps for reconstruction of soft tissue defects in lower extremity have evolved into a reliable procedure over last decades; however, there lacked high level of evidence.MethodsA systematic literature research was performed including studies between 2000 and 2014 in English, German, and Chinese (PubMed, EMBASE). Publications were selected applying inclusion/exclusion criteria. Postoperative complications were statistically analyzed with metaprop command of R GUI 3.0.1.ResultsAlltogether 30 articles overlooking 1,397 free flaps were included. The rate of total flap loss was 6.0% (95% confidence interval [CI] = 4.0%–8.0%, PQ (P values of Q statistics) = 0.03); the thrombosis rate was 6.0% (95% CI = 4.0%–9.0%, PQ = 0.01); the hematoma rate was 4.0% (95% CI = 3.0%–5.0%, PQ = 0.79); the partial necrosis rate was 6.0% (95% CI = 4.0%–10.0%, PQ < 0.01); the early infection rate was 4.0% (95% CI = 2.0%–6.0%, PQ = 0.03), and the dehiscence rate was 3.0% (95% CI = 2.0%–5.0%, PQ = 0.12). Reconstruction for diabetic foot may be not associated with a significant increase of procedural risk (Total flap loss rate = 6%, 95% CI = 3.0%–9.0%, PQ = 0.44).ConclusionsMicrosurgical reconstruction of soft tissue defects in the lower extremity reconstruction could be regarded safe and reliable. A standardization of report of perioperative parameters and clinical outcomes is needed. © 2016 Wiley Periodicals, Inc. Microsurgery 36:511–524, 2016.

Krüppel-like factor (KLF)-10 is an important transcriptional regulator of TGF-β1signaling in both CD8+and CD4+T lymphocytes. In the present study, we demonstrate a novel role for KLF10 in the regulation of TGFβRII expression with functional relevance in macrophage differentiation and activation. We first show that transfer of KLF10−/−bone marrow-derived macrophages into wild-type (WT) mice leads to exacerbation of experimental colitis. At the cell biological level, using two phenotypic strategies, we show that KLF10-deficient mice have an altered colonic macrophage phenotype with higher frequency of proinflammatory LyC6+MHCII+cells and a reciprocal decrease of the anti-inflammatory LyC6−MHCII+subset. Additionally, the anti-inflammatory CD11b+CX3CR1hisubset of colonic macrophages is significantly decreased in KLF10−/−compared with WT mice under inflammatory conditions. Molecularly, CD11b+colonic macrophages from KLF10−/−mice exhibit a proinflammatory cytokine profile with increased production of TNF-α and lower production of IL-10 in response to LPS stimulation. Because KLF10 is a transcription factor, we explored how this protein may regulate macrophage function. Consequently, we analyzed the expression of TGFβRII expression in colonic macrophages and found that, in the absence of KLF10, macrophages express lower levels of TGFβRII and display an attenuated Smad-2 phosphorylation following TGF-β1stimulation. We further show that KLF10 directly binds to the TGFβRII promoter in macrophages, leading to enhanced gene expression through histone H3 acetylation. Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGFβRII expression in macrophages and the acquisition of a “regulatory” phenotype that contributes to intestinal mucosal homeostasis.

Lung cancer is one of the most common types of human malignancies and the leading cause of cancer-related death. Patients with surgically resectable early stage lung cancer are more likely curable, but currently only a small population of patients can be diagnosed at such a stage, partly due to our incomplete understanding of the biology of lung cancer and the lack of diagnostic and prognostic biomarkers. Recent studies have shown that NOTCH1 is a critical regulator of human carcinogenesis and has been implicated in multiple steps of cancer development and progression. Herein, we review recent findings about the role of NOTCH1 in lung cancer and discuss its potential usefulness as both a therapeutic target and a biomarker for lung cancer.