Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer death in the US. The protein kinase D (PKD) family has emerged as a promising target for cancer therapy with PKD1 being most intensively studied; however, its role in HNSCC has not been investigated. The expression of PKD was evaluated in human HNSCC by quantitative RT-PCR, Western blot and immunohistochemistry. Cell proliferation, wound healing, and matrigel invasion assays were performed upon siRNA-mediated knockdown of PKD1 in HNSCC cells, and subcutaneous xenograft mouse model was established by implantation of the stable doxycycline (Dox)-inducible PKD1 expression cell lines for analysis of tumorigenic activity in vivo. PKD1 was frequently downregulated in HNSCC cell lines at both transcript and protein levels. In human HNSCC tissues, PKD1 was significantly down-regulated in localized tumors and metastases, and in patient-paired tumor tissues as compared to their normal counterparts, which was in part due to epigenetic modification of the PRKD1 gene. The function of PKD1 in HNSCC was analyzed using stable doxycycline-inducible cell lines that express native or constitutive-active PKD1. Upon induction, the rate of proliferation, survival, migration and invasion of HNSCC cells did not differ significantly between the control and PKD1 overexpressing cells in the basal state, and depletion of endogenous PKD1 did not impact the proliferation of HNSCC cells. However, the median growth rate of the subcutaneous HNSCC tumor xenografts over time was elevated with PKD1 induction, and the final tumor weight was significantly increased in Dox-induced vs. the non-induced tumors. Moreover, induced expression of PKD1 promoted bombesin-induced cell proliferation of HNSCC and resulted in sustained ERK1/2 activation in response to gastrin-releasing peptide or bombesin stimulation, suggesting that PKD1 potentiates GRP/bombesin-induced mitogenic response through the activation of ERK1/2 in HSNCC cells. Our study has identified PKD1 as a frequently downregulated gene in HNSCC, and functionally, under certain cellular context, may play a role in GRP/bombesin-induced oncogenesis in HNSCC.
Background: In the Carotid or Middle cerebral artery Occlusion Surgery Study (CMOSS), we found no significant difference between the bypass surgery group and the medical group with respect to the primary composite outcome of stroke or death within 30 days or any subsequent ipsilateral ischemic stroke within 2 years of follow-up. We now extend the long-term follow-ups to 10 years. Methods: We randomly assigned symptomatic patients with hemodynamically compromised internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion to extracranial-intracranial (EC-IC) bypass surgery plus medical treatment or medical treatment alone at 13 centers in China. We extended the follow-ups from the original 2 years to 10 years to assess long-term outcomes. The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days after randomization. Results: 324 patients were assigned to the surgery (n=161) or medical group (n=163); the median duration of follow-up was 7.6 years (interquartile range [IQR], 2.3 to 9.2). The primary outcome occurred in 18 of 161 patients (11.2%) in the surgical group, significantly lower than that in the medical group (32 out of 163 patients [19.6%]; relative risk [RR], 0.57; 95% confidence interval [CI], 0.33 to 0.97; P=0.04). The risk of any stroke was 16.1% in the surgical group vs 23.3% in the medical group (RR, 0.76; 95% CI, 0.52 to1.13; P=0.15); the all-cause mortality was 8.1% in the surgical group vs. 8.6% in the medical group (RR, 0.94; 95% CI, 0.46 to 1.94]; P=0.93). Conclusions: Among symptomatic ICA or MCA occlusion patients with hemodynamic insufficiency, the addition of extracranial-intracranial bypass surgery to medical treatment was safe and led to a lower risk of recurrent stroke through 7 years of follow-up than medical treatment alone. (ClinicalTrials.gov number, NCT01758614.)
Anaphase-promoting complex/cyclosome (APC/C) is a multifunctional ubiquitin-protein ligase that targets various substrates for proteolysis inside and outside of cell cycle. The activation of APC/C is depended on two WD-40 domain proteins, Cdc20 and Cdh1. While APC/Cdc20 principally regulates mitotic progression, APC/Cdh1 shows a broad spectrum of substrates in and beyond cell cycle. In past several years, numerous biochemical and mouse genetic studies have greatly attracted our attention to the emerging role of APC/Cdh1 in genomic integrity, cellular differentiation and human diseases. This review will aim to summarize the recent expended understanding of APC/Cdh1 in regulating biological function and how its dysfunction may lead to diseases.
Abstract Purpose: Stomatin-like protein 2 (SLP-2) is a novel and unusual stomatin homologue of unknown functions. It has been implicated in interaction with erythrocyte cytoskeleton and presumably other integral membrane proteins, but not directly with the membrane bilayer. We show here the involvement of SLP-2 in human esophageal squamous cell carcinoma (ESCC), lung cancer, laryngeal cancer, and endometrial adenocarcinoma and the effects of SLP-2 on ESCC cells. Experimental Design: Previous work of cDNA microarray in our laboratory revealed that SLP-2 was significantly up-regulated in ESCC. The expression of SLP-2 was further evaluated in human ESCC, lung cancer, laryngeal cancer, and endometrial adenocarcinoma by semiquantitative reverse transcription-PCR, Western blot, and immunohistochemistry. Mutation detection of SLP-2 exons was done by PCR and automated sequencing. Antisense SLP-2 eukaryotic expression plasmids were constructed and transfected into human ESCC cell line KYSE450. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, clonogenecity assay, flow cytometry assay, nude mice tumorigenetic assay, and cell attachment assay were done to investigate the roles of SLP-2 gene. Results: All tumor types we tested showed overexpression of SLP-2 compared with their normal counterparts (P ≤ 0.05). Moreover, immunohistochemistry analysis of mild dysplasia, severe dysplasia, and ESCC showed that overexpression of SLP-2 occurred in premalignant lesions. Mutation analysis indicated that no mutation was found in SLP-2 exons. KYSE450 cells transfected with antisense SLP-2 showed decreased cell growth, proliferation, tumorigenecity, and cell adhesion. Conclusions: SLP-2 was first identified as a novel cancer-related gene overexpressed in human ESCC, lung cancer, laryngeal cancer, and endometrial adenocarcinoma. Decreased cell growth, cell adhesion, and tumorigenesis in the antisense transfectants revealed that SLP-2 may be important in tumorigenesis.
We previously demonstrated the essential role of the flt-1 gene in regulating the development of the cardiovascular system. While the inactivation of the flt-1 gene leads to a very severe disorganization of the vascular system, the primary defect at the cellular level was unknown. Here we report a surprising finding that it is an increase in the number of endothelial progenitors that leads to the vascular disorganization in flt-1(-/-) mice. At the early primitive streak stage (prior to the formation of blood islands), hemangioblasts are formed much more abundantly in flt-1(-/-) embryos. This increase is primarily due to an alteration in cell fate determination among mesenchymal cells, rather than to increased proliferation, migration or reduced apoptosis of flt-1(-/-) hemangioblasts. We further show that the increased population density of hemangioblasts is responsible for the observed vascular disorganization, based on the following observations: (1) both flt-1(-/-) and flt-1(+/+) endothelial cells formed normal vascular channels in chimaeric embryos; (2) wild-type endothelial cells formed abnormal vascular channels when their population density was significantly increased; and (3) in the absence of wild-type endothelial cells, flt-1(-/-) endothelial cells alone could form normal vascular channels when sufficiently diluted in a developing embryo. These results define the primary defect in flt-1(-/-) embryos at the cellular level and demonstrate the importance of population density of progenitor cells in pattern formation.
Brugada syndrome (BrS) is an arrhythmogenic disorder which was first described in 1992. This disease is a channelopathy characterized by ST-segment elevations in the right precordial leads and is susceptible to sudden death. BrS is a fatal disease with gender and age preferences. It occurs mainly in young male subjects with a structurally normal heart and silently progresses to sudden death with no significant symptoms. The prevalence of BrS has been reported in the ranges of 5–20 per 10 000 people. The disease is more prevalent in Asia. Nowadays, numerous variations in 23 genes have been linked to BrS since the first gene SCN5A has been associated with BrS in 1998. Not only can clinical specialists apply these discoveries in risk assessment, diagnosis and personal medicine, but also forensic pathologists can make full use of these variations to conduct death cause identification. However, despite the progress in genetics, these associated genes can only account for approximately 35% of the BrS cases while the etiology of the remaining BrS cases is still unexplained. In this review, we discussed the prevalence, the genes associated with BrS and the application of molecular autopsy in forensic pathology. We also summarized the present obstacles, and provided a new insight into the genetic basis of BrS.
It has been found out that the normal growth of Coptis chinensis is heavily affected and both NRA in leaves and berberine contents in rhizome are very low when seedlings are short of nitrogen, phosphorus and potassium. The plants grow especially worse and most of them soon die off when nitrogen is short. The new leaves are smaller both in number and size when phosphorus and potassium are short. Few roots can grow up and easily get old in the solution short of potassium.
INTRODUCTION: Autologus fat grafting is becoming widely used for breast reconstruction. However, the bioactive adipose stromal cells have been shown in many in vitro and animal studies to promote cancer cell growth. We report a new animal model that accurately simulates the clinical scenario of reconstructive fat grafting. METHODS: 40 female NOD-SCID gamma mice were injected with 1K MCF7 breast cancer cells in 4 sites of mammary fat pads. After tumor engraftment in 2 weeks, injections of human lipoaspirate prepared according to Coleman’s technique (N=20) or sterile saline (N=20, control) were performed at tumor sites. In 8 weeks, animals were euthanized and necropsied, tumor volume and mass were measured, and histological samples were assessed for presence of tumors, Nottingham histological grade, Ki67 positivity and metastatic spread. RESULTS: In 8 weeks, all sites injected with breast cancer cells formed macroscopic tumors and all fat grafts were retained and colocated with breast cancer. Tumors from animals in the lipo group did not grow faster (p=0.54); and had lower volume (p=0.046) and lower mass (p=0.038) compared to saline group. Macroscopic invasion detected in necropsy was higher in saline group (p=0.003). Proliferation index assessed by Ki67 positivity was significantly lower in lipo group (p=0.01). No metastatic lesion was identified in lung, liver or spleen of any animal. CONCLUSION: Reconstructive fat grafting performed in the setting of residual breast tumor in a clinically relevant animal model does not increase tumor size, mass, proliferation or metastatic spread. This supports the oncologic safety of fat grafting for breast reconstruction after cancer therapy.
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