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Cytology-based Papanicolaou test on and primary HPV screening have been widely used in the identification of cervical cancer and precancerous lesions, which is of great significance for the prevention and treatment of cervical cancer. Patients diagnosed as ASCUS/LSIL usually need follow-up because some of them may develop into CIN2+. The consequences of women positive for HPV vary from person to person; some of them may progress into cervical dysplasia, reversible forms of precancerous lesions, and eventually invasive cervical cancer. Therefore, it is necessary to establish an effective biomarker to triage different patients according to the preliminary screening results. p16 acts as a cell cycle regulatory protein that induces cell cycle arrest, and Ki-67 is a cell proliferation marker. Under physiological conditions, they could not co-express in the same cervical epithelial cells. The co-expression of these two molecules suggests a deregulation of the cell cycle mediated by HR-HPV infection and predicts the presence of high-grade cervical epithelial lesions. There is increasing evidence that p16/Ki-67 dual-staining cytology can be used as an alternative biomarker, showing overall high sensitivity and specificity for identifying high-grade CIN and cervical cancer. In this review, we discuss the significance of p16/Ki-67 dual-staining and summarize its application in the screening and triaging of cervical cancer and precancerous lesions.

Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5-mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non-progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with

Objectives To evaluate the diagnostic values of urine liquid-based cytology (LBC), fluorescence in situ hybridization (FISH), and p16/Ki-67 dual immunostaining in the detection of upper tract urothelial carcinomas (UTUCs). Methods Sixty-one patients with UTUCs were retrospectively analyzed. All patients were diagnosed both by urine cytology and by FISH, and histologically confirmed as UTUCs. Thirty-two patients had been stained with p16/Ki-67 dual labeling. Results The sensitivities for low-grade UTUCs (LGUTUCs) and high-grade UTUCs (HGUTUCs) were 33.3% and 67.4% by LBC, 60% and 69.6% by FISH, and 12.5% and 66.7% by p16/Ki-67 dual labeling, respectively. Conclusions Our results indicated that LBC was more suitable to identify HGUTUCs, FISH was highly valuable for predicting LGUTUCs, and p16/Ki-67 dual labeling was useful for distinguishing HGUTUCs from LGUTUCs. The combined application of these methods may improve the sensitivity or accuracy in the detection or diagnosis of UTUCs.

Background Circulating tumor cells (CTC) shows great prospect to realize precision medicine in cancer patients. Methods We developed the NanoVelcro Chip integrating three functional mechanisms. NanoVelcro CTC capture efficiency was tested in stage III or IV lung adenocarcinoma. Further, ALK-rearrangement status was examined through fluorescent in situ hybridization in CTCs enriched by NanoVelcro. Results NanoVelcro system showed higher CTC-capture efficiency than CellSearch in stage III or IV lung adenocarcinoma. CTC counts obtained by both methods were positively correlated (r = 0.45, p

Introduction Cervical cancer rates in China remain high, with only limited opportunistic screening in urban centers and large mostly unscreened rural areas. Cervical cytology practices in China have been changing over the last decade with introduction of The Bethesda System reporting terminology, liquid-based cytology (LBC), and programs for cervical cytology screening of underserved rural populations. An effort was undertaken for the first time to collect nationwide data on cervical cytology laboratory practices in China, a possible first step toward increased standardization and potential development of nationwide cytology quality benchmarks. Materials and methods Data on cervical cytology practices from 1572 laboratories operating in 26 nationwide Provisional Level Administrative Divisions was collected in an online survey approved through the Obstetrics and Gynecology Hospital of Fudan University in Shanghai. Results Over 90% of cervical cytology laboratories in China now solely use Bethesda System reporting terminology. LBC is now the most commonly utilized form of cervical cytology, with lower-cost Chinese-manufactured LBC formulations used in almost 70% of laboratories. Nationwide, significantly higher abnormal cytology rates were reported with LBC than with the conventional Papanicolaou smear (CPS); however, the CPS remains a useful low-cost alternative as China strives to extend cervical screening to large underserved rural areas. Conclusions Abnormal cytology rates were not significantly different when different levels of hospitals were compared. The survey identified nationwide opportunities for cytology quality improvement, including low rates of reporting of unsatisfactory cases and low rates for atypical glandular cells.

Estrogen signaling influences the development and progression of ovarian tumors, but the underlying mechanisms are not well understood. In a previous study we demonstrated that impairment of estrogen receptor alpha (ERα)-mediated olfactomedin 4 (OLFM4) expression promotes the malignant progression of endometrioid adenocarcinoma, and we identified OLFM4 as a potential target of miR-486-5p. In this study we investigated the role of OLFM4 in ovarian serous adenocarcinoma. Ovarian serous adenocarcinoma tissues had reduced OLFM4 expression. Expression of OLFM4 was positively correlated with ERα expression, and estrogen (E2) treatment in ovarian cancer cells induced OLFM4 expression in an ERα-dependent manner. In contrast to ERα, miR-486-5p levels were inversely correlated with OLFM4 expression in ovarian serous adenocarcinoma. Ovarian cancer cells transfected with miR-486-5p mimics showed decreased OLFM4 mRNA expression, and ovarian cancer cells treated with E2 showed reduced cellular miR-486-5p levels. OLFM4 knockdown enhanced proliferation, migration, and invasion by ovarian cancer cells. Low expression of OLFM4 was also associated with high tumor FIGO stage and poor tumor differentiation. These results suggest OLFM4 is downregulated by miR-486-5p, which contributes to ovarian cancer tumorigenesis. Conversely, estrogen receptor signaling downregulates miR-486-5p and upregulates OLFM4 expression, slowing the development and progression of ovarian cancer.

// Minzhi Hou 1, 3, * , Zhiqiang Cheng 2, * , Hongwei Shen 3, * , Shanyang He 3 , Yang Li 1 , Yunping Pan 4 , Chongjin Feng 4 , Xinlin Chen 5 , Yang Zhang 6 , Millicent Lin 7 , Liantang Wang 1 , Zunfu Ke 1 1 Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Province Guangdong, P.R. China 2 Department of Pathology, ShenZhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong, P.R. China 3 Department of Gynecology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Province Guangdong, P.R. China 4 Department of Stomatology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Province Guangdong, P.R. China 5 Department of Preventive Medicine and Biostatistics, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China 6 Biomedical Engineering, University of Texas at El Paso, El Paso, Texas, USA 7 Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging (CIMI), California NanoSystems Institute (CNSI), University of California, Los Angeles, California, USA * These authors have contributed equally to this work Correspondence to: Zunfu Ke, e-mail: kezunfu@126.com Keywords: CTHRC1, epithelial-mesenchymal transition, epithelial ovarian cancer, β-catenin Received: May 04, 2015 Accepted: September 21, 2015 Published: October 03, 2015 ABSTRACT Collagen triple helix repeat-containing 1 (CTHRC1) is aberrantly overexpressed in multiple malignant tumors. However, the expression characteristics and function of CTHRC1 in epithelial ovarian cancer (EOC) remain unclear. We found that CTHRC1 expression was up-regulated in the paraffin-embedded EOC tissues compared to borderline or benign tumor tissues. CTHRC1 expression was positively correlated with tumor size ( p = 0.008), menopause ( p = 0.037), clinical stage ( p = 0.002) and lymph node metastasis ( p < 0.001) and was also an important prognostic factor for the overall survival of EOC patients, as revealed by Kaplan-Meier analysis. CTHRC1 increased the invasive capabilities of EOC cells in vitro by activating the Wnt/β-catenin signaling pathway. We showed that ectopic transfection of CTHRC1 in EOC cells up-regulated the expression of EMT markers such as N-cadherin and vimentin, and EMT-associated transcriptional factor Snail. Knockdown of CTHRC1 expression in EOC cells resulted in down-regulation of N-cadherin, vimentin, Snail and translocation of β-catenin. Collectively, CTHRC1 may promote EOC metastasis through the induction of EMT process and serve as a potential biomarker for prognosis as well as a target for therapy.

Purpose: Examining the role of developmental signaling pathways in “driver gene–negative” lung adenocarcinoma (patients with lung adenocarcinoma negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as “driver gene–negative”) may shed light on the clinical research and treatment for this lung adenocarcinoma subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of “driver gene–negative” lung adenocarcinoma. Experimental Design: In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired lung adenocarcinoma and adjacent normal tissues. In the training phase, tissue microarrays and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature. Results: Kyoto Encyclopedia of Genes and Genomes pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “driver gene–negative” lung adenocarcinoma. Furthermore, the Wnt/β-catenin pathway–based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/β-catenin pathway–based CSDW signature comprising 4 genes (CTNNB1 or β-catenin, SOX9, DVL3, and Wnt2b) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival [HR, 10.42; 6.46–16.79; P < 0.001) than patients with low-risk scores. Conclusions: The CSDW signature is a reliable prognostic tool and may represent genes that are potential drug targets for “driver gene–negative” lung adenocarcinoma.

The present study aimed to investigate the significance of detecting cyclin dependent kinase inhibitor 2A (p16) gene aberrations in the diagnosis of urothelial carcinoma (UC) using fluorescence in situ hybridization (FISH). A total of 77 voided urine specimens from 65 patients with UC and 12 patients with benign urinary disease were recruited into the current study. Under a fluorescence microscope, cells with large and irregular nuclei were assessed for chromosomal aberrations. The positive rate of p16 amplification in UC samples was 32.3% (21/65), which was significantly higher than that in benign urinary disease samples (16.7%, 2/12; P

// Zunfu Ke 1, * , Weiling He 2, * , Yuanhui Lai 3, * , Xuefeng Guo 4 , Sharon Chen 5 , Shuhua Li 1 , Yuefeng Wang 1 , Liantang Wang 1 1 Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Province Guangdong, P.R. China 2 Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Province Guangdong, P.R. China 3 Vascular and Thyroid Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Province Guangdong, P.R. China 4 Department of Gastrointestinal Surgery, the Sixth Affliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 5 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, 570 Westwood Plaza, Los Angeles, CA USA * These authors contributed equally to this work. Correspondence to: Dr. Zunfu ke, e-mail: kezunfu@mail.sysu.edu.cn Dr. Liantang Wang, e-mail: wanglt@mail.sysu.edu.cn Keywords: CTHRC1 non-small cell lung cancer β-catenin metastasis prognosis Received: August 04, 2014 Accepted: August 28, 2014 Published: September 24, 2014 ABSTRACT Collagen triple helix repeat-containing 1 (CTHRC1), a novel oncogene, was identified to be aberrantly overexpressed in several malignant tumors. However, the expression profile of CTHRC1 and its clinical significance in non-small cell lung cancer (NSCLC) remain unknown. In this study, we showed that CTHRC1 was evidently overexpressed in human NSCLC tissues and NSCLC cell lines at the protein and mRNA level. Ectopic up-regulation of CTHRC1 in cancer cells resulted in elevated invasive and proliferative abilities, which were attenuated by the specific CTHRC1 siRNA. The biological effect of CTHRC1 on metastasis and proliferation was mediated by the activation of the Wnt/β-catenin pathway. Furthermore, CTHRC1 immunoreactivity was evidently overexpressed in paraffin-embedded NSCLC tissues (212/292, 72.60%) in comparison to corresponding adjacent non-cancerous tissues (6/66, 9.09%) ( p

Aberrant expression of high mobility group box 1 (HMGB1) is associated with tumor development and progression. The current study was conducted to evaluate the significance of HMGB1 immunostaining on cell block (CB) preparations in the diagnosis of neoplastic and preneoplastic lesions of the cervix. The CBs were prepared from 157 residual liquid-based gynecologic cytology specimens which were collected from women whose cervical lesions had been confirmed by histopathology. The expression of HMGB1 and p16INK4A (p16) was visualized by immunocytochemistry on the CB preparations, and the association of their expression patterns was correlated with the severity of cervical lesions. HeLa cells were used as positive control. HMGB1 expression was observed in dysplastic and neoplastic cells and increased along with the progression of cervical neoplasia. The rates of positive staining for HMGB1 in cervical intraepithelial neoplasia 1 (CIN-1), CIN-2, CIN-3, and invasive squamous cell carcinomas (ISCCs) were 69.4, 96.9, 100.0, and 100.0%, respectively. The differences between positive rates of patients with chronic cervicitis and various CINs as well as ISCCs were significant (P

Objective. To evaluate the characteristics and antiangiogenic effects of endostatin-loaded PAMAM on endometriosis in a noninvasive animal model.Materials and Methods. A noninvasive animal model was established by injecting adenovirus-GFP transfected endometrial stromal and glandular epithelial cells subcutaneously into nude mice. Endostatin-loaded PAMAM was prepared and identified by transmission electron microscopy. Forin vitrostudies, the DNA protection and cytotoxicity of PAMAM were investigated and compared with Lipofectamine 2000. Forin vivostudy, endostatin-loaded PAMAM was injected into the noninvasive model and evaluated by continuously observing the fluorescent lesion, lesion weight, microvessel density and VEGF immunostaining.Results. Compared with Lipofectamine 2000, PAMAM and HC PAMAM-ES group, MC PAMAM-ES group and LC PAMAM-ES group demonstrated a better stromal cells protective such that MC PAMAM-ES group of CCK8 was 0.617 ± 0.122 at 24 hr and 0.668 ± 0.143 at 48 hr and LC PAMAM-ES group of CCK8 was 0.499 ± 0.103 at 24 hr and 0.610 ± 0.080 at 48 hr in stromal cells (P<0.05) but similar cytotoxicity in glandular epithelial cellsin vitro. After 16 hrs of digestion, DNA decreased slightly under the protection of PAMAM. Endostatin-loaded PAMAM of HD PAMAM-ES group and LD PAMAM-ES group inhibited the growth of the endometriotic lesionin vivoat days 15, 20, 25 and 30 detected by noninvasive observation after injecting one dose endostatin of various medicines into the endometrial lesion in each mouse on day 10 (P<0.05) and confirmed by lesion weight at day 30 with HD PAMAM-ES group being 0.0104 ± 0.0077 g and LD PAMAM-ES group being 0.0140 ± 0.0097 g (P<0.05). Immunohistochemistry results showed that endostatin-loaded PAMAM reduced the microvessel density 3.8 ± 2.4 especially in HD PAMAM-ES group in the lesion (P<0.05).Conclusion. Endostatin-loaded PAMAM inhibits the development of endometriosis through an antiangiogenic mechanism and can be observed through the noninvasive endometriosis model.

Purpose: We used a superficial parotid lobe–sparing delineation approach for dose optimization with better protection for the parotid glands in intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) patients. Methods: Compared with traditional contouring of the entire parotid glands as organs at risk (OARS) in IMRT for NPC, we used a superficial parotid lobe–sparing delineation approach of contouring the superficial parotid lobes as OARS. Changes in dose to the parotid glands, the targets, and other OARS were evaluated. Results: The mean dose to the parotid glands overall decreased by more than 4 Gy in the test plans. Impressively, the mean dose to the superficial parotid lobes in the test plans was not more than 30 Gy, regardless of clinical stage. In T1–3 NPC patients, the dose distributions for targets were not significantly different in the control plans and the test plans. However, for some T4 patients, the dose distributions for targets and brainstem in the test plans could not meet clinical requirements. Conclusions: The superficial parotid lobe–sparing delineation approach can significantly lower the mean dose to the entire parotid and to the superficial parotid lobe in T1–3 NPC patients, which would be expected to result in less xerostomia and better quality of life for those patients.

Tumor endothelial marker 8 (TEM8) was recently suggested as a putative anti-tumor target in several types of human cancer based on its selective overexpression in tumor versus normal endothelial cells. The objective of this study was to detect the potential functions of TEM8 in osteosarcoma. Overall, TEM8 was mainly located in cytoplasm and was up-regulated in osteosarcoma compared to benign bone lesions and adjacent non tumor tissue (ANT). High TEM8 expression group had a significant lower overall survival rate than that in the low TEM8 expression group. TEM8 knock-down by siRNA or shRNA results in significant reduction of osteosarcoma cell growth and proliferation both in vitro and in vivo. Ablation of TEM8 led to increasing of p21 and p27 and suppression of cyclin D1 mediated by Erk1/2 activity. These findings suggest that down-regulation of TEM8 play an important role in the inhibition of tumorigenesis and development of osteosarcoma.

Expression of astrocyte-elevated gene-1, a novel oncoprotein, is elevated in multiple cancers and plays a vital role in tumor cell growth, invasion, angiogenesis, and progression to metastasis. However, the functional significance of astrocyte-elevated gene-1 in non-small cell lung cancer still remains unclear. Our present study showed that the markedly up-regulated expression of astrocyte-elevated gene-1 was observed in non-small cell lung cancer cell lines and tissues at the level of both transcription and translation. Simultaneously, ectopic expression or small interfering RNA silencing of astrocyte-elevated gene-1 markedly enhanced or inhibited the invasive ability of non-small cell lung cancer cells, respectively. At the molecular level, we also revealed that the function of astrocyte-elevated gene-1 in promoting metastasis was associated with the activation of matrix metalloproteinase-9 expression. Consistent with these observations, immunostaining analysis revealed a significant positive correlation between astrocyte-elevated gene-1 and matrix metalloproteinase-9. Moreover, subcutaneous xenografts of non-small cell lung cancer cells engineered to express astrocyte-elevated gene-1 were highly invasive compared with the parental cells and expressed a high level of matrix metalloproteinase-9. In archival non-small cell lung cancer specimens, high astrocyte-elevated gene-1 expression correlated significantly with clinical staging (P = .048), differentiation (P = .023), and lymph node metastasis (P = .032). The overall survival time in patients with high astrocyte-elevated gene-1 expression was notably shorter than that in patients with low astrocyte-elevated gene-1 expression (P < .001). Taken together, our results indicate that astrocyte-elevated gene-1 plays a crucial role in the carcinogenesis and aggressiveness of non-small cell lung cancer, promoting its metastasis by modulating matrix metalloproteinase-9 expression and leading to a poor clinical prognosis.

Previous studies have demonstrated that the expression of prostate-specific membrane antigen (PSMA) is restricted to endothelium from tumor-associated neovasculature. But the expression of PSMA in osteosarcoma and its clinical significance are unknown. Using immunohistochemical analysis and quantum dot probes, we found that 46.7% (21/45) of the osteosarcoma showed positive staining for PSMA while no PSMA staining in osteofibrous dysplasia. The expression and localization of PSMA was confirmed by CD34 staining. More importantly, the expression of PSMA is correlated with tumor size, pulmonary metastasis and worse survival (survival rate 63.2% in the PSMA-negative group versus 36.6% in the PSMA-positive group). Thus, PSMA could be used as an independent prognostic marker for the osteosarcoma patients, and PSMA staining in tumor-associated neovasculature may be a potential target for antineovasculature-based therapy in osteosarcoma.

Endophthalmitis after cataract surgery is an uncommon but devastating complication. Prophylactic intracameral injection of cefuroxime 1 mg at the end of surgery decreases the incidence five-fold. The visual outcome can be good (53% of cases having a visual acuity [VA] of better than 20/40) if treatment is initiated rapidly and follows the Endophthalmitis Vitrectomy Study (EVS) guidelines; but even with the best treatment, some patients end up with a poor visual outcome. Previous studies on postoperative endophthalmitis mainly focus on the cases performed in metropolitan tertiary hospitals; however, little information is available on the cases performed in local hospitals in rural areas.We retrospectively reviewed the medical records of patients with acute endophthalmitis following cataract surgery, which were performed in local hospitals and later treated at the Zhongshan Ophthalmic Center between 1 January 1998 and 31 December 2009. Details of each case, including the interval from symptoms to presentation, initial treatment in local hospitals, microorganisms isolated, treatment, and visual outcome, were recorded. Cross-tabulations were conducted in order to identify the prognostic factors of final visual outcome.Forty-six patients referred from 36 local hospitals and later treated at the Zhongshan Ophthalmic Center were reviewed over the audit period. Most of these cases occurred in April. Gram-positive bacteria were the predominant etiology, with fungal infection accounting for 15%. Even though 54% of patients had symptoms within 3 days post-cataract surgery, they did not present to a tertiary center until a mean of 10 days. The main initial treatment in local hospitals is systemic antibiotics, instead of the intravitreal injection of antibiotics. A high proportion of cases (27/46) received immediate pars plana vitrectomy (PPV) in the tertiary center, and the antibiotic used for intravitreal injection was mainly tobramycin. The final visual outcome was poor, with only three cases having a VA ≥20/40.A relatively high rate of fungal endophthalmitis suggests that sterilization patterns in local hospitals should be further revised. A delayed presentation, inappropriate treatment procedures, poor presenting VA, and causative organism virulence may account for the unfavorable visual outcome in this study.

Wang Z, Yang S, Shi H, Du H, Xue L, Wang L, Dong Y & Han A (2011) Histopathology 58, 1013–1018 Histopathological and immunophenotypic features of testicular tumour of the adrenogenital syndrome Aims: Testicular tumour of the adrenogenital syndrome (TTAGS) is a rare neoplasm histologically resembling Leydig cell tumour (LCT). We report six cases of TTAGS and analyse histopathological and immunophenotypical features that distinguish TTAGS from LCT. Methods and results: Six cases of congenital adrenal hyperplasia with bilateral TTAGS were examined histologically and immunohistochemically and compared to seven cases of testicular LCT. TTAGS was characterized histologically by sheets of polygonal cells separated by dense fibrous tissue with focal lymphocyte infiltration. All cases of TTAGS lacked cytological atypia except for one, which displayed scattered large pleomorphic, nuclei with one or two prominent nucleoli and sporadic mitotic figures. Immunohistochemically, all cases of TTAGS showed diffuse and strong positivity for CD56 and negative reactivity for androgen receptor. Reactivity for synaptophysin varied from focal (five cases) or diffuse (one case). In contrast, LCT displayed focal weak to moderate or negative reactivity for CD56 and focal weak or negative reactivity for synaptophysin, but positive reactivity for androgen receptor in six of seven cases. Conclusions: In addition to clinical information, biochemical profile and histopathological findings, our results suggest that immunohistochemistry using a panel of antibodies including CD56, synaptophysin and androgen receptor is helpful in differentiating TTAGS from LCT.

Nephrosialidosis is a rare subgroup of sialidosis characterized by a progressive and fatal course of nephropathy. The authors report a 2-year-old boy who had suffered from steroid-resistant nephrotic syndrome. Renal biopsy showed diffuse and severe vacuolization of glomerular and tubular epithelial cells. The vacuoles were ultrastructurally membrane bound, most of which were not empty but contained electron-dense material lining the inner surface of the membrane. The pathologic changes were consistent with neuraminidase-deficient disorders, which was later confirmed by biochemical analysis. Although rare, nephrosialidosis should be considered in children with steroid-resistant nephrotic syndrome if renal biopsies exhibit severe vacuolar degeneration of renal epithelial cells.

Interleukin (IL)-27 is an IL-12-related cytokine that can promote both anti- and pro-inflammatory immune responses. This study investigated the potential role of IL-27 in autoimmune diabetes. We detected a high level of IL-27 in diabetic NOD mice. In addition, blockade of IL-27 significantly delayed the onset of diabetic splenocyte-transferred diabetes, while IL-27-treated diabetic splenocytes promoted the onset of the disease, compared with untreated controls. Furthermore, IL-27 up-regulated pro-inflammatory cytokines IFN-gamma and IL-17 and down-regulated anti-inflammatory cytokines IL-4, TGF-beta, and IL-10 secreted by diabetic splenocytes. These results demonstrate a pathogenic role of IL-27 in T cell-mediated autoimmune diabetes.

Deleted in pancreatic carcinoma locus 4 influences tumorigenesis and tumor progression by various mechanisms, including apoptosis. The aim of this study is to determine whether deleted in pancreatic carcinoma locus 4 participates in apoptosis in lung cancer and clarify its relationship with clinical parameters of non-small cell lung cancer. Immunohistochemical results revealed that the positive rate of deleted in pancreatic carcinoma locus 4 in normal tracheal-bronchial epithelium (89.5%, 17/19) was much higher than that in tumor tissues (63.5%, 33/52) (P < .05) and closely correlated with lymph node metastasis (P < .001). These results were further confirmed by Western blot analysis. Furthermore, deleted in pancreatic carcinoma locus 4 overexpression was inversely associated with Bcl-2 immunostaining (P < .01), and the apoptosis index in deleted in pancreatic carcinoma locus 4-positive carcinomas (8.65 +/- 1.46) was much higher than that in deleted in pancreatic carcinoma locus 4-negative carcinomas (2.12 +/- 0.04) (P < .05). The results of deleted in pancreatic carcinoma locus 4 small interfering RNA in A549 cells also showed that deleted in pancreatic carcinoma locus 4 could inhibit cell proliferation, decrease Bcl-2 mRNA and protein expression, and increase Bax messenger RNA and protein expression. These findings indicated that Deleted in pancreatic carcinoma locus 4 might be an important biomarker for malignant transformation and be involved in inducing apoptosis by modulating Bcl-2/Bax balance.

Patients with coronary artery disease (CAD) have impaired endothelial function. Arterial elasticity is modulated by endothelial function. The association between arterial elasticity and endothelial function has not been reported in patients with CAD. The present study was designed to investigate whether endothelial dysfunction contributes to impaired arterial elasticity. Thirty patients with CAD and 30 control subjects were recruited. Large and small artery elasticity indices were non-invasively assessed using pulse wave analysis. Brachial artery endothelium-dependent and -independent function were assessed by vascular response to flow-mediated vasodilation (FMD) and sublingual nitroglyceride (NTG), respectively. C1 large artery elasticity index was not different in the CAD group compared with the control group. However, C2 small artery elasticity index was significantly reduced in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) was also impaired in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) in the brachial artery correlated with C2 small arterial elasticity index. But NTG-mediated brachial artery vasodilation was similar between the two groups. The present findings suggest that the patients with CAD have reduced C2 small arterial elasticity index and impaired FMD. Endothelial dysfunction is involved in diminished arterial elasticity, suggesting that C2 small arterial elasticity index is a novel surrogate measure for the clinical evaluation of endothelial function.

Improvement in the current understanding of the molecular basis of lung cancer at multiple levels, including the genetic, epigenetic and protein levels, has the potential to impact the diagnosis, prognosis and treatment of lung cancer. The mutation status of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is known to be a predictor of the response to gefitinib in lung cancer. Furthermore, mutations in the EGFR and KRAS genes appear to be mutually exclusive. The present study reports a rare case of a patient harboring two EGFR mutations (L858R and T790M) and a KRAS mutation (G12V). The development of gefitinib resistance was detected in the subsequent treatment. The present study indicates that EGFR and KRAS mutational analysis should be recommended for all patients with non-small-cell lung carcinoma.

ABSTRACT Aims: To investigate the alterations in miRNA expression during the progression of dysplasia in cervical epithelium. Methods: A global miRNA expression profile of normal cervical squamous epithelium (Normal), cervical intraepithelial neoplasia (CIN) 3 and invasive squamous cell carcinoma (ISCC) was produced using the seventh generation of the miRCURY™ LNA microRNA Array (Exiqon, Vedbaek, Denmark). The reliability of miRNA arrays was verified by reverse transcription PCR. Results: Normal, CIN 3 and ISCC showed distinct miRNA expression profiles. The differentially expressed miRNAs in ISCC versus CIN 3 clearly differed from that in CIN 3 versus Normal. Compared with ISCC versus Normal, more identical miRNAs were found in ISCC versus CIN 3 than in CIN 3 versus Normal. Conclusion: A particular set of miRNAs was associated with the progression of normal cervical epithelium to CIN 3 and CIN 3 to ISCC. The miRNA profile changed more noticeably in the progression of CIN to ISCC than normal cervical epithelium to CIN.

Endometrial adenocarcinoma is the most common tumour of the female genital tract in developed countries, and oestrogen receptor (ER) signalling plays a pivotal role in its pathogenesis. When we used bioinformatics tools to search for the genes contributing to gynecological cancers, the expression of Olfactomedin 4 (OLFM4) was found by digital differential display to be associated with differentiation of endometrial adenocarcinoma. Aberrant expression of OLFM4 has been primarily reported in tumours of the digestive system. The mechanism of OLFM4 in tumuorigenesis is elusive. We investigated OLFM4 expression in endometrium, analysed the association of OLFM4 with ER signalling in endometrial adenocarcinoma, and examined the roles of OLFM4 in endometrial adenocarcinoma. Expression of OLFM4 was increased during endometrial carcinogenesis, linked to the differentiation of endometrioid adenocarcinoma, and positively related to the expression of oestrogen receptor-α (ERα) and progesterone receptor. Moreover, ERα-mediated signalling regulated expression of OLFM4, and knockdown of OLFM4 enhanced proliferation, migration and invasion of endometrial carcinoma cells. Down-regulation of OLFM4 was associated with decreased cumulative survival rate of patients with endometrioid adenocarcinoma. Our data suggested that impairment of ERα signal-mediated OLFM4 expression promoted the malignant progression of endometrioid adenocarcinoma, which may have significance for the therapy of this carcinoma.

Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor; however, the key strategy necessary for LVH regression in hypertensive patients is not clear. A meta-analysis was conducted to study the effect of blood pressure reduction on LVH regression. We explored the relationship between different degrees of systolic blood pressure (SBP)/diastolic blood pressure (DBP) reduction and LVH regression. A total of 17 randomized controlled trials comprising 2196 hypertensive patients (mean age, 56.3 years; 64.1% were men) were identified. Different degrees of SBP and DBP reductions were significantly associated with LVH regression: SBP reduction ≥20 mm Hg (SBPM20) (weighted mean difference (WMD): 14.35 g m(-2); 95% confidence interval (CI): 10.44, 18.26; P0.0001); SBP reduction20 mm Hg (SBPL20 group) (WMD: 14.82 g m(-2); 95% CI: 9.83, 19.8(2); P0.0001); DBP reduction ≥10 mm Hg (DBPM10 group) (WMD: 15.17 g m(-2); 95% CI: 11.86, 18.48; P0.0001); and DBP reduction10 mm Hg (DBPL10 group) (WMD: 11.76 g m(-2); 95% CI: 3.75, 19.76; P=0.004). Significant regression of LVH was found in the DBPM10 group compared with the SBPM20, SBPL20 and DBPL10 groups (P0.0001). The most significant decrease in LVH was seen in patients with a mean age over 60 years in the DBPM10 group. Moreover, the renin-angiotensin system inhibitor was found to be the most effective antihypertensive drug for LVH regression. This meta-analysis result indicates that proper DBP reduction plays an important role in the regression of echocardiographic LVH in hypertensive patients.

Recent studies have emphasized causative links between aberrant microRNA expression patterns and cancer progression. miR-183 is dysregulated in certain types of human cancers. The expression pattern, clinical significance, and biological role of miR-183 in osteosarcoma, however, remain largely undefined. In this paired analysis, we found that miR-183 was markedly down-regulated in osteosarcoma cells and tissues compared with matching normal bone tissues using RT-qPCR. Statistical analyses revealed that the expression levels of miR-183 significantly correlated with lung metastasis as well as with local recurrence of osteosarcoma. miR-183 expression was inversely correlated with Ezrin mRNA and protein expression levels in osteosarcoma cells as well as in a subset of primary osteosarcoma. Ectopically expressed miR-183 inhibited migratory and invasive abilities of osteosarcoma cells, whereas knockdown of endogenous miR-183 significantly enhanced these abilities. Using a luciferase reporter carrying the 3'-untranslated region (3'-UTR) of Ezrin, we identified Ezrin as a direct target of miR-183. Moreover, ectopic expression of Ezrin could significantly rescue miR-183-suppressed migration and invasion. Of interest, suppression of Ezrin by miR-183 caused a reduction of phosphorylated p44/42 (p-p44/42). Finally, suppression of Ezrin by RNAi mimicked miR-183 action in the suppression of migration and invasion, which was associated with down-regulation of p-p44/42. Taken together, these results suggest that as a tumor suppressor miRNA, miR-183 plays an important role in the aggressiveness of osteosarcoma.

Notch signaling is often involved in early development which helps to determine the differentiation state and fate of stem cells destined to form different tissues in the body. Its role in the differentiation of BM-MSCs (bone marrow-derived mesenchymal stem cells) is much less clear. As there is great interest in the potential of BM-MSCs as a source of cells for treating liver damage, it is important to understand if Notch signaling promotes or suppresses BM-MSCs differentiation into hepatocytes. In the present study, RT-PCR, Western blot results and morphologic changes demonstrated that BM-MSCs could successfully differentiate into hepatocytes in our special induction system including the tissue extract of damaged liver. On the 21st day when the differentiation direction was determined in BM-MSCs, the mRNA level of Jagged2, Delta1, Delta3, Notch1, Notch2, Notch3 and Presenilin1, was significantly lower than that on days 0, 7, and 11. In the further experiments, down-regulation of Notch signaling was shown to be critical for BM-MSCs to differentiate into hepatocytes, as increased Jagged1 resulted in up-regulated Notch activation leading to higher levels of expression of Hes1 and Hey1, which completely blocked Albumin expresion in BM-MSCs. These results in our study showed that Notch signaling in BM-MSCs was necessary to initiate differentiation into hepatocytes, but must be down-regulated for the differentiation to proceed continuously.

Astrocyte elevated gene-1 (AEG-1) is overexpressed in several cancers and plays an important role in cancer progression. However, AEG-1 expression, biological function, and clinical significance in osteosarcoma have not been uncovered. Utilizing manipulated human osteosarcoma cell lines and osteosarcoma tissues, we found that increasing expression of AEG-1 enhanced osteosarcoma cell proliferation and invasion in vitro, and knockdown of AEG-1 significantly attenuated osteosarcoma cell malignancy. Moreover, AEG-1 was overexpressed in osteosarcoma tissues, and overexpression of AEG-1 was strongly associated with gender (p = 0.018), clinical stages (p < 0.001), classification (p < 0.001), metastasis (p = 0.013), differentiation (p < 0.001), and poor survival (p = 0.021). Mechanistic studies conducted in vitro and in vivo revealed that AEG-1-mediated carcinogenesis and invasiveness might be through upregulating MMP-2. Taken together, our data strongly suggest that AEG-1 plays a crucial role in osteosarcoma progression through MMP-2, and AEG-1 could be a useful biomarker for the prediction of osteosarcoma progression and prognosis.

Introduction:Olfactomedin 4 (OLFM4) is expressed in gastrointestinal cancers and related to progression and differentiation of these malignancies. However, whether OLFM4 contributes to tumorigenesis of other tissues has not been thoroughly investigated. The purpose of the study was to investigate OLFM4 expression in cervical epithelium and its association with progression of cervical neoplasia and differentiation of cervical carcinomas.Methods:Immunohistochemistry and real-time reverse transcription-polymerase chain reaction were used to evaluate the expression and distribution of OLFM4 in cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinomas (ISCCs).Results:The overall positive OLFM4 staining levels in normal cervical epithelia, CIN I, CIN II, CIN III, and ISCCs are 22.0%, 94.2%, 93.7%, 94.6%, and 96.7%, respectively. The intensity of OLFM4 staining was enhanced according to increased pathologic grade of cervical squamous intraepithelial lesion. The immunoreactivity to OLFM4 was stronger in well-differentiated ISCCs than in poorly differentiated ISCCs.Conclusions:Olfactomedin 4 expression has been associated with progression of CIN and differentiation of cervical cancer. The results provide new evidence that OLFM4 plays an important role in tumorigenesis in the female reproductive tract.

A retrospective study of all intra-ocular operations performed at Zhongshan Ophthalmic Centre, China between 1 January 2000 and 30 December 2009 was conducted to gain further knowledge about nosocomial acute-onset postoperative endophthalmitis. In total, 147,244 intra-ocular operations were performed during this period. Acute-onset postoperative endophthalmitis was diagnosed in 29 cases, giving a frequency of 0.020%. The frequency remained low and did not increase over the 10-year period. The highest rate of endophthalmitis was found following secondary intra-ocular lens implantation (0.129%). Cataract surgery had a rate of 0.01%, which is on the lower end of estimates from other large-scale studies. Gram-positive bacteria were the most commonly isolated organisms (71%), with the majority being Staphylococcus epidermidis (64%). However, no S. epidermidis was identified in the cases following cataract extraction; these patients received intracameral vancomycin at the end of the procedure. Visual outcomes of patients with postoperative endophthalmitis were generally poor. Three (10%) patients had visual acuity (VA) ≥20/40 at the final follow-up visit (all had undergone cataract surgery) and 15 (52%) patients had VA ≤20/400 at the final follow-up visit (10 had undergone pars plana vitrectomy). Factors associated with poor visual outcomes included initial VA of hand motions or worse, and positive culture results. The results of this 10-year study may serve as a source of comparison for other centres and future studies.

Clear cell chondrosarcoma, a subtype and separate entity from the traditional chondrosarcoma, is characterized by its special histologic features, site of predilection, slow growth and better prognosis. Three cases are presented with elucidation of clinicopathologic correlation and detection by the ABC immunohistochemical method using several antibodies. The observation of positive reaction to S-100 pretein (S- 100), vimentin (Vim), alpha 1-antichymotrypsin (AACT) and lysozyme (Lyso) by the tumor cells of clear cell chondrosarcoma, similar to traditional chondrosarcoma and chondroblastoma. proves that this tumor has its origin from the cartilaginous tissue. It was found for the first time that the clear cell chondrosarcoma was positive for wheat germ agglutinin (WGA) and concanavalin A (Con A). The authors believe that clear cell chondrosarcoma may result from the anaplastic changes of chondroblastoma cells into another subtype of that tumor. The osteoclast- like multinucleated giant cells (MGC), retaining the antigens of phagocytes, are not considered to be neoplastic.

Spontaneous regression of hepatocellular carcinoma (HCC) is a rare event. However, only a few of the causes of cases of HCC spontaneous regression are clear. More cases are ambiguous. We report on a patient who had a spontaneous regression of HCC as detected by histological and immunohistochemical exam, and compared this case to 20 cases of non-specific HCC. In our case, we found that the odd phenomenon is that CD163(+) macrophages are overactivated in surviving HCC, which is spontaneously regressing. Concomitantly, we cannot find a similar phenomenon in peritumoral liver tissue or non-specific HCC. According to our microscopical morphology and immunohistochemical study, we considered that a clue of a possible etiology about HCC spontaneous regression is that CD163(+) macrophages are overactivated.

Background Non-small cell lung cancer (NSCLC) is a highly metastatic cancer with limited therapeutic options, so development of novel therapies that target NSCLC is needed. During the early stage of metastasis, the cancer cells undergo an epithelial-mesenchymal transition (EMT), a phase in which Wnt/β-catenin signaling is known to be involved. Simultaneously, AEG-1 has been demonstrated to activate Wnt-mediated signaling in some malignant tumors. Methods Human NSCLC cell lines and xenograft of NSCLC cells in nude mice were used to investigate the effects of AEG-1 on EMT. EMT or Wnt/β-catenin pathway-related proteins were characterized by western blot, immunofluorescence and immunohistochemistry. Results In the present study, we demonstrated that astrocyte elevated gene-1(AEG-1) ectopic overexpression promoted EMT, which resulted from the down-regulation of E-cadherin and up-regulation of Vimentin in lung cancer cell lines and clinical lung cancer specimens. Using an orthotopic xenograft-mouse model, we also observed that AEG-1 overexpression in human carcinoma cells led to the development of multiple lymph node metastases and elevated mesenchymal markers such as Vimentin, which is a characteristic of cells in EMT. Furthermore, AEG-1 functioned as a critical protein in the regulation of EMT by directly targeting multiple positive regulators of the Wnt/β-catenin signaling cascade, including GSK-3β and CKIδ. Notably, overexpression of AEG-1 in metastatic cancer tissues was closely associated with poor survival of NSCLC patients. Conclusions These results reveal the critical role of AEG-1 in EMT and suggest that AEG-1 may be a prognostic biomarker and its targeted inhibition may be utilized as a novel therapy for NSCLC.