International Journal of Clinical and Experimental Pathology

The biology and pathomechanism of bilateral breast cancers is not fully understood. We compared the morphological and immunohistochemical characteristics of primary tumors in patients with synchronous bilateral breast cancers and metachronous bilateral breast cancers, with special focus on intrinsic tumor phenotype. Tumor morphology and expression of 8 immunohistochemical markers were assessed in tissue microarrays containing primary breast tumor cores from 113 metachronous bilateral breast cancers and 61 synchronous bilateral breast cancers. Analyzed markers included hormone receptors (estrogen receptor, progesterone receptor), HER2, Ki67, cytokeratin 5/6, E-cadherin, vimentin and epidermal growth factor receptor. Cutoff levels are provided in the table. Metachronous bilateral breast cancers tumors had lower estrogen receptor expression (p=0.047) and higher expression of cytokeratin 5/6 (p=0.017) and of vimentin (p=0.008); in multivariate analysis only vimentin retained the significance (p=0.01). Ten (13%) and 11 (26%) of metachronous bilateral breast cancers and synchronous bilateral breast cancers had luminal A phenotype, 39 (50%) and 15 (36%) were luminal B HER2-negative, 13 (17%) and 12 (28%) - luminal B HER2-positive, 3 (4%) and 2 (5%) - HER2-positive (not luminal), and 12 (16%) and 2 (5%) had triple negative phenotype (p=0.07). Metachronous bilateral breast cancers, compared to synchronous bilateral breast cancers, are characterized by more aggressive phenotype, expressed by lower expression of estrogen receptor and stronger expression of cytokeratin 5/6 and vimentin; this does not, however, translate into differences in the distribution of intrinsic tumor phenotypes.

Human papillomavirus (HPV) infection is a major risk factor for cervical cancer. However, only some high risk human papillomavirus (HR-HPV)-infected women progress to cervical cancer, host immunogenetic factors human leukocyte antigen (HLA) may account for viral antigens presenting individually or together in the progression to cervical cancer. This study examined the association between the development of invasive cervical cancer (ICC) and the determinant factors including HLA-DRB1*1501 and DQB1*0602, HR-HPV infection among Chinese Uighur and Han populations. Blood samples, cervical swabs and biopsies were obtained from 287 patients with ICC (192 Uighurs and 95 Hans) and 312 healthy controls (218 Uighurs and 94 Hans). HPV DNA was detected by PCR and HLA-DRB1*1501 and DQB1*0602 alleles were performed using PCR-SSP method. HPV16 infection rates was significantly higher among Uighur and Han with ICC as compared to healthy controls (OR = 58.317; 95% CI: 39.663-85.744; OR = 33.778; 95% CI: 12.581-90.691; P < 0.05 for all). HLA-DRB1*1501 (OR = 0.305; 95% CI: 0.115-0.813; P < 0.05) and HLA-DRB1*1501-DQB1*0602 haplotype frequencies (OR = 0.274; 95% CI: 0.086-0.874; P < 0.05) were significantly reduced in Han ICC. The HLA-DQB1*0602 frequency significantly decreased among Uighur women with ICC (OR = 0.482; 95% CI: 0.325-0.716; P < 0.05). Similar tendencies were observed for DQB1*0602 with HPV16-positive ICC (OR = 0.550; 95% CI: 0.362-0.837; P < 0.05). This study suggests that HLA-DRB1*1501 and DQB1*0602 alleles may influence the immune response to HPV16 infection and decrease the risk of ICC among Uighurs and Hans in Xinjiang, China.

We aimed to investigate the correlations between the expression of VEGF, PDGF-B, and their receptors (VEGFR2 and PDGFR-β) with pathologic stage or cell type in non-metastatic renal cell carcinoma. VEGF, VEGFR2, PDGF-B, and PDGFR-β protein expression were evaluated immunohistochemically in prospectively collected 1,423 tumour samples obtained during radical or partial nephrectomy at a tertiary referral center. Intensity of expression was quantified on a scale of 0 to 3, and was compared among renal cell carcinoma cell types. The study cohort consisted of 1,091 patients, of mean age 54 years, including 968 (88.7%) with clear cell, 82 (7.5%) with papillary, 31 (2.8%) with chromophobe, 4 (0.4%) with unclassified, and 6 (0.5%) with other types of renal cell carcinoma. VEGF expression increased with higher T and N stage and Fuhrman nuclear grade. PDGFR-β expression was highest in clear cell renal cell carcinoma, whereas VEGF and PDGF-B expression were highest in papillary renal cell carcinoma. After adjusting for T stage and Fuhrman nuclear grade using multivariate logistic regression analysis, VEGF (OR = 3.57, P < 0.001), VEGFR2 (OR = 1.82, P = 0.017), and PDGF-B (OR = 2.46, P = 0.019) expression were significantly greater in papillary than in clear cell type. Our results indicate that the cytoplasmic expression of VEGF, VEGFR2, PDGF-B, and PDGFR-β in RCC tumour cells is different in various pathologic stage and cell type. Notably, VEGF and PDGF-B expression are higher in papillary than in clear cell renal cell carcinoma. Further studies using quantitative measurement of proangiogenic factors in tumour cell are needed.

There are few comprehensive studies of small intestinal malignancies. The author retrospectively reviewed 1,312 archival pathologic specimens of the small intestine in the last 10 years in our pathologic laboratory in search for malignant tumors of the small intestine. There were 22 cases (1.7%) of primary adenocarcinoma, 3 cases (0.2%) of primary squamous cell carcinoma, 6 cases (0.5%) of metastatic carcinoma, 6 cases (0.5%) of malignant lymphoma, 3 cases (0.2%) of carcinoid tumor, and 1 case (0.08%) of gastrointestinal stromal tumor (GIST). Of the 25 cases of primary adenocarcinoma and squamous cell carcinoma, 24 cases were located in the duodenum and 1 case in the ileum. The 22 cases of adenocarcinoma were classified into 7 well differentiated, 7 moderately differentiated, and 8 poorly differentiated adenocarcinomas. All the three squamous cell carcinomas were moderately differentiated ones with keratinization and intercellular bridges. In the 25 cases of carcinoma, immunoreactive p53 protein was present in 23 cases, and the Ki-67 labeling ranged from 40% to 95% with a mean of 76%. In the 6 cases of metastatic adenocarcinoma, the origin was ovary in 1 case, pancreas in 2 cases, gall bladder in 1 case, lung in 1 case, and colon in 1 case. In the 6 cases of lymphoma, 4 cases were diffuse large B-cell lymphomas and 2 cases were peripheral T-cell lymphomas. In the 3 cases of carcinoid tumor, all were typical carcinoids and immunohistochemically positive for at least one of neuroendocrine markers (chromogranin, synaptophysin, neuron specific enolase, and CD56). In the 1 case of GIST, the cell type is spindle and GIST cells were immunohistochemically positive for KIT and CD34. The histological risk was intermediate. Forty-one cases of small intestinal malignancies were reviewed histopathologically.

The author investigated histopathology of 1,438 consecutive rectal specimens in the last 10 years of our pathology laboratory in Japan. A computer review of pathologic reports was done. Observations of pathologic slides were performed, when appropriate. The rectal specimens were composed of 1,022 benign lesions and 416 malignant lesions. The 1,022 benign lesions were composed non-specific proctitis (n=460, 45%), adenoma (n=248, 24%), ulcerative colitis (n=98, 10%), hyperplastic polyp (n=54, 5%), carcinoma in adenoma (n=40, 4%), rectal ulcer (n=37, 4%), serrated adenoma (n=24, 2%), hyperplastic nodule (n=21, 2%), Crohn's disease (n=9, 1%), ischemic proctitis (n=8, 0.8%), mucosal prolapse syndrome (n=7, 0.6%), juvenile polyp (n=6, 0.6%), lymphoid hyperplasia (n=5, 0.5%), lipoma (n=4, 0.4%) and amebic dysentery (n=2, 0.2%), and mature cystic teratoma (n=1, 0.1%). In this article, histopathological features of these benign lesions were described in details. In particular, adenomas were classified into adenomas with mild, moderate, and severe atypia, serrated adenoma, and carcinoma in adenoma. The later are mainly seen in large adenoma with severe atypia. Ulcerative colitis was characterized by continuous lesion, crypt abscess, abnormal branching, and deletion of goblet cells. Crohn's disease was characterized by transmural inflammation and epithelioid granulomas. Ischemic colitis was characterized by ischemic necrotic changes and pseudomembrane formation. Mucosal prolapse syndrome was characterized by abnormal muscle in the mucosa (fibromuscular obliterance). Juvenile polyp was characterized by abnormal dilations of the crypts. Lymphoid hyperplasia must be differentiated from MALT lymphoma. Lipoma was ordinary lipoma without lipoblasts. Amebic dysentery was characterized by ulcer and presence of histiocyte-like entamoeba histolitica. Mature cystic teratoma was characterized by hairs and other elements of skin and mesodermal and endodermal components.

The author investigated histopathology of 1,464 consecutive rectal specimens in of our pathology laboratory in Japan. A review of pathological reports was done by computer. Observation of histological slides was performed, when appropriate. The rectal specimens were composed of 1,041 benign lesions and 423 malignant lesions. The 423 malignant lesions were composed of 367 cases of primary rectal carcinoma, 41 cases of carcinoma in adenoma, 7 cases of neuroendocrine tumor, 3 cases of malignant lymphoma, 2 cases of gastrointestinal stromal tumors (GIST), and 3 cases of metastatic carcinoma. Of the 367 cases of primary rectal carcinoma, 37 cases were early carcinomas whose invasion was limited up to the submucosa (early rectal carcinoma). The remaining 330 cases were advanced carcinoma invading beyond the proper muscle layer. The histological types were well differentiated adenocarcinoma in 197 cases, moderately differentiated adenocarcinoma in 129 cases, poorly differentiated adenocarcinoma in 10 cases, mucinous adenocarcinoma in 24 cases, signet ring cell carcinoma in 6 cases, squamous cell carcinoma in 1 case In the 41 cases of carcinoma in adenoma, the carcinoma was well to moderately differentiated adenocarcinoma, and all cases were early carcinomas without invasion or with little invasions to subserosa. The size of carcinoma in adenoma was as follows: < 10 mm, 5 cases; 10-15 mm, 8 cases; 15-20 mm, 23 cases; > 20mm, 5 cases. The background adenoma was as follows: tubular adenoma (n=15), tubulo-villous adenoma (n=14), and villous adenoma (n=12). The 7 cases of neuroendocrine carcinoma consisted of 6 low grade neuroendocrine tumors (carcinoids) and 1 high grade neuroendocrine carcinoma (small cell carcinoma). All were submucosal lesions. Immunohistochemically, the tumor cells were positive for two or more of synaptophysin, chromogranin, neuron-specific enolase, CD56. In small cell carcinoma, KIT and PDGFRA were consistently positive. The 3 cases of malignant lymphoma were diffuse large B-cell lymphomas positive for CD20 and CD79a and negative for NK/T cell markers. The two cases of GIST was spindle cell type, and the risk was intermediate. Kit mutations were recognized in both GISTs. No PDGFRA mutations were seen. Of the 3 metastatic carcinomas, one was a metastasis from prostatic adenocarcinoma, and the remaining two was adenocarcinoma of unknown primary sites.

The effects of acute and subacute toxicity of 1,8-cineole in Kunming mice were studied. After acute oral administration, the LD50 value (95% CL) was 3849 mg/kg (3488.8~4247.1 mg/kg). In the subacute toxicity study, there were no significant differences in body weight and relative organ weight between the control group and 1,8-cineole treatment groups. The histopathological examinations showed that granular degeneration and vacuolar degeneration appeared in liver and kidney tissue after administration of high dose of 1,8-cineole. Under electron microscopy, a series of ultrastructural changes were observed: The electron microscopy assays indicated that the influence of 1,8-cineole on the target organ at the subcellular level were mainly on the mitochondria, endoplasmic reticulum and other membrane type structure of liver and kidney.

Aim: To investigate the role of miR-101 in the regulation of tumor proliferation, invasion, apoptosis and to its target gene in human ESCC. Methods: The expression level of miR-101 in Eca109 cell line was determined by real-time polymerase chain reaction (PCR). After transfected with miR-101 mimics and inhibitor, proliferation, migration and apoptosis in ESCC cell line (Eca109) were detected by MTT, cell wound healing assay and flow cytometry, respectively. The expression of EZH2 in Eca109 cell was examined by immunohistochemical staining. Results: We found that miR-101 was significantly down-regulated in ESCC cell than in matched normal esophageal epithelium cell. The expression level of miR-101 was inversely correlated to EZH2 protein expression in ESCC cell. In Eca109 cells, over-expression of miR-101 significantly inhibited the migration and invasion of ESCC cells, and promotes cell apoptosis. Conclusions: These findings suggest that decreased expression of miR-101 might promote metastasis of human ESCC by inducing accumulation of EZH2 protein.

MicroRNA-106b (miR-106b) is thought to be an oncogenic microRNA that promotes tumor growth and metastasis. The potential predictive value of miR-106b was studied in colonic cancer patients. The expression of miR-106b was examined in 180 colonic cancer cases using in situ hybridization (ISH) technique and was evaluated semi-quantitatively by examining the staining index. The Correlation of miR-106b expression and clinic-pathological features was analyzed by Spearman Rank Correlation. Wilcoxon signed rank test was used for assessing the expression difference of miRNA-106b between colonic cancerous and para-cancerous ones, and their effects on patient survival were analyzed by a log-rank test and the Kaplan-Meier method. MiR-106b was higher expressed in para-cancerous tissues, compared with colonic cancerous ones (P < 0.001). A positive correlation of miR-106b levels between colonic and para-cancerous tissues was also observed (CC = 0.523, P < 0.001). Furthermore, the expression of miR-106b was not significantly correlated with clinic-pathological parameters, including gender, age, histological grade, tumor size, pT stage, pN stage, pM stage and pTNM stage of the patients. Histological grade was positively correlated with pT stage (P = 0.011), pN stage (P = 0.036) and pTNM stage (P = 0.009). Patients expressing high levels of miR-106b both in colonic cancer tissues and para-cancerous ones have a relatively longer survival time but the difference is not statistically significant (P = 0.16). The expression difference of miR-106b levels between colonic tissues and para-cancerous tissues is statistically significant, but the miR-106b levels were not quite correlated with clinic-pathological characteristics and overall survival times of patients with colonic cancer. Lower levels of miR-106b may be connected with neoplastic effects due to interference with TGF-β signaling, providing evidence that down-regulation of miR-106b might also play an important role in the progression of the disease. The study results are consistent with the literature and support the notion that miR-106b is an oncogenic microRNA.

Previous studies demonstrated that the acquired drug resistance of non-small cell lung cancer (NSCLC) was related to deregulation of miRNAs. However, the effects of miR-107 and the mechanism through which miR-107 affects the cisplatin chemoresistance in NSCLC have not been reported. TaqMan RT-PCR or Western blot assay was performed to detect the expression of mature miR-107 and cyclin dependent kinase 8 (CDK8) protein. The viabilities of treated cells were analyzed using MTT assay. We found that the expression level of miR-107 in A549 cells was significantly lower than that in normal human bronchial epithelial cells (0.45 ± 0.26 vs. 1.00 ± 0.29, P = 0.032). The MTT assay showed that the A549 cells transfected with miR-107 mimics were significantly more sensitive to the therapy of cisplatin than control cells. A549 cells transfected with miR-107 mimics showed a decreased CDK8 protein expression. Downregulation of CDK8 expression by siRNAs, A549 cells became more sensitive to the therapy of cisplatin. In addition, the enhanced growth-inhibitory effect by the miR-107 mimic transfection was enhanced after the addition of CDK8 siRNA. In conclusion, the present study provides the first evidence that miR-107 plays a key role in cisplatin resistance by targeting the CDK8 protein in NSCLC cell lines, suggesting that miR-107 can be used to predict a patient's response to chemotherapy as well as serve as a novel potential maker for NSCLC therapy.

Abnormal expression of aquaporins (AQPs) has been reported in several human cancers. Epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinases1/2 (ERK1/2) are associated with tumorigenesis and cancer progression and may upregulate AQPs expression. In this study, we investigated acquaporin-8 expression and signaling via epidermal growth factor receptor-extracellular signal-regulated kinases1/2 in human esophageal cancer Eca-109 cells by western blot, immunofluorescence and wound healing (scratch) assays. Our results showed that epidermal growth factor (EGF) induced both Eca-109 migration and AQP8 expression. Wound healing results showed that cell migration was increased by 1.23-1.10-fold at 24 h and 48 h after EGF treatment. AQP8 expression was significantly increased (1.19-fold) at 48 h after EGF treatment in Eca-109. The EGFR kinase inhibitor, PD153035, blocked EGF-induced AQP8 expression and cell migration. AQP8 expression was decreased from 3.65-fold (EGF-treated) to 0.55-fold (PD153035-treated) in Eca-109. Furthermore, the MEK [MAPK (mitogen-activated protein kinase)/Erk1/2]/Erk1/2 inhibitor U0126 also inhibited EGF-induced AQP8 expression and cell migration. AQP8 expression was decreased from 3.92-fold (EGF-treated) to 1.38-fold (U0126-treated) in Eca-109. In conclusions, EGF induces AQP8 expression and cell migration in Eca-109 cells via the EGFR/Erk1/2 signal transduction pathway.

Being sleep-deprived can relieve the depressed emotions in rats, but the underlying mechanisms remain unknown. In this study, male rats were divided into 3 groups: normal control (NC), chronicunpredictable stress (CUPS) and sleep-deprived (SD). All of the groups were examined using the sucrose consumption test and the open field test. The sucrose consumption test and the open field test were performed for all three groups. The BDNF and miR-10B expressions were examined using real-time PCR and the level of BNDF was discovered by western blotting. In the sucrose consumption test and the open field test, the CUPS rats consumed less sucrose and got fewer score than the NC rats, however the SD rats consumed significantly more sucrose and received higher scores than the CUPS rats. Both the expression of BNDF and the protein levels in the CUPS group was significantly lower than in the NC group. Also, the CUPS group also showed a higher miR-10B expression than the NC group. However, the SD group demonstrated higher BDNF expression and lower miR-10B expression when compared with the CUPS group. Further investigation demonstrated that the BDNF is the direct target gene of miR-10B and BDNF expression, which is negatively correlated with the expression of miR-10B. In the sucrose consumption test, BNDF expression is positively correlated with the sucrose preference rate whereas miR-10B has an opposing correlation. Moreover, the open field test demonstrated that BNDF expression is positively correlated with the scores and the miR-10B expression is negatively correlated. These results indicate that sleep deprivation is closely linked with the downregulation of miR-10B and possibly the upregulation of BDNF in the hippocampus in the CUPS rats.

Lymphoma is the most frequent malignant tumor of the ocular adnexa with the most common histologic type being extranodal marginal zone B-cell lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT lymphoma). Here we report a case of a 28 year-old male who presented with a left conjunctival mass of one year duration. A diagnosis of primary MALT lymphoma of the conjunctiva was made based on morphologic and immunopheno-typic studies. Chromosome analysis revealed a male karyotype with a translocation t (5;11) (q33;p11.2) as the primary chromosomal abnormality, which, to the best of our knowledge, is the first reported translocation in MALT lym-phomas and ocular MALT lymphomas as well.

The metalloproteinases (MMP) 11 and 12 have been shown to be expressed in cervical cancer (CC). In order to extend our previous results, these MMPs were evaluated in cervical precursor lesions. One hundred seventeen cervical scrapes: thirty-six normal, thirty-six low grade squamous lesions (LSIL), thirty-six high grade (HSIL), nine CC; and, also ninety-nine paraffin-embedded cervical lesions: fifteen normal cervices, thirty eight LSIL, sixteen HSIL, and five CC were collected. The samples were analyzed for relative expression by real time RT-PCR or immunohistochemistry assay. We were able to identify a relative increased expression of MMP11 in 75% and 78% from LSIL and HSIL samples, respectively. While MMP12 expression was 64% and 75% in LSIL and HSIL, respectively. Positive samples for MMP11 expression were also positive for MMP12 expression and also increased according to illness progression. In the tissues, MMP11 or MMP12 expression was observed in the cytoplasm of the neoplastic cells, while in the normal epithelium was absent. The reaction was always stronger for MMP12 than MMP11. MMP11 expression was present in 77% and 66% of LSIL and HSIL, while MMP12 expression was 73% and 68%. There was a relationship between MMP11 or MMP12 expression and HPV infection. Our data are showing a relationship between diagnostic of precursor lesions and the MMP11 and 12 expressions, suggesting that their expression could be an early event in the neoplastic lesions of the cervix and could have clinical significance.

Heart transplantation (HTX) has become an established therapy for patients with end-stage heart failure. However, cancer incidence has been shown to be increased in the context of transplant-associated immunosuppression. The objective of this study is to analyze the incidence, histological spectrum, treatment and survival of various cancer types in HTX patients. We evaluated retrospectively all patients who underwent orthotopic HTX between 2000 and 2011 at our hospital including those patients who underwent HTX in other centers, but did their routine follow-up examinations at our department because of changing residence. 142 patients had HTX performed at our center in the last 11 years and another 9 patients visited our department for monitoring after HTX performed at an external center (total: 151). Ten patients (6.6%) developed a metachronous malignancy (3 non-melanoma skin cancer, 2 lung cancer and 1 each parotid gland cancer, prostate cancer, renal cancer, urinary bladder cancer and ductal pancreatic cancer). The latency between HTX and the diagnosis of the secondary neoplasm ranged from 33 to 152 months (median 76 months; mean 88 months). In all cases, surgery with or without chemoradiation was the treatment for the metachronous cancer. While most cases followed a favorable course after appropriate surgical and/or oncological treatment, four tumors (1 salivary duct carcinoma, 1 urinary bladder carcinoma, 1 ductal pancreatic cancer and 1 skin cancer) revealed a remarkable aggressiveness with wide-spread metastatic disease at the time of diagnosis or shortly thereafter. Incidence of various cancer types among HTX patients in this survey was consistent with previous studies, with lung and skin cancer as the commonest malignancies encountered. Regular cancer screening may be of benefit in reducing morbidity and mortality in these patients.

Trisomy 11 (+11) as an isolated abnormality is a rare event in patients with acute myeloid leukemia (AML) and is associated with poor prognosis. We describe the clinicopathologic features of 18 AML patients with isolated +11 and their mutation status of NPM1, FLT3, NRAS ,KRAS, and KIT. Fourteen patients had de novo AML and 4 patients had a history of myelodysplastic syndrome (MDS). Fifteen patients had a progressive clinical course with refractory or relapsed disease. The median overall survival was 5 months (range, 2 to 48 months). Only 1 patient achieved complete remission after undergoing stem cell transplantation. The bone marrow median blast count was 65% (range, 22 to 86) and 14 patients had blasts >50%. The most common type of AML was AML without maturation (7 patients) classified by the World Health Organization classification system, or M1 (10 patients) by the French-American-British (FAB) system. FLT3 mutations were detected in 3 of 15 (20%) cases tested. RAS mutation was present in 1 of 16 (6%) cases and there was no evidence of NPM1 of KIT mutations (each tested in 12 cases). Our findings confirm previous reports that isolated +11 is associated with a poor prognosis in patients with AML and tends to be associated with FAB-M1 morphologic features. No evidence of NPM1 or KIT mutations were identified.

Heart transplantation (HTX) has become an established therapy for patients with end-stage heart failure. Endomyocardial biopsy (EMB) still represents the gold standard for routine surveillance of heart transplant rejection. The objective of this article is to report our experience regarding the use of EMB in monitoring heart transplant recipients. We evaluated retrospectively all patients who underwent orthotopic HTX between 2000 and 2011 at our hospital. From all patients, we created a follow-up, determined the number of EMB events and described the complications associated with this procedure. HTX was performed in 142 cases at our center in the last 11 years (1.3% of the total of 10693 cardiac surgical operations in that period). Further 9 patients visited our department for monitoring after HTX performed at an external center (total: 151). For all patients, a total of 1896 EMB events have been recorded. The majority of biopsies were performed through the right internal jugular vein. The overall complication rate was 1% (n=19). The histological examination of right ventricular EMB still represents the gold standard of care for cardiac allograft rejection monitoring. EMB is an invasive, but safe and dedicated diagnostic procedure. However, the usefulness of recent non-invasive diagnostic approaches as an adjunct tool in monitoring for rejection remains to be further analyzed.

Breast cancer is the leading cause of cancer death in women world wide which is closely related to metastasis. Recent studies argue that breast cancer cells that have undergone epithelial-to-mesenchymal transition (EMT) acquire aggressive malignant properties, but the molecular mechanisms underlying this transition are poorly understood. In this study, we found that increased expression of proline-rich protein 11 (PRR11) was associated with the progression of breast cancer and that PRR11 protein levels were significantly elevated in breast cancer. High PRR11 levels also predict shorter overall survival of breast cancer patients. Moreover, we found that the forced expression of PRR11 decreased the expression of the epithelial marker E-cadherin but increased the mesenchymal markers in breast cancer cells. In contrast, silencing PRR11 in metastatic breast tumor cells promoted a shift toward an epithelial morphology concomitant with increased expression of E-cadherin and decreased expression of mesenchymal markers. PRR11 silencing also reduced the expression of EMT-inducing transcription factors (Snail, Slug, ZEB1 and ZEB2).

To determine the diagnostic features of Robertsonian (Rob) translocation (11; 13) in mice and the mechanisms underlying the effect on spermatogenesis and reproductive decline. A Rob translocation (11; 13) mouse model was established by cross-breeding, and confirmed by chromosome analysis. Chromosome aberrations and translocation patterns were identified in mice with Rob translocation (11; 13) by fluorescence in situ hybridization (FISH). Spermatogenic disorders were investigated at different stages of spermatogenesis. Immunofluorescent analysis was performed on sections of testis and epididymis specimens during spermatogenic meiosis. The weight of the testes and reproductive decline were recorded. The crossed Rob translocation (11; 13) mouse has 39 chromosomes, including a fusion chromosome (included chromosomes 11 and 13) using dual color FISH. There was no difference in the distribution pattern of SYCP3 and γH2AX in spermatocytes between Rob translocation and wild-type mice; however, round haploid spermatids presented characteristic morphologic changes of apoptosis and the number of haploid spermatids was decreased. Furthermore, the immature germ cells were released into the epididymis and the number of mature sperm was reduced. Chromosome aberrations and spermatogenic disorders may result from apoptosis of round haploid spermatids and a reduced number of mature sperm in Rob translocation (11; 13) mice. Abnormal sperm and reduced number of sperm may be one of the main reasons for reproductive decline and male infertility in Rob translocation (11; 13) mice.

MiR-1179, a new identified miRNA highly associated with metastasis of colorectal cancer which was never reported in esophageal squamous cell carcinoma (ESCC). Here we measured the expression levels of miR-1179 and the candidate target gene in tissues from 40 patients with ESCC. Transwell, Dual-luciferase reporter assay and immunocytochemistry assay were employed to detect the function role of miR-1179 in vitro. We found that miR-1179 was up-regulated in human ESCC tumor tissues. Bioinformatics analysis indicated that SLIT2 acting as a new potential target of miR-1179 which was confirmed by luciferase reporter assay. Down-regulation of miR-1179 suppressed cell invasion in vitro with an increasing level of SLIT2 and ROBO1, besides, the up-regulation of SLIT2 decreased cell invasion through ROBO1. Taken together, these findings will shed light the role to mechanism of miR-1179 in regulating cell invasion via SLIT2/ROBO1 axis.

The aim of this study was to investigate the relationship between serum 11β-HSD2 mRNA level and insulin sensitivity in term small-for-gestational age (SGA) neonates after birth. The 38 infants were divided into two groups, the SGA group and the appropriate-for-gestational age (AGA) group. The placental 11β-HSD2 mRNA abundance and concentration of cortisol, fasting glucose, fasting insulin, adiponectin, visfatin and insulin-like growth factor-I (IGF-1) in the umbilical vein plasma were measured. The results showed that in the SGA group, neonates had lower levels of placental 11β-HSD2 mRNA and serum cortisol, and higher fasting insulin and HOMA-IR compared to AGA group. For some insulin sensitivity relative factor, levels of serum adiponectin and IGF-1 were lower while visfatin was higher in the SGA group than AGA group. Correlation analyses revealed that 11β-HSD2 mRNA level had a negative correlation with fasting insulin, HOMA-IR and visfatin.

Non-small lung cell carcinoma (NSCLC) is a leading lethal disease and a global health burden. The function of the Sex determining region Y (SRY)-related high mobility group box (SOX) family gene in cancer has attracted the attention of more and more scientists recently, yet there are few reports regarding the role of SOX in NSCLC. Our study aimed to investigate the expression of SOX8, a protein belonging to the E group of the SOX family, as well as SOX9, in non-small cell lung cancer (NSCLC) and the relationship of gene expression to clinicopathological factors and prognosis in patients. Immunohistochemical analysis was used to measure the expression of SOX8 in 80 NSCLC and 7 adjacent normal tissues. SOX8 expression was detected as elevated in tumor samples and correlated to tumor size (P < 0.001), lymph node metastasis (P = 0.001), differentiation classification (P = 0.015), and clinical stage (P = 0.013) significantly. Moreover, Kaplan-Meier survival analysis demonstrated that shorter survival time for patients who had higher SOX8 expression (P < 0.001). In addition, our experiments indicate that miRNA-124 functions as a tumor suppressor in NSCLC. We also demonstrate miRNA-124 directly targeted and decreased SOX8 in NSCLC cell lines, suggesting smiRNA-124 may regulate NSCLC cell proliferation via decreasing SOX8 (oncogenicity of biomarker in NSCLC).

Lung cancer is becoming the leading cause of cancer-related deaths with high mortality worldwide and in China as well. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer accounting for approximately 85% of all cases. Over 70% of cases are at loco-regionally advanced stages or have distant metastasis at the time of presentation with subsequently poor prognosis. MiRNAs are stable molecules in blood and used as biomarkers for the early diagnosis of various malignancy. The purpose of this study was to evaluate whether circulating miR-125a-5p, miR-145 and miR-146a could be used as biomarkers for the diagnosis of NSCLC through measuring their expression and assess their relationship with clinical pathological factors. Expression levels of serum miR-125a-5p, miR-145 and miR-146a were detected in 70 pairs of NSCLC patients and healthy controls using quantitative real-time PCR analysis. Serum miR-125a-5p, miR-145 and miR-146a were overexpressed in NSCLC patients compared with healthy controls. Their values of the area under the receiver -operating characteristic curve (AUC-ROC) were 0.71, 0.84 and 0.78. Optimal sensitivity and specificity were 73.53% and 55.71%, 92.75% and 61.43%, 84.06% and 58.57%, respectively in differentiating NSCLC patients from healthy controls. These preliminary data suggest that serum miR-125a-5p, miR-145 and miR-146a may be useful noninvasive biomarkers for the clinical diagnosis of NSCLC.

Tight junctions are structures located in the apicobasal region of the cell membranes. They regulate paracellular solute and electrical permeability of cell layers. Additionally, they influence cellular polarity, form a paracellular fence to molecules and pathogens and divide the cell membranes to apical and lateral compartments. Tight junctions adhere to the corresponding ones of neighbouring cells and by this way also mediate attachment of the cells to one other. Molecules forming the membranous part of tight junctions include occludin, claudins, tricellulin and junctional adhesion molecules. These molecules are attached to scaffolding proteins such as ZO-1, ZO-2 and ZO-3 through which signals are mediated to the cell interior. Expression of tight junction proteins, such as claudins, may be up- or downregulated in cancer and they are involved in EMT thus influencing tumor spread. Like in tumors of other sites, lung tumors show changes in the expression in tight junction proteins. In this review the significance of tight junctions and its proteins in lung cancer is discussed with a focus on the proteins forming the membranous part of these structures.

Although Clostridium perfringens (C. perfringens) is well known as the causative agent of several forms of enteric disease, precise epidemiological and pathobiological aspects are still unknown. We retrospectively reviewed the culture results of samples collected in our hospital from 2001 through 2013. In addition, for the detection and toxinogenic typing of C. perfringens, polymerase-chain-reaction amplification (PCR)-based rapid analysis was performed in 6 cases using DNA extracted from paraffin-embedded tissues. A total of 35 samples from 33 cases were positive for C. perfringens, representing an incidence of 0.017% (35/205, 114). Among 33 patients, 21 patients manifested sepsis and 7 patients had bacteremia. One of the septic cases was complicated by fatal intravascular hemolysis and thus, the prevalence was estimated at 3.0% among C. perfringens infections (1/33). The direct causative disease or state for C. perfringens infection was identified in 18 patients: surgery or intervention for cancers, 8 patients; chemotherapy for cancer, 2 patients; surgery or intervention for non-neoplastic disease, 6 patients; liver cirrhosis, 3 patients, etc. PCR-based toxinogenic typing of C. perfringens detected the alpha-toxin gene only in tissue from a patient who died of massive hemolysis; none of the toxin genes could be amplified in the other 5 cases examined. The prevalence of overt C. perfringens infection is low, but upon detection, infected patients should be carefully monitored for fatal acute hemolysis caused by type A C. perfringens. Furthermore, PCR-based rapid detection of C. perfringens and toxinogenic typing by archival pathological material is applicable as a diagnostic tool.

Background & aim: Aortic aneurysms represent one of the major causes of cardiovascular surgery. Their etiology varies greatly based on patient's age and other clinicopathologic determinants. In addition to common atherosclerotic vascular diseases, an inflammatory etiology, in particular IgG4-related disease (IgG4-RD) has increasingly emerged as a cause of dissecting inflammatory aortic aneurysms (IAA). To assess the frequency and types of IAA, we reviewed all cases of aortic aneurysms resected at our Erlangen Heart Center during 2000-2013. 376 patients underwent resection of aortic aneurysms in the study period. These are further categorized as ascending aortic aneurysms (45%), aortic arch aneurysm (2%), descending aortic aneurysm (3%), type A dissection (46%) and type B dissection (4%). Fifteen cases (4%) showed variable lymphoplasmacytic inflammation thus qualifying as IAA. Affected were 9 females and 6 males (female to male ratio = 1.5:1; age range: 52-80 yrs; mean: 70 yrs; median: 72 yrs). None was known to have IgG4-RD and serum IgG4 and/or IgG levels (known in 6 cases) were normal. Variable sclerosing lymphoplasmacytic inflammation was seen either confined to the adventitia (periaortitis; mainly in males) or extending through all layers (mainly in females). A wide range of IgG4 plasma cells (range: 3-182/HPF; mean: 51/HPF) and IgG4: IgG ratios (range: 0.02 to 0.91; mean: 0.37) were detected. All but one of the cases with at least focally transmural inflammation showed a higher IgG4: IgG ratios in excess of 0.3 (range, 0.32-0.91; median, 0.62). Lymphoid follicle and variable fibrosis were common but obliterative phlebitis was not seen. IgG4-rich sclerosing lymphoplasmacytic thoracic aortitis is a constant histological feature of thoracic IAA. Normal serum IgG4 in most patients, predilection for women and absence of other features of IgG4-RD all suggest a tissue-specific localized autoimmunological process and argue against a systemic disorder. The relationship (if any) of IgG4-rich lymphoplasmacytic thoracic aortitis in those patients with IAA lacking other organ manifestations or an elevated serum IgG4 level to systemic IgG4-RD remains unclear and merit further studies.

MiR-130a has been demonstrated to play important roles in many types of cancers. Nevertheless, its biological function in breast cancer remains largely unknown. In this study, we found that the expression level of miR-130a was down-regulated in breast cancer tissues and cells. Overexpression of miR-130a was able to inhibit cell proliferation, invasion and migration in MCF7 and MDA-MB-435 cells. With the bioinformatics analysis, we further identified that RAB5A was a directly target of miR-130a, and its mRNA and protein level was negatively regulated by miR-130a. Immunohistochemistry verified RAB5A was upregulated in breast cancer tissues. Therefore, the data reported here demonstrate that miR-130a is an important tumor suppressor in breast cancer, and imply that miR-130a/RAB5A axis have potential as therapeutic targets for breast cancer.

The role played by recently discovered novel cytokine IL-33 in controlling T-helper (Th)1 and Th2 cytokines under conditions of diabetic nephropathy (DN) is less well studied. In the present study, we estimated the levels of IL-33 along with both Th1 and Th2 cytokines in the serum of normal glucose tolerant (NGT), diabetic subjects with (DN) or without nephropathy (DM) and correlated it with the clinical risk factors of diabetes and nephropathy. 222 study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES): 61 NGT, 79 DM and 82 DN. IL-33 level was estimated by ELISA while other Th1 (IL-12, IFN-gamma and IL-2) and Th2 (IL-4, IL-5 and IL-13) cytokines were measured using a Bio-plex bead assay. DM subjects showed a mixed Th1-Th2 profile (increased IFN-g, IL-12, IL-4 and IL-13 and decreased IL-33) while DN subjects showed enhanced Th1 profile (increased IFN-g, IL-2 and IL-12) with suppression of Th2 cytokine (decreased IL-33 and IL-13). The IL-33 levels showed a serial decline with increasing severity of insulin resistance and microalbuminuria. DN was associated with enhanced Th1 response and suppression of Th2 responses which might be due to inreased levels of IL-12 and decreased levels of IL-33 cytokines respectively.

We intended to investigate the role of microRNA 137 (miR-137) in regulating pancreatic cancer cells' growth in vitro and tumor development in vivo. QTR-PCR was used to examine the expression of miR-137 in pancreatic cancer cell lines and tumor cells from human patients. Lentivirual vector containing miR-137 mimic was used to overexpress miR-137 in PANC-1 and MIA PaCa-2 cells. The effects of overexpressing miR-137 on pancreatic cancer cell invasion and chemo-sensitivity to 5-fluorouracil (5-FU) were examined by cell migration and survival essays in vitro. The molecular target of miR-137, pleiotropic growth factor (PTN), was down-regulated by siRNA to examine its effects on cancer cell invasion. MIA PaCa-2 cells with endogenously overexpressed miR-137 were transplanted into null mice to examine tumor growth in vivo. We found miR-137 was markedly underexpressed in both pancreatic cancer cell lines and tumor cells from patients. In cancer cells, transfection of lentivirus containing miR-137 mimic was able to markedly upregulate endogenous expression of miR-137, inhibited cancer cell invasion and increased sensitivities to chemotherapy reagent 5-FU. PTN was significantly down-regulated by overexpressing miR-137 in pancreatic cancer cells, and knocking down PTN was effective to rescue the reduced cancer cell invasion ability caused by miR-137 overexpression. More importantly, overexpressing miR-137 led to significant inhibition on tumor formation, including reductions in tumor weight and tumor size in vivo. Our study demonstrated that miR-137 played an important role in pancreatic cancer development. It may become a new therapeutic target for gene therapy in patients suffered from pancreatic cancer.

MicroRNAs (miRNAs) play an important role in the regulation of gene expression and are involved in almost biological procession. Recently, miR-139-5p has been reported to be downregulated in some types of cancer, and inhibits cancer cell invasion and metastasis. However, there are few reports on the role of miR-139-3p in cancer. In this study, we examined the expression level of miR-139-3p in 63 pairs of colon cancer and adjacent paracancerous tissues using quantitative reverse transcription PCR. The levels of miR-139-3p in colon cancer tissues were significantly lower than those in adjacent noncancerous tissues. There was an inverse correlation between the level of miR-139-3p and patient's age. Lower level of miR-139-3p was significantly associated with poor overall survival, especially in patients with TNM stages I and II. In conclusion, miR-139-3p has potential as a prognostic biomarker for colon cancer. Further prospective studies are required to validate this result.

Cellular angiofibroma (CAF) is a rare soft tissue tumor characterized by random arrangement of spindle tumor cells in the stroma with short collagen bundles and thick- and hyalinized small vessels. CAFs share histological characteristics with spindle cell lipomas and mammary type myofibroblastomas. Because these tumors harbor monoallelic 13q14, common genetic and molecular mechanism for tumorigenesis is presumed. In this study, we reported a case of CAF in a 69-year-old man with monoallelic 13q14. Immunohistochemical analysis revealed that FOXO1, which is located in chromosome 13q14, was not expressed in the tumor. We also detected oxidative stress markers and found p38 MAPK activation, which is often induced by cellular stressors such as reactive oxygen species (ROS). Because FOXO1 induces the expression of genes encoding enzymes that generate antioxidants, oxidative stress induced by loss of FOXO1 expression may be common among CAFs, spindle cell lipomas, and mammary type myofibroblastomas.

Microdeletions of chromosome 13q31.1 are relatively rare. These types of deletions may cause different genetic effects on genotypes and/or phenotypes. There are several ways to detect microdeletions; noninvasive prenatal testing (NIPT) is the newest detection method. In this study, we aimed to investigate the genetic effects of a 13q31.1 microdeletion detected by NIPT and to reconfirm the feasibility of this procedure in predicting sub-chromosomal copy number variations (CNVs). The 13q31.1 microdeletion, which has previously been described as a disease-associated fragment, was detected by NIPT in a pregnant woman. To validate the finding and to explain the origin of this sub-chromosomal CNV, we collected fetal amniotic fluid and parental blood samples and tested the samples using array-based comparative genomic hybridization (aCGH). Karyotype analysis was performed on all of the samples to rule out balanced or mosaic anomalies. The aCGH results confirmed the NIPT findings. We detected the same type of microdeletion in the fetus and the mother via aCGH. The mother had a normal phenotype; therefore, in a post-test genetic counseling session, we predicted a normal phenotype for the fetus. After delivery, the normal phenotype of the newborn confirmed our prediction. Based on the present study, this 13q31.1 microdeletion may be considered as a chromosomal polymorphism. This study also reconfirmed the feasibility of obtaining a molecular karyotype of a fetus via NIPT.

14-3-3sigma is a p53-regulated G2/M inhibitor involved in numerous cellular signaling pathways related to cell cycle, DNA repair and apoptosis. Recent studies have showed that 14-3-3sigma was silenced transcriptionally through promoter hypermethylation mainly in HPV-negative vulvar squamous cell carcinoma (SCC). However, the expression of 14-3-3sigma protein has not yet been studied in anal SCC and its precursor, anal intraepithelial neoplasm (AIN). In this study, we evaluated the expression of 14-3-3sigma, p16 and p53 in 34 cases of normal perianal squamous mucosa, 5 cases of squamous hyperplasia and 62 cases of AIN, including 54 bowenoid and 8 differentiated AINs. Fourteen cases of invasive anal SCC were also included in the study, including 8 cases associated with bowenoid AIN and 6 cases associated with differentiated AIN. Expression of p16, p53 and 14-3-3sigma proteins was not seen in normal squamous epithelium. Weak staining for 14-3-3sigma was seen in anal squamous hyperplasia. Strong and diffuse p16 immunoreactivity was seen in 98.1% of bowenoid AIN, but only in 12.5% of differentiated AIN. In contrast, increased basal staining with suprabasal extension of p53 was seen in 100% of differentiated AIN, but in none of the bowenoid AIN. Expression of p16 and p53 was essentially mutually exclusive except in one case. Overexpression of 14-3-3sigma was detected in 97% (60/62) of AIN cases, including 96.3% of bowenoid AIN and 100% of differentiated AIN. Expression of 14-3-3sigma was independent of immunoreactivity status for p16 and p53. In conclusion, two histopathologic types of AIN, bowenoid and differentiated, have distinct immunoprofiles for p16 and p53, which suggests dual molecular pathways during anal carcinogenesis. Increased expression of 14-3-3sigma protein was found in approximately 97% of AIN lesions, regardless of histopathologic type and independent of p16 and p53 expression. Our study indicates that immunohistochemical detection of 14-3-3sigma in conjunction with p16 and p53 may be useful in histopathologic recognization of AIN.

The aim of this study was to clarify the clinicopathological significance of miRNA-148b (miR-148b) expression in NSCLC, and to explore the correlation between miR-148b level and the prognosis of patients with NSCLC. 151 patients diagnosed with NSCLC between May 2007 and April 2012 were included in the present study. Real-time RT-PCR method was used to assess the expression levels of miR-148b. The differences between two groups were assessed using Student's t -test, and the Kaplan-Meier method was used to estimate overall survival. The expression of miR-148b was decreased in tumor tissues compared to corresponding adjacent normal lung tissues (0.37 ± 0.12 vs. 1.00 ± 0.53, P < 0.05). Low miR-148b expression was significantly associated with TNM stage (P = 0.014), lymph node metastasis (P = 0.031), and distant metastasis (P = 0.008). Kaplan-Meier survival analysis showed that patients with low expression of miR-148b had significantly worse overall survival rates compared with those who had cancers with high miR-148b expression (log-rank test P = 0.039). Furthermore, multivariate Cox proportional hazards model analysis showed that miR-148b expression was independently associated with overall survival of patients with NSCLC (HR = 2.357, 95% CI: 1.612-9.212, P = 0.011). our data indicate that decreased expression of miR-148b in NSCLC tissues has prognostic value.

The aim was to evaluate the clinical significance and prognostic value of tissue miR-150 expression in non-small cell lung cancer (NSCLC) patients. Quantitative real-time PCR was used to analyze the expression of miR-150. Overall survival (OS) was estimated using the Kaplan-Meier method, and the differences in survival were compared using the log-rank test. A Cox proportional hazards model was used for multivariate analysis. Mean miR-150 levels were significantly higher in NSCLC tissues compared with matched non-cancerous tissues (4.07 ± 2.33 vs. 1.00 ± 0.46, P < 0.0001). The level of miR-150 in NSCLC was strongly correlated with lymph node metastasis (P = 0.04), distant metastasis (P = 0.01) and clinical TNM stage (P = 0.02). Kaplan-Meier analysis showed that the cumulative 5-year OS rate was 40.8% in the high expression group, and 69.2% in the low expression group. The log-rank test showed that the OS rate of patients with high miR-150 expression was significantly poorer than that of the remaining cases (P = 0.007). Our data indicated that overexpression of miR-150 in NSCLC tissues has prognostic value.

MicroRNA-155 (miR-155) is overexpressed in many human cancers; however, the function of miR-155 is largely unknown in esophageal squamous cell carcinoma (ESCC). In the present study, we found that miR-155 is dramatically increased in ESCC tissues compared with the paired adjacent normal tissues, which suggested that miR-155 acts as an oncogene in ESCC. We predicted that tumor protein p53-induced nuclear protein 1 (TP53INP1) is a candidate target gene of miR-155 given that miR-155 expression decreased mRNA and protein levels of TP53INP1 as determined by RT-PCR and Western blot analysis. In addition, miR-155 and TP53INP1 showed a negative relation in ESCC tissues. Dual luciferase-based reporter assay indicated direct regulation of TP53INP1 by miR-155. Furthermore, we demonstrated that RNA interference of TP53INP1 increased the proliferation and colonies formation of EC-1 cells. Up-regulation of TP53INP1 abrogated miR-155 induced growth in EC-1 cells and mutation of TP53INP1 in 3'-UTR restored the effects when co-transfected with miR-155. We also indicated that overexpression of miR-155 significantly promoted the proliferation of EC-1 cells in vitro and the development of tumors in nude mice. Taken together, our study reveals that miR-155 acts as an oncogene by targeting TP53INP1 in ESCC.

This study is to evaluate the association between the catechol-O-methyltransferase (COMT) gene val(158)met polymorphism and FM risk. We performed a meta-analysis of 8 case-control studies that included 589 FM cases and 527 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, this meta-analysis showed that the COMT gene val(158)met polymorphism was not associated with FM risk in all genetic models, i.e., allele (met vs. val: OR=1.46, 95% CI=0.80-2.66, P heterpgeneity<0.001), homozygous (met/met vs. val/val: OR=1.72, 95% CI=0.61-4.87, P heterpgeneity<0.001), heterozygous (val/met vs. val/val: OR=1.25, 95% CI=0.82-1.92, P heterpgeneity=0.050), recessive (met/met vs. val/val+val/met: OR=1.52, 95% CI=0.60-3.86, P heterpgeneity<0.001) and dominant model (met/met+val/met vs. val/val: OR=1.52, 95% CI=0.80-2.90, P heterpgeneity<0.001). Similarly, there were no significant associations in the subgroup analyses by ethnicity and HWE. No publication bias was found in the present study. This meta-analysis suggests that the COMT gene val(158)met polymorphism is not associated with FM risk. Further large and well-designed studies are needed to confirm this association.

Acute pancreatitis (AP), in particular, severe acute pancreatitis (SAP), is a rare but challenging complication during pregnancy in terms of diagnosis and management. The objective of this paper is to investigate the causes and therapeutic strategies of AP in patients during the third trimester of pregnancy. We performed a retrospective analysis of the clinical features, laboratory data, and outcomes in 16 patients with acute pancreatitis during the third trimester of pregnancy. Information was collected on admission, management, and outcome. A total 16 patients were diagnosed with acute pancreatitis during pregnancy. In 7 of 9 patients with mild AP, pregnancy was terminated by cesarean section and all 9 cases were cured. In 4 out of 7 patients with SAP, pregnancy was terminated by cesarean section in conjunction with peritoneal irrigation and drainage, and the mothers and infants survived. In the remaining 3 patients with SAP, there was one case of intrauterine death in which Induced labor was performed and 2 patients died of multiple organ failure. A high-fat diet and cholelithiasis are the triggers of AP in pregnancy. Conservative treatment is the preferred therapeutic method; in particular, for mild AP. Endoscopic surgery and peritoneal drainage are effective for acute biliary pancreatitis. Patients with hyperlipidemic pancreatitis should undergo lipid-lowering therapy, and hemofiltration should be done as soon as it becomes necessary. For patients with SAP, termination of pregnancy should be carried out as early as possible.

Rheumatoid arthritis (RA) is a common autoimmune disease of chronic systemic inflammatory disorder that will affect multiple tissues and organs such as skin, heart or lungs; but it principally attacks the joints, producing a nonsuppurative inflammatory and proliferative synovitis that often progresses to major damaging of articular cartilage and joint ankylosis. Although the definite etiology is still unknown, recent studies suggest that T-helper cells (Th17) may play a pivotal role in the pathogenesis of RA. And interleukin-17 (IL-17), which is a cytokine of Th17 cells, may be a key factor in the occurrence of RA. The binding of IL-17 to specific receptor results in the expression of fibroblasts, endothelial and epithelial cells and also synthesis of several major factors such as tumor necrosis factor alpha (TNF-α), IL-1β that result in the structural damage of RA joints. Though some previous studies have shown that IL-17 exists in the synovium of RA, few has definite proof quantitatively by pathology about its existence in synovial membrane. This study comprised of 30 RA patients and 10 healthy control, pathologic study of the synovial membrane showed increased expression of IL-17 in the synovial tissue of RA patients, the intensity is compatible with clinical severity of disease as validated by DAS28 score and disease duration. Northern blot study also confirmed the increased expression of IL-17 in the synovial tissues. This study sheds further light that IL-17 may be a key factor in the pathogenesis of RA and a determinant of disease severity.

Intraprostatic leukocyte function may vary depending on local inflammatory or malignant cell microenvironment. Interleukin (IL)-17 producing cells play key roles in chronic inflammation and autoimmunity. Little is known about the relevance of IL-17 producing cells at sites of prostate tissue inflammation and/or prostate adenocarcinoma. In this study, we analyzed thirty formalin-fixed paraffin-embedded whole-mount radical prostatectomy specimens of prostate cancer patients. Immunohistochemistry was employed to identify IL-17 producing cells in all sites of mononuclear cell accumulation, noting their relationships to areas of prostate cancer, proliferative inflammatory atrophy (PIA), or hyperplastic benign tissue. Levels of IL-17 producing cells were similar in zones of benign prostate tissue and areas of prostate cancer. Pronounced intraluminal and peri-glandular IL-17 producing cell accumulations were identified in the mononuclear cell infiltrates associated with PIA lesions. Glandular and peri-glandular CD68+ macrophages and neutrophils were the predominant IL-17 producing cells in PIA lesions. The accumulation of IL-17 expressing cells in PIA lesions presents direct evidence of an inflammatory microenvironment that may support the development of prostate cancer.

The HER2 oncogene shows expression or amplification, or both, in approximately 15% to 20% of breast cancers and has been associated with poor prognosis and a response to trastuzumab therapy. HER2 gene status determines the eligibility of breast cancer patients for trastuzumab therapy and a large fraction (41-56%) of these patients respond to targeted therapy. Several studies have related the increased expression of HER2 to an increased copy number of chromosome 17, rather than amplification of the HER2 gene. We compared the results of immunohistochemistry and fluorescence in situ hybridization in both invasive ductal and invasive lobular carcinomas, to determine the frequency of chromosome 17 aneuploidy associated with discordant results. In total, 390 invasive ductal carcinomas and 180 invasive lobular carcinomas diagnosed from January 2000 to December 2005 were included in the study only if results were available for immunohistochemistry (HercepTest; DAKO, Carpinteria, California) and fluorescence in situ hybridization (PathVysion HER2 DNA Probe Kit; Abbott Laboratories, Des Plaines, Illinois). Tumors classified as invasive ductal carcinomas were graded according to the Bloom-Richardson grading system. Correlation between the results of immunohistochemistry and fluorescence in situ hybridization was performed for all categories. Among invasive ductal carcinomas, 29% (115/390) showed chromosome 17 aneuploidy, mostly associated with grade 3/HER2 2+ (45%) or grade 2/HER2 3+ (55%) that were not amplified. Also, 34% (12/35) of invasive lobular carcinomas showed chromosome 17 aneuploidy; approximately one-third of these cases were HER2 2+ (33%) and HER2 3+ (37%) that were not amplified. Discordance between the results of immunohistochemistry and fluorescence in situ hybridization in both ductal and lobular carcinomas is largely associated with chromosome 17 aneuploidy.

Current American Society of Clinical Oncology/College of American Pathologists guidelines define HER2-positive tumors as those with > 6 HER2 genes per nucleus or those with HER2/CEP17 (chromosome 17) ratio > 2.2. These guidelines are potentially contradictory in tumors with polysomy of chromosome 17. The current study was performed to determine the impact of polysomy 17 on the interpretation of HER2 testing of invasive breast carcinomas. Chromosome 17 copies and HER2 gene status were identified by fluorescent in situ hybridization in 384 cases with invasive breast cancer, and the corresponding HER2 expression was obtained by immunohistochemistry stain. The average CEP17 copy number for the group was 2.1 (range, 1.0-12.4). Forty-eight cases (13.8%, 48/348) were identified as chromosome 17 polysomy with CEP 17 copy number ≥ 3. Ninety-two (26.4%) cases had > 6 copies of HER2 per nucleus, and 92 cases (26.4%) qualified as HER2 gene amplified using the HER2/CEP17 ratio (> 2.2) guideline. Polysomy 17 showed poorly positive correlations with both HER2 gene copy number and HER2 overexpression (P < 0.01, r = 0.338 and 0.271, respectively). The distribution of clinicopathologic parameters of Polysomy 17 tumors was more similar to HER2 negative than HER2 positive tumors. Polysomy 17 is a crucial cause of equivocal HER2 testing results by FISH, depending on which criterion (ratio vs. absolute number) is used for interpretation. Polysomy 17 cannot be an independent predictive factor for HER2 gene amplification or protein overexpression.

Previously, we demonstrated that Tim-1-Fc prevents acute cardiac graft rejection by inhibiting Th1 response. In the present report, we tackled the impact of Tim-1-Fc on Th17 cells in a model of cardiac chronic rejection. Administration of Tim-1-Fc did not result in a detectable impact on innate immunity and regulatory T cells, while it provided protection for Bm12-derive cardiac grafts against chronic rejection in B6 recipients, as manifested by the reduction of inflammatory infiltration along with less severity of vasculopathy. Studies in T-bet(-/-) recipients by implanting Bm12-derived cardiac grafts further revealed that Tim-1-Fc significantly protected cardiac grafts from chronic rejection along with attenuated production of IL-17 producing T cells. Depletion of CD4 and CD8 T cells or blockade of IL-17 in T-bet(-/-) recipients demonstrated that Tim-1-Fc selectively suppresses Th17 differentiation along with attenuated IL-17 secretion. Together, our data suggest that Tim-1-Fc protects cardiac grafts from chronic rejection by suppressing CD4 Th17 development and functionality. Therefore, Tim-1-Fc might be a potential immunosuppressive agent in the setting of cardiac transplantation.

This study is dedicated to investigate the expression patterns of sperm protein 17 (Sp17), melanoma-specific antigen (MAGE)-C1 and New York esophageal squamous cell carcinoma-1 (NY-ESO-1), to explore the correlation between these cancer-testis antigens and clinical parameters, and to evaluate their values in diagnosis and differentiation of hepatocellular carcinoma. Immunohistochemical staining was performed in 45 paraffin-embedded hepatocellular carcinoma specimens. 45 normal peripheral hepatic tissues collected from adjacent non-cancerous areas were used as controls. Positive results of immunohistostaining were obtained in 16 (35.6%), 7 (15.6%) and 36 (80.0%) samples using MAGE-C1, NY-ESO-1 and Sp17 antibodies, respectively. The immunoreactivity of Sp17 was also found in 7 (14.0%) control samples. A statistical correlation between the frequency of Sp17 expression and tumor differentiation grade in hepatocellular carcinoma was confirmed. Sp17 is highly expressed in hepatocellular carcinoma cells. The frequency of Sp17 expression is closely related to the pathologic differentiation in hepatocellular carcinoma.

To be a successful implantation, endometrial receptivity should be established. Forkhead box M1 (FoxM1) is described as a major oncogenic transcription factor in tumor initiation, promotion, and progression. FoxM1 regulates the expression of lots of targeted genes important to cell differentiation, proliferation and apoptosis; cell-cycle progression; and tumor angiogenesis, migration, invasion, and metastasis. According to these functions, we believe that FoxM1 should also play an essential role in embryo implantation. To test our hypothesis, we observed the expression and distribution of FoxM1 during the early pregnancy of mouse. Then, we used Immunohistochemistry to examine the expression of FoxM1 induced by E2 and/or P4 in the ovariectomized mouse uterus and human endometrium cells. This study further investigated whether FoxM1 was an important factor in the implantation. Our results showed that FoxM1 expressed in the mouse uterus during early pregnancy (Day 1 to 5). The expression of FoxM1 gradually increased along pregnancy process; FoxM1 expression could be increased by E2. On the contrary, FoxM1 expression could be decreased by P4 and E2 plus P4. We also detected the proliferation of human endometrium cells. We found that E2 might promote cells proliferation, while P4 and E2 plus P4 inhibited cells proliferation; Inhibiting FoxM1 could interfere the embryo implantation of mouse. Amplification or inhibiting of FoxM1 in JAR cells can increase or decrease the adhesion rate to Rl95-2 and HEC-1A cells separately. Our data indicate that FoxM1 might play an important role during the process of mouse embryo implantation.

Upper urinary tract urothelial carcinomas (UUTUC) are infrequent and show an occurrence of about 5-10% of all urothelial carcinomas. In this study, we investigated the HER2 status of 171 UUTUC patients with nephroureterectomy. The number of patients is the largest of any HER2 study. All 171 cases were analyzed for both HER2 overexpression using immunohistochemistry and HER2 gene amplification using dual-color in situ hybridization. The scoring system proposed by the ASCO/CAP and ToGA trials was used. Out of 171 patients, 140 patients had a HER2 score-0 or score-1 (81.9%), 17 a score-2 (9.9%), and 14 a score-3 (8.2%) with immunohistochemistry. HER2 gene amplification was observed in 31 out of 171 cases (18.1%). A good correlation was observed between protein overexpression and gene amplification (p<0.0001). Twenty-three UUTUC (13.5%) were determined as HER2-positive cancer according to ASCO/CAP and ToGA criteria. HER2 positivity in patients over 70 years old was higher than that of patients under 70 years old (p=0.0132). HER2 expression correlated to a high histological grade (p=0.0003) and the coexistence of a high grade carcinoma in situ (p=0.0089). No HER2-positive cancer was observed in patients with renal pelvic UUTUC (0 out of 76, p<0.0001). HER2-positive UUTUC showed a shorter recurrence time in the residual urinary bladder after nephroureterectomy with Kaplan-Meier analysis (p=0.0284) and multivariate analysis (p=0.0034). The results suggest that HER2 positivity in UUTUC is an independent predictive marker for early recurrence of urothelial carcinoma in the residual urinary bladder after surgery.

Severe asthma is a chronic airway disease characterized by the Th2/Th17-polarized inflammation along with permanent airway remodeling. Despite past extensive studies, the exact role for Th2 and Th17 cytokines in asthmatic pathoetiology, particularly in the pathogenesis of bronchial epithelial-mesenchymal transition (EMT), is yet to be fully addressed. We herein conducted studies in 16-HBE cells and demonstrated that Th2-derived IL-4 and Th17-derived IL-17A provide a chronic inflammatory milieu that favors TGF-β1 to induce bronchial EMT. A synergic action was noted between TGF-β1, IL-4 and IL-17A in terms of induction of EMT. IL-4 and IL-17A synergized with TGF-β1 to induce epithelial cells re-entering cell cycle, and to promote epithelial to mesenchymal morphological transistion, and by which they enhanced the capacity of TGF-β1 to suppress E-cadherin expression, and to induce a-SMA expression in epithelial cells. Mechanistic studies revealed that this synergic action is coordinated by the regulation of ERK1/2 activity. Our results not only provide a novel insight into the understanding of the mechanisms underlying airway remodeling in asthmatic condition, but also have the potential for developing more effective therapeutic strategies against severe asthmatics in clinical settings.

The diagnosis of endometrial hyperplasia and endometrial type adenocarcinoma arising within the uterine cavity has long been rested on morphologic criteria. Although distinction between normal endometrial epithelium from adenocarcinoma is usually straightforward, the separation between normal and hyperplastic endometrium, particularly those cases without atypia, can be a diagnostic challenge. The same is true in separation of hyperplastic endometrium with atypia from endometrial-type endometrial adenocarcinoma. Type 2 3alpha-/type 5 17beta-hydroxysteroid dehydrogenase (HSD) (AKR1C3) is a multifunctional enzyme involved in androgen, estrogen, progesterone, and pros-taglandin metabolism. Its expression has been shown in the epithelium of the renal tubules, urothelial epithelium, and endothelial cells in normal tissues as well as in prostatic adenocarcinoma. The proliferation and maintenance of endometrial epithelium is dependent on both estrogen and progesterone; and AKR1C3-mediated steroid metabolism may play a critical role in the maintenance of viable normal and abnormal endometrial epithelium. We studied the expression of AKR1C3 in 33 endometrial biopsy specimens including 13 cases of normal proliferative endometrium, 8 cases of hyperplastic endometrium with and without atypia, and 12 cases of primary endometrial adenocarcinoma of endometrial type. We demonstrated a uniform, diffuse, and strong expression of AKR1C3 in normal endometrial epithelium but not in endometrial stromal cells. In contrast, the expression of AKR1C3 is reduced in both hyperplastic and carcinomatous endometrial epithelium. These findings suggest that AKR1C3 may play important roles in the physiology of endometrial cells and that suppressed AKR1C3 expression may represent a feature that allows differentiation of hyperplastic and neoplastic endometrial epithelium from normal endometrial epithelium. However, reduced AKR1C3 expression cannot distinguish hyperplastic endometrium from endometrial adenocarcinoma of endometrial type. The biologic and pathological roles of AKR1C3 in endometrial epithelium require further investigation.

Human aldo-keto reductase (AKR) 1C3, type 2 3α-hydroxysteroid dehydrogenase (HSC)/ type 5 17β-HSD, is known to be involved in steroids, prostaglandins, and lipid aldehydes metabolism. The expression of AKR1C3 has been demonstrated in hormone-dependent normal tissues such as breast, endometrium, prostate, and testis; and de -regulated AKR1C3 expression has been shown in breast carcinoma, endometrial hyperplasia, endometrial carcinoma, and prostate carcinoma. AKR1C3 expression has also been demonstrated in hormone-independent normal tissues (renal tubules and urothelium) and neoplastic tissues (renal cell carcinoma, Wilm's tumor, and urothelial cell carcinoma). Extensive expression of AKR1C3 in normal and neoplastic as well as hormone-dependent and hormone-independent tissues indicates that AKR1C3 may have functions beyond steroid hormone metabolism. In this report, we describe a widespread expression of AKR1C3 in glial neoplasms and meningiomas, with limited expression in medulloblastoma and no expression in Schwannoma. These tumors, except meningioma, are not classically considered to be sex hormone-dependent or related brain tumors. The current results corroborate our earlier observations that AKR1C3 is expressed in both sex hormone-dependent and hormone-independent malignancies. Similar to AKR1C3 distribution in Wilm's tumor, we also demonstrate that expression of AKR1C3 is reduced in tumors with embryonic phenotypes.

Intravascular large B-cell lymphoma (IVLBCL), which involves the lumen of small vessels, is a rare variant of extranodal diffuse large B-cell lymphomas. Herein, we present a case of IVLBCL manifesting as cholecystitis in a 77-year-old Japanese man. He presented with fever, fatigue, and weight loss. Physical examination revealed tenderness of the right upper quadrant. The white blood cell count and C-reactive protein levels were elevated. Computed tomography revealed gallbladder thickening and pericholecystic fluid collection; these observations were consistent with the diagnosis of cholecystitis. Serum soluble interleukin-2 receptor levels were highly elevated, and gallium scintigraphy revealed an abnormal accumulation in the spleen, implying lymphoma. Consequently, G-banding analysis of the patient's bone marrow aspirates revealed the presence of different abnormal clones, including those with gain of chromosome 18 and deletion of chromosome 6q. As cholecystectomy was necessary, a concurrent splenectomy was performed to diagnose the disease definitively. Histopathologically, atypical large lymphoid cells were observed to be localized in the vasculature in both the spleen and gallbladder; the atypical cells expressed high levels of CD20, CD5, and CD10, immunohistochemically. These findings were consistent with IVLBCL. The patient underwent post-operative treatment with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone. However, a pancreatic fistula developed during chemotherapy, causing left pleural effusion and peritoneal effusion; the patient developed sepsis from multidrug-resistant microorganisms, and subsequently died of multi-organ failure 6 months after the diagnosis. No obvious recurrence of the tumor was found during autopsy. We discuss the characteristic karyotype and immunohistochemical status observed in this case.