Search

Purpose: This study measured serum hypoxia--inducible factor-1 (HIF-1α) and survivin levels in patients with diabetes and investigated their association with the severity of retinopathy., Methods: This study included 88 patients with type 2 diabetes mellitus who underwent routine eye examinations. Three groups were created. Group 1 consisted of patients without diabetic retinopathy. Group 2 included patients with non-proliferative diabetic retinopathy. Group 3 included patients with proliferative diabetic retinopathy. To measure serum HIF-1α and survivin levels, venous blood samples were collected from patients., Results: The mean HIF-1α levels in groups 1, 2, and 3 were 17.30 ± 2.19, 17.79 ± 2.34, and 14.19 ± 2.94 pg/ml, respectively. Significant differences were detected between groups 1 and 3 (p=0.01) and between groups 2 and 3 (p=0.01). The mean survivin levels in groups 1, 2, and 3 were 42.65 ± 5.37, 54.92 ± 5.55, and 37.46 ± 8.09 pg/ml, respectively. A significant difference was only detected between groups 2 and 3 (p=0.002)., Conclusion: The present study revealed that serum HIF-1α and survivin levels are increased in patients with non-proliferative diabetic retinopathy compared to those in patients without diabetic retinopathy.

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. However, limited effective biomarkers are associated with the tumorigenesis and prognosis of CRC., Methods: The present study identified potential signatures from The Cancer Genome Atlas (TCGA) database and further validated the identified biomarkers in CRC tissues by immunohistochemistry (IHC)., Results: The expression of insulin-like growth factor 1 receptor (IGF-1R) and Livin gene was significantly upregulated in CRC samples compared to the adjacent normal samples in the TCGA dataset. IHC indicated that IGF-1R and Livin protein levels are increased in CRC and adenoma tissues compared to normal tissues. Notably, the IGF-1R protein levels differed significantly between adenoma and CRC. The elevated IGF-1R and Livin expression was associated with CRC clinicopathological features, including age, gender, histological subtype, individual cancer stages, nodal metastasis, and TP53-mutant in TCGA. Additionally, the IGF-1R promoter methylation level was closely related to CRC. Consistent with the TCGA study, IHC indicated that overexpressed IGF-1R and Livin proteins were independent risk factors for stage and metastasis. A marked correlation was established between IGF-1R and Livin expression in CRC, while the survival map showed no significant correlation with CRC. Kaplan-Meier survival curves showed that CRC patients with high IGF-1R or Livin expression had a prolonged overall disease-free survival than those with low expression in TCGA., Conclusion: IGF-1R and Livin are associated with CRC tumorigenesis and might be valuable for novel biomarker identification and targeted therapeutic strategy development., (© 2022. The Author(s).)

Objective: The aim of this study was to explore the expression of Livin in benign and malignant parotid gland tumors. We also investigate the role of Livin in the occurrence and progression of parotid gland tumors., Patients and Methods: Livin expression in 30 cases of normal parotid gland tissues, 40 cases of benign parotid gland tumors and 60 cases of malignant parotid gland tumors was detected by immunohistochemistry. The correlation between Livin expression and pathological characteristics of patients with parotid gland tumors was analyzed. The differentially expressed Livin in normal parotid gland tissues and malignant parotid gland tumors was determined by Western blot and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), respectively., Results: Livin expression was unable to be detected in normal parotid gland tissues. The positive rate of Livin expression in benign and malignant parotid gland tumors was 17.50% and 71.67%, respectively (p<0.05). Livin expression was correlated to malignant level, clinical stage and tumor diameter in 60 cases of malignant parotid gland tumors (p<0.05). However, the positive rate of Livin expression was not correlated to lymph node metastasis, age and sex of patients with parotid gland tumors (p>0.05)., Conclusions: Livin expression is closely related to the pathological progression of parotid gland tumors, which may serve as a hallmark in diagnosis, treatment and prognosis of patients with parotid gland tumors.

Gallbladder cancer (GBC) is a demanding fatal disease with no ideal treatment for inoperable patients. Recent reports have determined TNF-α associated lymphatic metastasis in GBC, while its resistance to TNF-α-killing remains largely unexplored. In this assay, we first found cellular inhibitor of apoptosis (cIAP1) overexpressed in GBC tissues and the roles in promoting the proliferation and migration of GBC in vitro as its homology cIAP2 does. Then how GBC cell survives TNF-α toxicity and TNF-α-induced apoptosis first prevail as follows. The reduction in cIAP1 does not give rise to apoptosis even with the stimulation of TNF-α. Importantly, the loss of cIAP1 enhanced TNF-α/cycloheximide-induced apoptosis in higher activation statuses of Caspase-8, Caspase-3 without the induction of Complex Ⅱ. In response to TNF-α, the reduction in cIAP1 caused the suppression in nuclear factor-κB (NF-κB) pathway and inhibition of transcription of cell death regulator cellular FLICE-like Inhibitory Protein (c-FLIP) instead. To conclude, cIAP1 is an oncological protein abundant in GBC tissues, which enhances proliferation and immigration and blocks TNF-α from apoptosis through NF-κB pathway in vitro ., (© 2019 The Author(s).)

The poor prognosis of ovarian cancer (it is the leading cause of death from gynecological cancers) is mainly due to the acquisition of resistance to carboplatin. Among the possible resistance pathways, resistance to apoptosis and especially the overexpression of inhibitor of apoptosis proteins (IAP) cIAP1 and X-linked IAP (XIAP), have been implicated. DEBIO 1143, a SMAC (second mitochondria-derived activator of caspase) mimetic, belongs to a new class of targeted agents currently being evaluated in clinical trials, which activate apoptotic cell death and block pro-survival signaling in cancer cells. Here, we demonstrate that DEBIO 1143 in vitro inhibits the cell viability of two carboplatin-sensitive cell lines (IGROV-1 and A2780S) as well as three carboplatin-resistant cell lines (A2780R, SKOV-3 and EFO-21). Of note, DEBIO 1143 is able to reverse resistance to carboplatin by inducing cell death either by apoptosis or necroptosis depending on the cell lines. To identify a biomarker able to predict the sensitivity of the cell lines to DEBIO 1143 treatment we analyzed the expression of the DEBIO 1143 targets cIAP1 and XIAP, and one of their downstream targets, caspase 9. These proteins did not constitute a marker of DEBIO 1143 sensitivity/resistance. Importantly, we confirmed these findings in vivo in SKOV-3 xenograft models where DEBIO 1143 highly potentiated carboplatin treatment.

Purpose: To evaluate histopathological and ultrastructural changes and expression of proteins related to apoptosis CASPASE 3 and XIAP after experimental induction of temporary focal cerebral ischemia (90 minutes) due to obstruction of the middle cerebral artery in alcoholism model., Methods: Forty adult Wistar rats were used, subdivided into 5 experimental groups: control group (C); Sham group (S); Ischemic group (I); Alcoholic group (A); and Ischemic and Alcoholized group (I+A): animals submitted to the same treatment of group A and after four weeks were submitted to focal cerebral ischemia during 90 minutes, followed by reperfusion of 48 hours. Were processed for histopathological analysis and immunohistochemistry (for the protein expression of CASPASE -3 and XIAP)., Results: Greater histopathological changes were observed in the animals of groups I and I+A in the three areas analyzed. The neuronal loss was higher in the medial striatum region of the animals of groups I and I + A. The protein expression of CASPASE -3 was higher than that of XIAP in the groups I and I + A for both proteins., Conclusion: The expression of XIAP was slightly higher where the histopathological changes and expression of CASPASE -3 was less evident.

Background: microRNA-23b (miR-23b) is a multiple functional miRNA. We hypothesize that miR-23b plays a role in the pathogenesis of sepsis. Our study investigated the effect of miR-23b on sepsis-induced immunosuppression., Methods: Mice were treated with miR-23b inhibitors by tail vein injection 2 days after cecal ligation puncture (CLP)-induced sepsis. Apoptosis in spleens and apoptotic signals were investigated, and survival was monitored. T-cell immunoreactivities were examined during late sepsis. Nuclear factor κB (NF-κB)-inducing kinase (NIK), tumor necrosis factor (TNF)-receptor associated factor 1 (TRAF1), and X-linked inhibitor of apoptosis protein (XIAP), the putative targets of miR-23b, were identified by a dual-luciferase reporter assay., Results: miR-23b expression is upregulated and sustained during sepsis. The activation of the TLR4/TLR9/p38 MAPK/STAT3 signal pathway contributes to the production of miR-23b in CLP-induced sepsis. miR-23b inhibitor decreased the number of spleen cells positive by terminal deoxynucleotidyl transferase dUTP nick-end labeling and improved survival. miR-23b inhibitor restored the immunoreactivity by alleviating the development of T-cell exhaustion and producing smaller amounts of immunosuppressive interleukin 10 and interleukin 4 during late sepsis. We demonstrated that miR-23b mediated immunosuppression during late sepsis by inhibiting the noncanonical NF-κB signal and promoting the proapoptotic signal pathway by targeting NIK, TRAF1, and XIAP., Conclusions: Inhibition of miR-23b reduces late-sepsis-induced immunosuppression and improves survival. miR-23b might be a target for immunosuppression.

Survivin, which is highly expressed in the majority of tumors, but not in most normal adult tissues, has been identified to have significant clinical applications. In the present study, using survivin‑specific monoclonal antibodies (mAbs), we aimed to establish methods for detecting the expression of survivin in cancer cell lines, serum samples, urine samples and cancer tissues from patients with bladder cancer (BCa) and renal cell carcinoma (RCC), and to evaluate the efficacy of survivin as a tumor marker in the surveillance of BCa and RCC. First, mAbs were labeled with horseradish peroxidase (HRP), and a sandwich enzyme‑linked immunosorbent assay (ELISA) with mAbs and HRP‑conjugated mAbs was developed to detect survivin expression in serum and urine samples from BCa and RCC patients, with samples from healthy controls (HCs) used for comparison. The HRP‑conjugated mAbs were also used to detect survivin expression in cancer cell lines by western blotting. Survivin expression in cancer tissues from BCa patients was also evaluated by immunohistochemistry. The results showed that the sandwich ELISA was successfully established, and significantly higher expression of survivin was subsequently detected in BCa and RCC patients as compared with HCs in both urinary and serum samples (P<0.05), and was more pronounced in urine. The HRP‑mAbs could recognize survivin in cancer cell lines. Western blotting and immunohistochemistry results confirmed survivin expression in the 5637 BCa cell line, as well as BCa tissues. In addition, the expressions of survivin in BCa tissues, urine and serum were consistent in our study. In conclusion, the sandwich ELISA successfully established in the present study was of high sensitivity and specificity in the detection of survivin expression. The results also indicated that survivin is a potential tumor marker for the surveillance of BCa and RCC.

Aim: To evaluate the usefulness of Ki-67 index and survivin as predictive prognostic factors for rectal cancer treated with preoperative chemoradiotherapy., Patients and Methods: The Ki-67 index and survivin expression were examined in patients with stage II/III rectal cancer (n=46) by immunohistochemistry. Patients were divided into a high-group and a low-group for the Ki-67 index, and positive and negative groups for survivin expression. Overall and disease-free survival were compared between the groups, and the correlation between Ki-67 index and survivin expression was assessed., Results: The 5-year disease-free survival rate of the group with high Ki-67 index was significantly lower than that of the group with low Ki-67 index (53% and 88%, p=0.03), as was the 5-year overall survival rate (68% and 100%, p=0.03). Findings for survivin were not significant., Conclusion: Ki-67 index and survivin may be useful biomarkers for rectal cancer with preoperative CRT., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Non-dysplastic Barrett's oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro-oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF-κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF-κB activation along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Survivin is an NF-κB-inducible anti-apoptotic protein, and Bcl3 is a negative regulator of NF-κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Bcl3 expression was upregulated in non-dysplastic Barrett's oesophagus, low-grade, high-grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barrett's stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF-κB activation. In addition, the study suggests that NF-κB activation may infer resistance to apoptosis through the expression of anti-apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barrett's metaplasia., (© 2018 The Authors. International Journal of Experimental Pathology © 2018 International Journal of Experimental Pathology.)

Aims: Survivin-a member of the family of inhibitor of apoptosis proteins that control cell division, apoptosis and metastasis-is overexpressed in virtually all human cancers, including laryngeal squamous cell carcinoma (LSCC). Recent findings also correlate survivin expression with the regulation of angiogenesis. The novel main aim of this study was a preliminary investigation into the potential role of survivin expression in LSCC neoangiogenesis, as determined by endoglin-assessed microvascular density (MVD)., Methods: Immunohistochemical expression of nuclear survivin and endoglin-assessed MVD were ascertained by image analysis in 75 consecutive LSCCs., Results: Statistical analysis disclosed a strong direct correlation between nuclear survivin expression and MVD. Patients whose nuclear survivin expression was ≥6.0% had a significantly higher LSCC recurrence rate, and a significantly shorter disease-free survival (DFS) than those with a nuclear survivin expression <6.0%. The LSCC recurrence rate was also higher and the DFS shorter in patients with endoglin-assessed MVD ≥6.89%. The OR for recurrence was 2.79 in patients with LSCC with a nuclear survivin expression ≥6.0%, and 12.31 in those with an MVD≥6.89%., Conclusions: Survivin-targeting strategies to enhance tumour cell response to apoptosis and inhibit tumour growth should receive more attention with a view to developing agents for use in multimodality advanced LSCC treatment, or combined with conventional chemotherapy. Given the present preliminary evidence in LSCC, survivin targeting should also be further investigated for anti-angiogenic purposes, to reduce tumour blood flow and induce cancer necrosis., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Survivin, an inhibitor of the apoptosis protein family, is a potent tumor marker for diagnosis and prognosis. The enzyme-linked immunosorbent assay (ELISA) is one of the methods that has been used for detection of survivin. However, ELISA has several disadvantages caused by the use of conventional antibodies, and we have therefore been trying to develop a novel ELISA system using camelid single-domain antibodies (VHHs) as advantageous replacements. Here we report a supplemental approach to improve the VHH-polyclonal antibody sandwich ELISA for survivin detection. Iodoacetyl-functionalized pullulan was synthesized, and its thiol reactivity was characterized by a model reaction with l-cysteine. The thiophilic pullulan was applied to an immunoassay asan additive upon coating of standard assay plates with an anti-survivin VHH fusion protein with C-terminal cysteine. The results showed that the mole ratio of the additive to VHH had a significant effect on the consequent response. Mole ratios of 0.07, 0.7, and 7 led to 90% lower, 15% higher, and 69% lower responses, respectively, than the response of a positive control in which no additive was used. The background levels observed in any additive conditions were as low as that of a negative control lacking both VHH and the additive. These results indicate the applicability of the thiol-reactive pullulan as a response enhancer to VHH-based ELISA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective To investigate the expressions of the inhibitor of apoptosis protein survivin and signal transducer and activator of transcription 2 (STAT2) in the tissues of the plaque-like lesions of patients with psoriasis vulgaris (PV) in the progressive stage and discuss their correlation. Methods We collected the plaque-like lesion samples and non-lesion samples from 22 PV patients and the normal skin sample from 18 healthy controls. Real-time quantitative PCR was used to evaluate the mRNA levels of survivin and STAT2 in these samples. Western blot analysis was performed to determine the protein expressions of survivin and STAT2. Immunohistochemical staining was also used to detect the expressions of survivin and STAT2. The correlation between survivin and STAT2 in the PV lesions was determined by Pearson's correlation analysis. Results Compared with healthy control skin and PV non-lesion tissues, the mRNA and protein expressions of survivin and STAT2 were significantly elevated in PV lesion tissues, and the mRNA expression of survivin was positively correlated with STAT2 mRNA in PV lesion tissues (r=0.5282). Conclusion The expressions of survivin and STAT2 are up-regulated in skin lesions of PV patients, and their mRNA expressions are positively correlated.

Distinguishing WHO grade II astrocytomas from grade III is a difficult task. This study looks into the potential prognostic use of mitotic activity and the proliferation markers Ki67/MiB-1 (Ki67), survivin and DNA topoisomerase IIα (TIIα) in 59 WHO grade II diffuse astrocytomas (DA) and 33 WHO grade III anaplastic astrocytomas (AA), IDH1 R132H-mutated and not otherwise specified (NOS) by means of immunohistochemistry. All proliferation markers showed higher expression in AA compared with DA. Only Ki67 had significantly greater expression in astrocytomas, NOS vs. astrocytomas, IDH1-mutated. Uni-/multivariable COX-regression analyses showed that greater expression of both survivin and TIIα were associated with poorer survival when stratified for IDH1-mutation status and, additionally, achieved hazard rates surpassing clinically established prognostic factors such as age and WHO performance status. Ki67 achieved only statistical significance in univariable analyses, whereas mitoses did not reveal any relation to survival. IDH1-mutated astrocytomas had significantly better survival than astrocytomas, NOS. Among IDH1-mutated astrocytomas no significant difference in survival was shown between DA and AA. Our findings suggest a potential usefulness of proliferation markers in the prognostic setting of astrocytomas independent of IDH1-mutation status, and survivin and TIIα are potential candidates in that regard., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Objective: To assess the association of survivin expression with clinicopathological features and biochemical recurrence (BCR) after radical prostatectomy (RP) in a large multi-institutional cohort., Methods: Survivin expression was evaluated by immunohistochemistry on a tissue microarray of RP cores from 3 117 patients. Survivin expression was considered altered when at least 10% of the tumour cells stained positive. The association of altered survivin expression with BCR was evaluated using Cox proportional hazards regression models., Results: Survivin expression was altered in 1 330 patients (42.6%). Altered expression was associated with higher Gleason score on RP (P = 0.001), extracapsular extension (P = 0.019), seminal vesicle invasion (P < 0.001) and lymph node metastases (P = 0.009). The median (interquartile range) follow-up was 38 (21-66) months. Patients with altered survivin expression had a shorter BCR-free survival time than those with normal expression (5-year BCR-free survival estimates: 74.7 vs 79.0%; P = 0.008). Altered survivin expression did not retain its prognostic value, however, after adjustment for the effect of established clinicopathological factors (P = 0.73). Subgroup analyses also showed no independent prognostic value of survivin., Conclusions: Survivin expression is commonly altered in patients undergoing RP. Altered survivin expression is associated with the clinicopathological features of biologically and clinically aggressive PCa. Survivin expression was associated with BCR only in univariable analysis, limiting its value in daily clinical decision-making., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

We examined the survivin expression pattern by immunohistochemistry in 43 fibroadenomas and 153 ductal carcinomas of the breast. The subcellular localization of survivin and the intensity of immunoreaction were assessed. We analyzed the differences of survivin expression between fibroadenomas and carcinomas. We also correlated the survivin expression pattern in carcinomas with other clinicomorphological parameters such as the age of patients, the grade and size of primary tumor as well as the lymph node metastasis. Overall, survivin was detected in 107/153 carcinomas (69.9%) and in 26/43 fibroadenomas (60.5%). Statistical analysis confirmed significant correlations between the assessed parameters in fibroadenomas and carcinomas. Grade of carcinomas was significantly related to survivin expression in both subcellular localization and the intensity of immunoreaction. Tumor grade 3 was associated with nuclear positivity and combined nuclear and cytoplasmic localization. Carcinomas larger than 20 mm showed nuclear and combined localization in 81% of cases and higher intensity of survivin immunoreaction was also notably related to larger carcinomas. Statistically significant differences were also observed between subcellular survivin localization and intensity of immunoreaction. Our result suggest that nuclear accumulation of survivin is associated with proliferative fenotype and survivin was shown to be a worse prognostic marker in breast ductal carcinoma.

Purpose: Survivin is thought to play an important role in carcinogenesis and is found to be associated with poor clinical outcome in various malignancies. Gene -31 G/C polymorphism has been identified as a risk factor for the development of several types of tumors. The purpose of this study was to investigate the association between survivin gene promoter -31C/G polymorphism and urothelial carcinoma (UC) risk in Serbian population and to compare the different expressions of survivin in UC of different disease stages, histological grades and tumor location in the upper or lower urinary tract., Methods: DNA from 94 patients with primary UC and from 82 healthy subjects was subjected to PCR restriction fragment length polymorphism analysis (PCR-RFLP) to identify individual genotypes. UC samples were subjected to immunohistochemical analysis to assess survivin expression in these lesions., Results: It was observed that the frequency of G/G genotype was greater in patients with UC (58.7%) than in controls (32%). Compared with study subjects carrying the C/G or C/C genotypes, significantly increased UC risk was found for individuals carrying the G/G genotype. Those carrying the G/G genotype had a significantly increased UC risk compared with those with C/G or C/C genotypes. Patients with UC carrying the G/G genotype had a greater prevalence of muscle-invading (stage T2-T4), high-grade (G2) tumor and immunohistochemicaly overexpressed survivin compared with those carrying the C/G or C/C genotypes., Conclusions: G/G genotype of the -31C/G polymorphism might be a risk factor for UC development.

Introduction: Actinic cheilitis (AC) is a lip intraepithelial neoplasia, whose cells present alterations similar to those presented by invasive squamous cell carcinomas (SCCs)., Objective: To conduct clinical and laboratory evaluation by histopathology and immunohistochemistry of the efficacy of actinic cheilitis treatment using photodynamic therapy (PDT) with methyl aminolevulinate (MAL) and noncoherent red light., Materials and Methods: Patients with actinic cheilitis detected by histopathological examination were submitted to two sessions of photodynamic therapy with a two-week interval between them. They were examined immediately after the sessions, four, six, and twelve weeks after beginning treatment when a new biopsy was carried out. Clinical histopathological and immunohistochemical parameters were evaluated before and after treatment., Results: Of the 23 patients who underwent biopsy, 16 completed two photodynamic therapy sessions and the material of one patient was insufficient for immunohistochemistry. Complete clinical response was achieved in 62.5% (10 of 16 patients) and 37.5% still remained with clinical evidence of AC. In spite of this, no case of cure by histopathological analysis was found. There was no significant statistical change among the values of Ki-67, survivin, and p53 observed before and after treatment., Conclusion: Photodynamic therapy, as carried out in this trial, was not an efficacious therapeutic option for treating patients with actinic cheilitis included in this sample., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To investigate whether bile survivin and carbohydrate antigen 199 (CA199) can be helpful in distinguishing cholangiocarcinoma (malignant obstructive jaundice) from benign obstructive jaundice., Methods: Receiver operating characteristic curve was used to evaluate the feasibility of bile survivin and CA199 in differentiating cholangiocarcinoma from benign obstructive jaundice., Results: The area under the curve for survivin and CA199 in bile and serum were 0.780 (p < 0.001), 0.6 (p = 0.084), 0.746 (p < 0.001) and 0.542 (p = 0.464), respectively. Combination of bile survivin and CA199 could improve the diagnostic capability., Conclusion: Bile survivin and CA199 are significantly increased in patients with cholangiocarcinoma and may be useful biomarkers in differentiating distinguishing cholangiocarcinoma from benign obstructive jaundice.

Background/aim: Survivin is a multifunctional protein abundantly expressed in tumors of various types, including melanoma. There are still sparse data regarding relationship of melanoma cell survivin expression with accepted histopathological characteristics as well as serum concentration. The aim of this study was to investigate the association of local tumor survivin expression (primary tumor and metastatic lesions) and serum concentration with clinical and histopathological parameters in melanoma patients., Methods: The level of survivin expression was determined immunocytochemically in tumor tissue and with ELISA test in the serum of 84 melanoma patients diagnosed from 2009 to 2013 at the Institute for Pathology and Forensic Medicine and Institute for Medical Research at Military Medical Academy, Belgrade, Serbia., Results: The intensity of survivin expression was significantly higher in the patients whose tumor had ulceration, higher mitotic index, higher Clark and Breslow stage, that made vascular invasion or spread through lymphatic vessels in primary tumor, and was significantly higher in the patients with metastatic disease. Survivin expression and the number of survivin positive cells in metastatic lesions were significantly associated with the duration of disease free interval (DFI). The patients with high expression score had almost double shorter DFI comparing to those with weak local survivin expression and a small number of survivin+cells (9 ± 7 vs 19 ± 13 months, respectively). The degree of tumor infiltrating lymphocytes presence in tumor tissue was significantly associated with serum survivin concentration, with lowest average level detected in samples of patients with the highest degree of infiltration. Serum survivin concentrations were highest in samples of melanoma patients with IA American Joint Commission on Cancer (AJCC) clinical stage, pT1a histological stage, patients whose tumors were still in horizontal growth phase, without signs of lympho-hematological disease spreading, with the highest number of mitoses and the smallest Clark index., Conclusion: Survivin expression in tumor tissue and its serum concetration significantly correlate with clinical and histopathological parameters. Serum levels could be important in initial follow-up as indicators of those patients that would have aggressive local tumor growth and spreading. Survivin determination in tumor tissue is of great significance in estimation of DFI.

High-grade papillary urothelial carcinoma with subepithelial connective tissue invasion (T1HG) is an aggressive disease at high risk of progression after transurethral resection/Bacillus Calmette-Guerin standardized therapy. The European Organization for Research and Treatment of Cancer has identified T1HG bladder carcinoma that is single and ≤3 cm in the largest dimension at first diagnosis as a category in which the prognosis cannot be further stratified based on conventional criteria. This category may benefit from biomarker analysis as a valuable tool to determine the patient's outcome. To further the issue of biomarkers in predicting aggressiveness in single T1HG bladder carcinoma ≤3 cm in greatest dimension at first diagnosis, we have conducted a validation study of the biomarker risk score set previously reported by our group. The study set included immunohistochemical detection of galectin-3, CD44, E-cadherin (E-CAD), CD138, p16, survivin, HYAL-1, and topoisomerase-IIα in 92 randomly selected specimens at participating institutions. Topoisomerase-IIα expression was identified as a predictor of disease-free survival. p16, survivin, and E-CAD expression predicted progression-free survival, but p16 and E-CAD also predicted overall survival. The current study validates a panel of immunohistochemical markers with the potential of being implemented in practice and supports the use of biomarkers in predicting aggressiveness in patients with first diagnosis of single T1HG bladder carcinoma ≤3 cm in greatest dimension and therefore in identifying patients who need closer surveillance or earlier aggressive treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The anti-apoptotic protein survivin (Sur) plays an important role in the regulation of cell division and inducing the chemotherapeutic drug resistance. The Sur protein and its mRNA have recently been studied as cancer biomarkers and potential targets for cancer therapy. In this work, we have focused on the design of immunosensors for the detection of Sur based on buried positive-potential barrier layer structure and anti-survivin antibody. The modification of solid AuQC piezoelectrodes was monitored by recording the resonance frequency shift and electrochemical measurements during each step of the sensor preparation. Our results indicate that the immunosensor with covalently bound monoclonal anti-survivin antibody can detect Sur with the limit of detection, LOD=1.7nM (S/N=3σ). The immunosensor applicability for the analysis of real samples was assessed by testing samples of cell lysate solutions obtained from human astrocytoma (glioblastoma) U-87MG cell line, with the experiments performed using the standard addition method. The good linearity of the calibration curves for PBS and lysate solutions at low Sur concentrations confirm the high specificity of the proposed biosensor and good discrimination against nonspecific interactions with lysate components. The calculations indicate that there is still room to increase the Sur capture capacity for Sur while miniaturizing the sensor. The important advantage of the sensor is that it can be reused by a simple regeneration procedure., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Gallbladder cancers (GBC) are characterized by rapid progression, early metastasis, and poor prognosis; the molecular mechanisms of the various signaling pathways involved should be elucidated to develop effective therapies. Survivin, an apoptosis inhibitor protein expressed in the G2/M phase of the cell cycle, plays a role in cell division and affects both cell survival and proliferation. Survivin has been investigated in many types of cancer, and this study aims to examine the relationship of survivin expression in gallbladder cancer patients with clinicopathological features and prognosis. We evaluated demographic characteristics (age, gender), tumor characteristics (histopathological type, differentiation, perineural, and lymphovascular invasion; serosal invasion, surgical margin positivity and lymphocytic response), and Survivin expression immunohistochemically, and we analysed the relationship between these characteristics and prognosis in 47 gallbladder carcinoma cases from 2000 to 2011. Immunohistochemically, while survivin expression was observed in 36 cases, it was absent in 11 cases. Follow-up data were obtained from 32 patients. Two (8.7%) of 23 cases with a Survivin-positive tumor were alive at 74th and 35th months, whereas 5 (%55.6) of nine cases with Survivin-negative tumor were alive at 50th, 89th, 124th, 126th, 131th months. Survivin expression was correlated with short survival (p = 0.043), and the univariate analysis showed that reduced overall survival was associated with age (p = 0.043), male gender (p = 0.038), infiltrative pattern (p = 0.019), lymphovascular invasion (p = 0.004), perineural invasion (p = 0.009), serosal invasion (p = 0.027), ulcer (p = 0.033), and surgical margin positivity (p = 0.022). Despite the low number of patients in our study, the analysis results suggest that survivin positivity might actually be a significant prognostic factor. This finding could be a reference point for targeted treatment studies. However, further studies involving broader series and longer follow-up are still required for highly lethal gallbladder cancers., (© 2016 APMIS. Published by John Wiley & Sons Ltd.)

Purpose: To investigate the role of CD44, cytokeratin 20 (CK20) and survivin for the detection and prognosis of patients with urothelial carcinoma of the bladder., Materials and Methods: The study included 82 patients who underwent transurethral resection of bladder tumors between 2009 and 2014. The patient and tumor characteristics with relevance to age, tumor size and focality, grade and stage, recurrence and progression were noted. Patients with carcinoma in situ, those who had at more than 3 sites of lesions and greater than 3 cm tumors were excluded. All cases were ex-smokers. All histological samples stained with hematoxylin and eosin were re-evaluated according to the 2004 World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification system and immunohistochemically stained for CD44, CK20 and survivin., Results: The study group comprised 57 (69.5%) males and 25 (30.5%) females with a mean age of 60 years (range, 26-87 years). All were newly-diagnosed patients with bladder tumors. Immunohistochemical evaluation revealed that there was a statistically significant correlation between the grade and stage of the tumor with CK20 and survivin positivity (P &lt; .05). As the grade and stage increased CD44 immunoreactivity significantly decreased (P = .002, P = .0001, respectively). However, relationship of protein expressions with recurrence and progression remained insignificant (P &gt; .05)., Conclusion: In cases of bladder urothelial carcinoma positivity for CD44, CK20, and survivin has significant relation with the tumor grade and stage while no significant relationship was determined in terms of recurrence and progression&nbsp.

Objective: To investigate the effect of silencing DJ-1 on xenografted human laryngeal squamous cell carcinoma (LSCC) Hep-2 cells in nude mice. Methods: Xenograft model of human LSCC was established by subcutaneous transplantation of Hep-2 cells in 24 nude mice. The LSCC-bearing nude mice were randomly divided into 3 groups ( n =8 in each):DJ-1 siRNA low dose group and DJ-1 siRNA high dose group were injected in tumors with 20 μg of DJ-1 siRNA or 40 μg of DJ-1 siRNA in 50 μL, respectively; control group was injected with 5% glucose solution in 50 μL, twice a week for 3 weeks. The weight and size of tumors were measured before injection. The animals were sacrificed 48 h after the final treatment, and the tumors were harvested and weighed. The apoptosis and proliferation of tumor cells were determined; the expressions of Caspase-3 and Ki-67 in tumor specimens were detected with immunohistochemistry. The expression of DJ-1, PTEN, survivin mRNA and protein in tumor tissues were detected by RT-PCR and Western blotting, respectively. Results: Tumor weight in low dose group[(0.66±0.15)g] and high dose group[(0.48±0.11)g] were significantly lower than that in control group[(0.83±0.16)g, all P <0.05]. The inhibition rates of low dose group and high dose group were (20.48±0.18)% and (42.16±0.13)%, respectively. Immunohistochemistry showed that the expression of Caspase-3 was increased and Ki-67 was reduced in tumor specimens, compared with the control group (all P <0.05). RT-PCR and Western blot results showed that in low dose group and high dose group the mRNA and protein expression of DJ-1 and survivin significantly decreased (all P <0.05), while PTEN mRNA and protein content increased (all P <0.05). Conclusion: High dose DJ-1 siRNA can inhibit the tumor growth in human LSCC xenograft nude mouse model, which indicates that down-regulating DJ-1 and survivin, and up-regulating PTEN expression may lead to blockage of PI3K-PKB/Akt signaling pathway and promoting tumor cell apoptosis.

Purpose: To determine whether the immunohistochemical markers survivin and E-cadherin can predict progress at initially diagnosed Ta bladder cancer., Methods: We retrospectively searched for every initially diagnosed pTa urothelial bladder carcinoma having been treated at our single-center hospital in Germany from January 1992 up to December 2004. Follow-up was recorded up to June 2010, with recurrence or progress being the endpoints. Immunohistochemical staining and analysis of survivin and E-cadherin of the TURB specimens were performed. Outcome dependency of progression and no progression with immunohistochemical staining was analyzed using uni- and multivariate regression analysis, Kaplan-Meier analysis and uni- and multivariate Cox regression analysis., Results: Overall, 233 patients were included. Forty-two percent of those were tumor free in their follow-up TURBs, 46 % had at least one pTa recurrence and 12 % even showed progress to at least pT1 bladder cancer. Aberrant staining of E-cadherin was found within 71 % of patients with progression in contrast to only 40 % in cases without progression (p = 0.004). Of all progressed patients, 92 % showed overexpression of survivin in their initial pTa specimen compared to 61 % without progression (p = 0.001). Kaplan-Meier analysis revealed aberrant E-cadherin staining to be associated with worse progression-free survival (PFS) (p = 0.005) as well as overexpression of survivin (p = 0.003). In multivariate Cox regression analysis, strong E-cadherin staining was an independent prognosticator for better PFS (p = 0.033) and multifocality (p = 0.046) and tumor size over 3 cm (p = 0.042) were prognosticators for worse PFS., Conclusion: Adding the immunohistochemical markers survivin and E-cadherin could help to identify patients at risk of developing a progressive disease in initial stage pTa bladder cancer.

Background: Clinical significance of survivin (antiapoptosis protein) in gallbladder cancer is not yet established., Aims: This study was performed to assess the expression pattern of survivin in benign and malignant gallbladder lesions using immunohistochemistry (IHC), and to assess its clinicopathological significance., Settings and Design: Prospective study from July 2012 to July 2014 was performed as a part of intramural research project., Materials and Methods: Tissue samples from resected gallbladder for cholelithiasis (n = 27) and carcinoma gallbladder (n= 24) were evaluated for survivin expression by IHC using a scoring system. Their expression was correlated with different clinicopathological parameters., Statistical Analysis: Fisher's exact test, Student's t-test, and Chi-square test were used as appropriate for data analysis. Kaplan-Meier methods were used to calculate overall and disease-free survival rates among different groups. Two-sided P< 0.05 was considered as significant., Results: Benign group (19 females, age [mean ± standard deviation [SD] 45 ± 14 years) and malignant group (20 females, age [mean ± SD] 48.9 ± 13.4 years) were comparable with respect to menopausal status, presence, size and types of stones. However, survivin expression was significantly higher (66.7%, 95% confidence interval [CI] 24-75) in gallbladder cancer than in cholelithiasis group (33%, CI 46-83), P= 0.025). Its expression did not correlate with gender, age, menopausal status, presence of gallstones or their size, number and type, tumor differentiation, and tumor stage., Conclusions: Significantly higher expression of survivin protein in gallbladder cancer as compared to cholelithiasis group suggests its role in gallbladder carcinogenesis though it may not have prognostic value.

Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34(+) cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34(+) cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells.

Introduction: The aim of this study was to detect the survivin, carcinoembryonic antigen (CEA) and ErbB2 in the saliva, serum and local tumor-exfoliated cells of oral squamous cell carcinoma (OSCC) patients, for providing reliable tumor markers for the early detection of oral malignant cancer., Materials and Methods: The saliva, serum, and local tumor-exfoliated cell samples of 26 OSCC patients without chemotherapy and 10 non-cancer patients were collected in Department of Oral and Maxillofacial Surgery, School of Stomatology, Peking University. The contents of survivin, CEA and ErbB2 using were detected usingenzyme-linked immunosorbent assay., Results: The survivin and CEA levels in saliva and local tumor-exfoliated cells of OSCC patients were significantly higher than those in the non-cancer patients (P < 0.05), but there was no significant difference in the content of the above factors in the serum sample between two groups. There was no significant difference in the ErbB2 content in the saliva, serum or local tumor-exfoliated cells between two groups., Conclusion: Survivin and CEA levels are significantly increased in the saliva and local tumor-exfoliated cells in OSCC patients, and they can be used as reliable markers for the early detection of oral malignant cancer.

Purpose: Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response., Materials and Methods: Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry., Results: Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p<0.001). The values for cancer specific survival were 76% and 56%, respectively (p<0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p=0.23) or cancer specific survival (55% vs 51%, p=0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials., Conclusions: Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor type, ranking as the third leading cause of all cancer-related deaths in the world. The post-surgical 5-year survival rate is low, largely due to the high recurrence rate. Therefore, the identification of target molecules that control the biological characteristics of HCC is of great importance. Ubiquitin-specific protease 22 (USP22) is a newly discovered deubiquitinating enzyme and is a cancer stem cell marker that plays a role in tumorigenesis, therapy resistance and cell cycle progression. Survivin is a member of the inhibitor of apoptosis protein (IAP) family and is known to function either as an inhibitor for apoptosis or as a regulator of cell division. Levels of survivin are correlated with the aggressiveness of tumors and a poor prognosis in various cancers including HCC. In the present study, we examined the USP22 expression and its association with survivin expression and clinicopathological features in HCC. First, we examined the expression of USP22 and survivin in 151 HCC cases by immunohistochemistry. High expression of USP22 and survivin was frequently observed in HCC cases, in comparison with normal adjacent liver tissues. Expression of USP22 and survivin was well correlated with malignant behavior including tumor size, stage and differentiation in HCC cases. Importantly, HCC patients with high expression of USP22 and survivin showed poor prognosis. USP22 expression was well correlated with survivin expression in HCC cases. This correlation was confirmed in HCC cell lines and tissues by RT-PCR and western blot analysis. Next, to investigate the biological role of USP22 in HCC, we examined the effect of USP22 knockdown on the cell growth and the expression of cell cycle-related protein including survivin in HCC cells. USP22 siRNA suppressed cell growth. Moreover, USP22 siRNA decreased survivin expression together with upregulation of CDK inhibitor, p21 and downregulation of cyclin B. These findings suggest that USP22 may be involved in HCC progression in cooperation with survivin. We suggest that USP22 can be useful as a new prognostic marker and therapeutic target in HCC patients.

Objective: Resveratrol inhibits cervical cancer (CC) cells by blocking STAT3 signaling. However, the mechanism of resveratrol-induced STAT3 inactivation remains largely unknown. SHP2, PIAS3, and SOCS3 are STAT3 negative regulators; therefore, their statuses in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa and C33A) cell lines without and with resveratrol treatment and their correlation with STAT3 activation in CC specimens were investigated., Methods: MTT and TUNEL assays were used to check the resveratrol sensitivity of CC cells, and immunocytochemical staining, Western blotting, and RT-PCR were used to analyze SHP2, PIAS3, and SOCS3 expression and the intracellular distribution of STAT3. Tissue microarray based immunohistochemical staining was performed to investigate potential correlations between SHP2, PIAS3, and SOCS3 expression and STAT3 activation., Results: PIAS3 and SOCS3 were found to be weakly expressed in CC cells and upregulated by resveratrol; this was accompanied by inhibition of STAT3 signaling. The SHP2 level remained unchanged in all three cell lines after resveratrol treatment. STAT3 nuclear translocation was more frequent in adenocarcinomas and squamous cell carcinomas than that of their noncancerous counterparts. The SOCS3 level and detection rate were higher in noncancerous squamous cells (but not in glandular epithelia) compared with their cancerous counterparts. The phospho-SHP2 detection rate was similar in noncancerous and tumor tissues of squamous and glandular origins; however, PIAS3 levels were distinct., Conclusions: Of the three STAT3 negative regulators, PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes. PIAS3 responsiveness may reflect greater resveratrol sensitivity and improved therapeutic outcome in CCs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To explore the expressions level of Livin, Survivin and Caspase-3 in prostatic cancer and the relationship among the 3 proteins and the clinicopathological features as well as the correlation among them. Totally, 43 paraffin-embedded prostate cancer tissues obtained from patients who were performed with rectal prostate biopsy or excision and 17 paraffin-embedded prostatic hyperplasia tissues were collected. All the specimens were confirmed by pathology. Immunohistochemistry SP method was used to detect the expressions of Livin, Survivin and Caspase-3 in prostatic cancer compared to hyperplasia tissues. The positive expression rates of both Livin and Survivin in prostatic cancer tissue were higher than those in prostatic hyperplasia tissue (93.02% vs. 64.70%, P < 0.05; 83.72% vs. 35.29%, P < 0.01). However, the positive expression rate of Caspase-3 in prostatic cancer tissue was obviously lower than that in prostatic hyperplasia tissue (25.58% vs. 58.82%, P < 0.01). Both Livin and Survivin expressions in prostatic cancer tissue were related to pathological grading (Gleason scores) (X(2) = 14.000, P = 0.001), but not related to preoperative PSA, clinical stages and distant metastasis (P > 0.05). Capsase-3 expression in prostatic cancer tissue was related to pathological grading (Gleason scores) (X (2) = 14.000, P = 0.001) and clinical stages (X (2) = 4.896, P = 0.027), but not related to preoperative PSA and distant metastasis (P > 0.05). In prostatic cancer tissue, Livin expression had no correlation with Survivin expression (r = 0.127, P = 0.419 > 0.05), but negatively correlated with Caspase-3 expression (r = -0.497, P = 0.001). Survivin expression was negatively correlated with Caspase-3 expression (r = -0.354, P = 0.020). Livin, Survivin and Caspase-3 are closely related to the occurrence and development of prostatic cancer and which are expected to become new targets for diagnosis and treatment in future.

Up to date, survivin, a well-known inhibitor of apoptosis, has attracted considerable attention as a potential biomarker and therapeutic target in diffuse large B-cell lymphoma (DLBCL). Nevertheless, there still remains no consensus on heterogeneous results. Herein, a meta-analysis was performed to clarify a convincing significance of survivin status on prognosis and clinicopathology of DLBCL patients.Eligible studies were identified by searching Medline, Embase, Scopus, CNKI, and Wanfang databases (last updated on November 30, 2014). Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Heterogeneity and sensitivity were also analyzed. Moreover, Begg, Egger test, and funnel plots were applied to evaluate the publication bias.We finally included 17 eligible studies with the total number of 1352 patients in the meta-analysis. The pooled results showed that positive survivin expression in DLBCL was associated with inferior overall survival (OS) (HR: 1.880, 95% CI: 1.550-2.270) in patients. Moreover, a significant association was revealed between survivin expression and advanced clinical stage (III + IV) (OR: 0.611, 95% CI: 0.452-0.827), higher International Prognosis Index (IPI) score (Score 3-5) (OR: 0.559; 95% CI: 0.410-0.761), elevated serum lactic dehydrogenase (LDH) (OR: 0.607, 95% CI: 0.444-0.831), presence of bone marrow involvement (OR: 2.127, 95% CI: 1.154-3.921) together with reduced complete remission (CR) rate (OR: 0.478, 95% CI: 0.345-0.662).The results suggest that survivin could be a useful prognostic biomarker, and a promising target for DLBCL therapeutic intervention. Considering limited HR data adjusted for standard prognostic variables could be retrieved, future high-quality studies will be needed in evaluating the independent prognostic value of survivin expression in DLBCL.

Apoptosis-related molecules can be abnormally expressed in cancers and underscore the hallmark of resisting cell death in cancer cells. This study was aimed to observe the expression patterns of apoptosis-related molecules in lung cancer and paired non-cancerous tissues, and to observe if there is a correlation between the expression of these apoptotic molecules and clinicopathologic parameters. Immunohistochemistry (IHC) was performed to analyze the expression level of CASP3, CASP8, CASP9, PARP1, Cleaved CASP3 (C-CASP3), Cleaved PARP1 (C-PARP1), XIAP, BIRC5 (Survivin) and BCL2 in lung cancer and paired non-cancerous tissues. We found that apoptosis-related molecules CASP3, CASP9, BCL2, BIRC5 and PARP1 are abnormally expressed in lung cancer cells and their expression were correlated with histology. BCL2, BIRC5 and PARP1 are expressed at higher levels in SCC than in non-SCC. C-PARP1 expression might be an independent prognostic factor for NSCLC.

Background: Survivin and monoamine oxidase A (MAOA) levels are elevated in prostate cancer (PCa) compared to normal prostate glands. However, the relationship between survivin and MAOA in PCa is unclear., Methods: We examined MAOA expression in the prostate lobes of a conditional PTEN-deficient mouse model mirroring human PCa, with or without survivin knockout. We also silenced one gene at a time and examined the expression of the other. We further evaluated the combination of MAOA inhibitors and survivin suppressants on the growth, viability, migration and invasion of PCa cells., Results: Survivin and MAOA levels are both increased in clinical PCa tissues and significantly associated with patients' survival. Survivin depletion delayed MAOA increase during PCa progression, and silencing MAOA decreased survivin expression. The combination of MAOA inhibitors and the survivin suppressants (YM155 and SC144) showed significant synergy on the inhibition of PCa cell growth, migration and invasion with concomitant decrease in survivin and MMP-9 levels., Conclusions: There is a positive feedback loop between survivin and MAOA expression in PCa. Considering that survivin suppressants and MAOA inhibitors are currently available in clinical trials and clinical use, their synergistic effects in PCa support a rapid translation of this combination to clinical practice.

Background: Merkel cell carcinoma (MCC) is a neuroendocrine cancer of the skin postulated to originate through Merkel cell polyomavirus (MCPyV) oncogenesis and/or by mutations in molecules implicated in the regulation of cell growth and survival. Despite the fact that MCPvV is detected more broadly within the population, only a part of the infected people also develop MCC. It is thus conceivable that together, virus and for example mutations, are necessary for disease development. However, apart from a correlation between MCPyV positivity or mutations and MCC development, less is known about the association of these factors with progressive disease., Objectives: To analyze MCPyV positivity, load and integration in MCC as well as presence of mutations in PDGFRα and TP53 genes and correlate these with clinical features and disease progression to identify features with prognostic value for clinical progression., Methods: This is a study on a MCC population group of 64 patients. MCPyV positivity, load and integration in parallel to mutations in the PDGFRα and TP53 were analyzed on genomic DNA from MCC specimens. In addition, expression of PDGFRα, survivin and p53 proteins was analyzed by immunodetection in tissues specimens. All these parameters were analyzed as function of patient's disease progression status., Results: 83% of MCCs were positive for the MCPyV and among these 36% also displayed virus-T integration. Viral load ranged from 0.006 to 943 viral DNA copies/β-globin gene and was highest in patients with progressive disease. We detected more than one mutation within the PDGFRα gene and identified two new SNPs in 36% of MCC patients, whereas no mutations were found in TP53 gene. Survivin was expressed in 78% of specimens. We could not correlate either mutations in PDGFR or expression of PDGFR, p53 and surviving either to the disease progression or to the MCPyV positivity., Conclusions: In conclusion, our data indicate that the viral positivity when associated with high viral load, correlates with poor disease outcome. Frequent mutations in the PDGFRα gene and high survivin expression were found in MCC independent of the viral positivity. These data suggest that these three factors independently contribute to Merkel cell carcinoma development and that only the viral load can be used as indicator of disease progression in virus positive patients., (Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: The mainstay of treatment in rectal cancer is neoadjuvant radio chemotherapy prior to surgery, in an attempt to downstage the tumour, allowing for more complete removal during surgery. In 40 % of cases however, this neoadjuvant radio chemotherapy fails to achieve tumour regression, partly due insufficient apoptosis signaling. X-linked Inhibitor of Apoptosis Protein (XIAP) is an anti-apoptotic protein that has been reported to contribute to disease progression and chemotherapy resistance., Methods: We obtained rectal biopsy normal and matched tumour tissue from 29 rectal cancer patients with varying degrees of tumour regression, and using Western blot, examined anti-apoptotic XIAP and pro-apoptotic Smac protein levels in these tissues, with the aim to examine whether disturbed XIAP/Smac levels may be an indicator of neoadjuvant radio chemotherapy resistance. Expression of inhibitor of apoptosis proteins cIAP-1 and cIAP-2 was also examined., Results: We found that levels of XIAP increased in accordance with the degree of radio chemotherapy resistance of the tissue. Levels of this protein were also significantly higher in tumour tissue, compared to matched normal tissue in highly resistant tissue. In contrast, Smac protein levels did not increase with radio chemotherapy resistance, and the protein was similarly expressed in normal and tumour tissue, indicating a shift in the balance of these proteins. Post treatment surgical resection tissue was available for 8 patients. When we compared matched tissue pre- and post- radio chemotherapy we found that XIAP levels increased significantly during treatment in both normal and tumour tissue, while Smac levels did not change. cIAP-1 and cIAP-2 levels were not differentially expressed in varying degrees of radio chemotherapy resistance, and neoadjuvant therapy did not alter expression of these proteins., Conclusion: These data indicate that disturbance of the XIAP/Smac balance may be a driver of radio chemotherapy resistance, and hence high levels of XIAP may be a useful indicator of neoadjuvant radio chemotherapy resistance in rectal cancer. Moreover, as XIAP levels increase with radio chemotherapy it is possible that a subset of more resistant tumour cells survive this treatment and may be resistant to further adjuvant treatment. Patients with resistant tumours highly expressing XIAP may benefit from alternative treatment strategies, such as Smac mimetics post neoadjuvant radio chemotherapy.

Background: The aim of this case-control study was to identify clinicopathological factors and test three relevant biomarkers for their ability to predict early intrahepatic recurrence after curative liver resection for colorectal liver metastases (CLM)., Methods: Of the 184 patients with CLM undergoing hepatectomy between January 2007 and December 2009, thirty patients had intrahepatic disease recurrence within 6 months. The control group was randomly selected from a cohort of patients between April 1997 and December 2005 who have survived without disease recurrence after CLM resection for over 5 years. Both groups were matched for size of metastasis greater than 5.0 cm, the presence of multiple metastases, and synchronous versus metachronous CLM. The final study population consisted of 60 patients with CLM undergoing R0 hepatectomy, 30 of whom had early intrahepatic-only recurrences (study group) and 30 patients without recurrence for more than 5 years (control group). Both groups were analyzed and compared for the presence of clinical factors and expression levels of CD133, survivin, and Bcl-2 within tumor tissue., Results: Characteristics of patients were similar between the two groups except primary tumor location and administration of postoperative chemotherapy. Expression level of CD133 and survivin were significantly increased in tumors of patients with recurrence compared to patients without recurrence. On multivariate analysis high tumor expression levels of CD133 (odds ratio [OR] 14.7, confidence interval [CI] 1.8-121.3, p = 0.012) and survivin (OR 9.5, CI 2.1-44.3, p = 0.004) and postoperative chemotherapy (OR 4.8, CI 1.01-22.9, p = 0.049) were independent factors associated with early intrahepatic recurrence., Conclusions: Tumor expression levels of CD133 and survivin may be a useful predictor of early intrahepatic recurrence after hepatectomy for CLM. Administration of postoperative chemotherapy may prevent early intrahepatic recurrence.

The clinical significance of the immunoexpression of survivin in prostate cancer and its correlation with the biological aggressiveness of prostate cancer remains unclear. Therefore, the present study was undertaken to compare the immunoexpression of survivin in prostate cancer (PCa) and benign prostatic hyperplasia (BPH) as well as to determine whether this immunoexpression could correlate with Gleason score, proliferation activity and prostate specific antigen (PSA) levels. The prostate needle biopsies from 28 patients with elevated serum PSA levels were studied. As a control, 12 needle biopsies of prostate diagnosed as BPH were used. The immunoexpression of survivin was evaluated semiquantitatively, whereas the Ki-67 index was assessed quantitatively. The immunoexpression of survivin and Ki-67 in epithelial cells in the prostate cancer group was significantly increased as compared to BPH cases. In the prostate cancer group there were positive significant correlations between the immunoexpression of survivin and Gleason score as well as Ki‑67 antigen. The correlation between the immunoexpression of survivin and PSA levels was also positive, but it did not reach statistical significance. In conclusion, we can confirm that in prostate cancer the immunoexpression of survivin is augmented as compared to BPH and positively correlated with parameters of tumor aggressiveness.

Background: Survivin, a novel inhibitor of apoptosis, plays a role in oncogenesis and has been correlated with poor prognosis. We investigated its expression in gallbladder tissues of control, cholelithiasis, and gallbladder cancer (GBC). Survivin expression was correlated with different clinicopathologic parameters including prognosis in patients with GBC., Materials and Methods: Gallbladder tissue samples were collected from GBC (n = 39), cholelithiasis (n = 30), and control (n = 25). Expression of survivin messenger RNA (mRNA) was evaluated by real time polymerase chain reaction. Protein quantification was done by enzyme-linked immunosorbent assay., Results: Significantly higher expression of survivin mRNA was observed in GBC (2.9-fold) and cholelithiasis (1.85-fold) as compared with control (P < 0.0001). In GBC, increased survivin expression (mRNA and protein) was significantly associated with higher tumor stage (stage III versus stage II) (P < 0.0001) and poor tumor differentiation (poor and moderate versus well) (P < 0.0001). No significant correlation was observed with any of the other clinicopathologic factors studied. Increased expression of survivin was associated with shorter survival (median survival 11.5 mo versus 18 mo)., Conclusions: Differential expression of survivin in GBC suggests its possible role in gallbladder carcinogenesis. Its overexpression is associated with poor prognosis. Assessment of survivin might be used to stratify GBC patients for optimal treatment modalities, including targeted therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is an intractable brain tumor, associated with poor prognosis and low survival rate. Combination therapy such as surgery, radiotherapy and temozolomide is considered standard in overcoming this aggressive cancer, despite poor prognosis. There is a need to identify potential agents, which may augment the chemotherapeutic effects of standard drugs such as temozolomide. In this project, we evaluated the effects of silibinin, a natural plant component of milk thistle seeds, to potentiate toxic effects of chemotherapy drugs such as temozolomide, etoposide and irinotecan on LN229, U87 and A172 (P53 and phosphatase and tensin homolog (PTEN) -tumor suppressor-mutated) glioma cell lines. Data from this work suggest that silibinin was effective in potentiating the cytotoxic efficacy of temozolomide in LN229, U87 and A172 cells. While silibinin reduced survivin protein expression only in LN229 cells, its ability to potentiate cytotoxicity of chemo therapy drugs occurred irrespective of survivin protein levels. The data also demonstrated that silibinin potentiated the effect of etoposide and but not irinotecan in LN229 cells. Future research will be required to evaluate the in vivo efficacy of silibinin to delineate its mechanism of action and its ability to cross the blood-brain barrier., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Survivin in pleural effusion is a promising marker for the diagnosis of malignant pleural effusion., Methods: Based on the principles and methods of Cochrane systematic reviews, PubMed, EMBASE, Web of Knowledge (ISI), the Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched to identify studies that assessed the diagnostic value of survivin in pleural effusion for malignant pleural effusion. Stata 12 and Meta-disc 1.4 software were used to test the heterogeneity and to perform the meta-analysis., Results: Our search returned 167 articles, of which ten fulfilled the inclusion criteria. These studies included a total of 614 patients with malignant pleural effusion and 430 patients with benign pleural effusion as controls. The summary assessments revealed that the pooled sensitivity was 0.86 (95% CI: 0.82-0.88) and the pooled specificity was 0.92 (95% CI: 0.89-0.94). The positive likelihood ratio was 8.76 (95% CI: 5.41-14.20), the negative likelihood ratio was 0.16 (95% CI: 0.13-0. 20) and the diagnostic odds ratio (DOR) was 59.72 (95% CI: 39.60-90.05). The area under the curve (AUC) for the pleural effusion survivin tests was 0.9485, and the *Q index estimate for these tests was 0.8885., Conclusions: Survivin in pleural effusion has potential diagnostic value with advanced sensitivity and specificity and it can be used as adjunct tool for non-invasive diagnosis of malignant pleural effusion., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Several high-risk human papillomavirus (HPV)-induced cell biomarkers have been proposed as possible candidates to identify patients harboring high-grade squamous intraepithelial lesions (HSILs) of the uterine cervix. We aimed to determine the feasibility of the detection of the mRNA of six biomarkers in cervical smear specimens obtained by liquid-based cytology and to evaluate whether this approach might be useful in the identification of patients with HSIL. One-hundred and twenty three women referred to colposcopy in the Hospital Clinic of Barcelona were included in the study. After a thorough study, including Pap test, high-risk HPV testing (Hybrid Capture 2 test), and colposcopy with directed biopsy and/or endocervical curettage, 48 patients were diagnosed with HSIL, whereas 75 were classified as negative (n=28), or harboring low-grade SIL (n=47). CDKN2A/p16, BIRC5, MMP9, TOP2A, MCM5, and MKI67 mRNA expression was analyzed by reverse transcription quantitative polymerase chain reaction in liquid-based cytology after the Pap test and Hybrid Capture 2 performance. The tissue expression of these biomarkers was analyzed by immunohistochemistry in the biopsy material. One-hundred and thirteen out of 123 (92%) liquid-based cytology yielded adequate material for mRNA analysis. TOP2A was the most sensitive (97%) biomarker for the detection of HSIL and CDKN2A/p16 the most specific (78%). The combination of TOP2A and CDKN2A/p16 showed a sensitivity of 96% (95% confidence interval (CI): 88-99) and a specificity of 71% (95% CI: 55-82). In the immunohistochemistry analysis, all biomarkers showed a high sensitivity but low specificity for HSIL, except CDKN2A/p16 which had a sensitivity of 100% and a specificity of 63%. The combination of TOP2A and CDKN2A/p16 showed a sensitivity of 100% (95% CI: 91-100) and a specificity of 43% (95% CI: 32-55). The detection of mRNA of cell biomarkers in liquid-based cytology material is feasible. The combination TOP2A and CDKN2A/p16 has a good balance between sensitivity and specificity for the detection of women with HSIL.

Multiplexing is an important tool in assay development as it allows simultaneous detection of numerous analytes. Current platforms with the capability to multiplex are often complex and expensive. Here, we describe a low-cost planar array on a chip capable of simultaneously detecting up to 80 different analytes using the MagArray technology in as little as 10 min. This technology is easy to operate, has a small footprint, and is highly portable as it does not require any moving parts and/or microfluidics. This technology also allows the user to obtain a real-time read-out, which is very useful for analyzing complex sample matrices and for assessing cross-reactivity easily, or to monitor the dissociation of low affinity proteins during washes. The recommended sample volume for analysis is 100 μL after dilution, but as little as 20 μL can be measured if needed.

Purpose of Investigation: To explore the significance of survivin, P16(INK4a), COX-2, and Ki-67 expressions for prediction of cervical cancer progression., Materials and Methods: A retrospective study was performed in 129 cases including 24 squamous carcinoma of the cervix (SCC), 70 cervical intraepithelial neoplasias (CIN), 15 cervical condyloma acuminatum (CCA), ten chronic cervicitis (CC), and ten normal cervix (NC). Protein expressions were evaluated using immunohistochemistry., Results: Survivin, P16(INK4a); COX-2, and Ki-67 were highly expressed in SCC and CIN compared with others. Their expression rates were gradually increased in CIN I, CIN II, CIN III, and SCC groups, showing 72.00%, 88.00%, 90.00%, and 95.83% for P16(INK4a), 68.00%, 84.00%, 95.00% and 100.00% for COX-2, 76.00%, 96.00%, 100.00%, and 100.00 for Ki-67, respectively. There were significant correlations between survivin and P16(INK4a), COX-2, Ki-67, as well as P16(INK4a) and Ki-67., Conclusion: Survivin, P16(INK4a), COX-2 and Ki-67 play critical roles for development and progression of cervical cancer.

The treatment of metastasized bladder cancer has been evolving during recent years. Cisplatin based chemotherapy combinations are still gold standard in the treatment of advanced and metastasized bladder cancer. But new therapies are approaching. Based to this fact biological markers will become more important for decisions in bladder cancer treatment. A systematic MEDLINE search of the key words "cisplatin", "bladder cancer", "DNA marker", "protein marker", "methylation biomarker", "predictive marker", "prognostic marker" has been made. This review aims to highlight the most relevant clinical and experimental studies investigating markers for metastasized transitional carcinoma of the urothelium treated by cisplatin based regimens.

Background and Objectives: The pathogenesis of human chronic rhinosinusitis with nasal polyps (CRSwNP) remains undetermined. Livin is a member of the inhibitor of the apoptosis protein family proteins. Caspase-3 and second mitochondria-derived activator of caspases (Smac) are critical in the induction of apoptosis. However, little is known about their roles in CRSwNP. We aimed to investigate the expression and role of Livin, caspase-3, and Smac in CRSwNP., Study Design: Basic research and descriptive study., Setting: Fuzhou General Hospital, Fuzhou, Fujian, China., Methods: The immunohistochemistry method was employed for detecting Livin, caspase-3, and Smac protein expression, and real-time polymerase chain reaction was used for assaying mRNA expression of Livin, caspase-3, and Smac in CRSwNP and controls. Moreover, the effects of various stimulators on Livin were evaluated on human nasal epithelial cells (HNECs) culture. Then, the effects of Livin on caspase-3 and Smac were observed on the culture of HNECs., Results: Stronger protein and mRNA expression of Livin was observed in CRSwNP, especially eosinophilic CRSwNP, weaker protein and mRNA expression of caspase-3 and Smac was observed in CRSwNP, and Livin expression was negatively related to caspase-3 or Smac expression, respectively. Livin mRNA was augmented by interleukin (IL)-4, IL-17A, and IL-1β but suppressed by interferon-γ. Caspase-3 and Smac mRNA expression were inhibited by Livin., Conclusions: Upregulation of Livin and downregulation of caspase-3 and Smac were observed in CRSwNP, especially in eosinophilic CRSwNP. Livin may exert its anti-apoptosis effect by suppressing caspase-3 and Smac in CRSwNP. IL-4, IL-17A, and IL-1β may be critical for Livin expression., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)