Combination of biomarkers for neoadjuvant systemic chemotherapy before cystectomy in patients with urinary bladder cancer.

Clinical utility of cisplatin based neoadjuvant chemotherapy (NAC) prior to radical cystectomy is limited because of lack of tools that can guide for a better patient selection. We aim to explore if a combination of biomarkers is superior to a single marker. Pretreatment tumor specimens and clinical data from two randomized trials including 250 patients with T2-T4 urothelial bladder cancer, were used. The information on the expressions on tumor tissue of four biomarkers; CCTα, emmprin, survivin, and BCL-2, detected by immunohistochemistry in our previous studies, was used. Cox proportional hazard models, including treatment-by-biomarker interaction terms, were used to assess the predictive value of the biomarkers for efficacy of NAC on overall survival. CCTα provided predictive information about the efficacy of NAC (interaction P=0.009). None of the other biomarkers provided statistically significant information additional to CCTα. The adjusted hazard ratio for NAC treated versus no-NAC was 0.42 (95% CI: 0.27-0.64) for patients with negative CCTα expression, when adding information about emmprin it decreased to 0.33 (95% CI: 0.19-0.56) for patients with both negative CCTα and emmprin. This corresponds to a decrease in number needed to treat from 4 to 3 patients. The combination of CCTα with survivin or BCL-2 yielded similar results. In a group of patients with muscle invasive bladder cancer a combination of two biomarkers might improve the possibility to identify patients most likely to benefit from the use of NAC. Further studies designed to have sufficient power to detect an interaction effect are needed.

Cytoproliferative effect of low dose alpha radiation in human lung cancer cells is associated with connexin 43, caveolin-1, and survivin pathway.

PURPOSE: High LET including alpha radiation-based approaches have been proved as a promising mode for cancer therapy owing to their biophysical and radiobiological advantages compared to photon beams. Studies pertaining to effect of α-radiation on cancer cells are limited to cytotoxic high doses. MATERIALS AND METHODS: In this study, human lung adenocarcinoma (A549) cells were α-irradiated using 241Am α-irradiator and effects of low dose of alpha radiation on these cells was studied under in vitro and in vivo conditions. RESULTS: Clonogenic and other assays showed increased cellular proliferation at lower doses (1.36 and 6.8 cGy) but killing at higher doses (13.6-54.4 cGy). Further studies at low dose of alpha (1.36 cGy) showed increased TGF-ß1 in the conditioned medium (CM) at early time point (24 h) but CM replacement did not affect the clonogenic survival. In these cells, increased phosphorylation of connexin 43 was correlated with decrease in gap-junction communication observed by dye transfer co-culture experiment. A decrease in caveolin-1 but increase in survivin expression was observed in low dose α-irradiated cells. An increase in cyclinD1 and decrease in Bcl-2, the target proteins of survivin, was observed in these cells. Low dose α-irradiated cancer cells transplanted in SCID mice showed significantly higher tumor volume, which was accompanied with an increased fraction of mitotic and PCNA/Ki67 positive cells in these tumor tissues. CONCLUSIONS: Taken together, our results suggest an increase in proliferation and tumor volume at in vitro and in vivo levels, respectively, when A549 cells were irradiated with low dose of α-radiation. These findings may be relevant for a better understanding of radiobiological processes during high LET-based cancer radiotherapy.

Concentration of survivin in children with oligo- and polyarticular juvenile idiopathic arthritis (JIA): diagnostic and prognostic value-a single-center study.

AIM: The goal of the study was to assess the diagnostic and prognostic utility of survivin in patients with juvenile idiopathic arthritis (JIA). METHODS: Seventy children with JIA-59 newly diagnosed and 11 biologically treated (46 girls and 17 boys) aged 1.5-18 years and 29 healthy children as a control group, appropriately matched in terms of sex and age, were included in the study. The disease activity was established on the basis of the JADAS-27 criteria. The concentration of survivin was assessed by an ELISA test in serum and also 18 matched synovial fluid samples collected from patients with JIA. RESULTS: Children with JIA were divided according to the subtype of the JIA. In 65.7% of patients, oligoarthritis was diagnosed. The largest group comprised children of low disease activity (62.9%) according to JADAS-27. The serum concentration of survivin was significantly higher in children with JIA compared to the controls (p < 0.001). The concentration of survivin was higher among patients positive for anti-cyclic citrullinated peptide autoantibodies (ACPA) (p = 0.001). In all synovial fluid samples, the concentration of survivin was higher than in matched serum (p = 0.003). Serum survivin concentration was not significantly associated with radiological damage status or active synovitis assessed by joint ultrasonography. Survivin level was not significantly associated with disease duration time or treatment with TNF-α inhibitors in DMARD's non-responders. CONCLUSIONS: Survivin should be considered as a biomarker of joint inflammation helpful in the diagnosis of oligo- and polyarticular JIA and probably not dependent on treatment with TNF-α inhibitors.

Effect of cinnamaldehyde on Cav-1 and Survivin expression in epilepsy: A protocol of systematic review and meta-analysis.

BACKGROUND: This systematic review aims to assess the effect of cinnamaldehyde on Cav-1 and Survivin expression in epilepsy. METHODS: We will search Cochrane Library, PUBMED, EMBASE, CINAHL, Web of Science, Google Scholar, PsycINFO, WANGFANG, VIP, CBM, and CNKI from their inceptions to the March 31, 2020, without language restrictions. Two authors will independently carry out searching literature records, scanning titles and abstracts, full texts, collecting data, and assessing risk of bias. RevMan 5.3 software will be used for statistical analysis. RESULTS: This systematic review will investigate whether cinnamaldehyde is effective on Cav-1 and Survivin expression in epilepsy. CONCLUSION: Its findings will provide helpful evidence for the effect of cinnamaldehyde on Cav-1 and Survivin expression in epilepsy.Systematic review registration: INPLASY202040152.

Prevalence and Prognostic Value of HPV among Tunisian Patients with Laryngeal Cancer and Relationship between DNA HPV and p16, IGF-1R, Survivin, p53 Expressions.

OBJECTIVES: Tobacco and alcohol are the main etiological factors common to laryngeal cancers. However, the Human Papilloma Virus (HPV) constitutes an alternative risk factor according to several studies. In Tunisia, despite the annual increasing incidence of laryngeal squamous cell carcinoma (LSCC), the prevalence and prognostic significance of HPV have never been explored.In this study, we sought to highlight HPV DNA in 70 biopsies of laryngeal cancer, and to analyze the status of HPV infection in association with p53, p16, survivin, and IGF-1R expressions. METHODS: HPV high risk (HPV HR) DNA was detected in tumors by in situ hybridization. However, the expression of p53, p16, survivin and IGF-1R were stained by immunohistochemistry test. The correlations of HPV status with clinicopathological parameters, overall survival, disease-free survival and proteins expressions were statistically evaluated. RESULTS: HPV HR DNA was detected in 39 out of 70 (55.71%) laryngeal tumors. HPV+ patients have a better overall survival (P = .081) and long disease-free-survival (P = .016) with a low rate of recurrence (P = .006) than HPV- patients. No significant correlations were found between HPV HR status and clinicopathological parameters (all P > .005). Moreover, HPV+ tumors were not associated with expression of p53, p16 and survivin. However, HPV HR status correlates with weak to moderate IGF-1R expression (P = .043). CONCLUSION: The substantial detection of HPV HR in LSCC tumors suggest that this virus plays an important part in laryngeal cancer in Tunisia. It is a good prognostic factor. In addition, HPV infection could act to block the pathway of IGF-1R expression.

Estudio de los niveles basales de survivina y otros marcadores para la predicción de los resultados de la pleurodesis con talco en derrames pleurales malignos / Study on the baseline levels of survivin and other markers to predict the results of pleurodesis with talc in malignant pleural effusions

La survivina se encuentra sobre-expresada en tumores, y podría ser un buen biomarcador diagnóstico y pronóstico en derrames pleurales malignos. OBJETIVO: estudiar la concentración de survivina en pacientes con derrame pleural maligno sometidos a pleurodesis con talco, relacionarla con el resultado de ésta y comparar sus resultados con otros marcadores como pH, glucosa y LDH en líquido pleural. MÉTODOS: se han incluido 84 pacientes con derrame pleural maligno (32 con cáncer de mama, 25 de pulmón y 27 mesoteliomas) sometidos a toracoscopia y pleurodesis con talco. Se recogieron muestras de líquido pleural antes (basal) y 24 horas después de la pleurodesis, y en ellas se midieron los niveles de survivina, pH, glucosa y LDH. También se estudió la carga tumoral en la pleura y la re-expansión del pulmón tras la toracoscopia y pleurodesis.R RESULTADOS: la presencia de niveles basales de survivina > 30 pg/mL se asoció a alto índice de fracaso de la pleurodesis (p = 0,002), y superó en poder predictivo a pH (p = 0,004), glucosa (p = 0,005) y LDH (p = 0,013) CONCLUSIÓN: la survivina juega un poderoso papel como marcador pronóstico en derrames pleurales malignos, y se suma a otros marcadores clásicos como pH, glucosa y LDH, que están asociados a la agresividad tumoral

Survivin is found to be overexpressed in tumors and could be a good diagnostic and prognostic biomarker in malignant pleural effusions. OBJECTIVE: To study the concentration of survivin in patients with a malignant pleural effusion who undergo pleurodesis with talc, associate it with the result of the procedure and compare the results with other markers like pH, glucose and LDH in pleural liquid. METHODS: 84 patients with malignant pleural effusion (32 with breast cancer, 25 lung cancer and 27 mesotheliomas) who underwent thoracoscopy and pleurodesis with talc were included in the study. Pleural liquid samples were taken before (baseline) and 24 hours after the pleurodesis, measuring the levels of survivin, pH, glucose and LDH. The tumor burden in the pleura and the re-expansion of the lung after thoracoscopy and pleurodesis were also studied. RESULTS: The presence of baseline levels of survivin >30 pg/mL was associated with a high rate of pleurodesis failure (p = 0.002) and surpassed the predictive power of pH (p = 0.004), glucose (p = 0.005) and LDH (p = 0.013). CONCLUSION: Survivin plays a powerful role as a prognostic marker in malignant pleural effusions and joins other classic markers like pH, glucose and LDH, which are associated with tumor aggression

Unraveling survivin expression in chronic myeloid leukemia: Molecular interactions and clinical implications.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL oncoprotein, known to drive leukemogenesis by orchestrating multiple signaling pathways ultimately involved in cell survival. Despite successful response rates of CML patients to tyrosine kinase inhibitors (TKIs), resistance eventually arises due to BCR-ABL-dependent and independent mechanisms. Survivin is an inhibitor of apoptosis protein acting in the interface between apoptosis deregulation and cell cycle progression. In CML, high levels of survivin have been associated with late stages of disease and therapy resistance. In this review, we provide an overview of important aspects concerning survivin subcellular localization and expression pattern in CML patients and cell lines. Moreover, we highlight the relevance of molecular networks involving survivin for disease progression and treatment resistance. Finally, we discuss the mechanisms accounting for survivin overexpression, as well as novel therapeutic interventions that have been designed to counteract survivin-associated malignancy in CML.

Loss of cytoplasmic survivin expression is an independent predictor of poor prognosis in radically operated prostate cancer patients.

Survivin is an inhibitor of apoptosis. Aberrant survivin expression occurs in malignant tumors and has often been linked to unfavorable patient outcome. Here we analyzed 12 432 prostate cancers by immunohistochemistry. Survivin immunostaining was regularly expressed at high levels in normal prostate epithelium but expression was often reduced in prostate cancers. Among 9492 evaluable prostate cancers, 9% expressed survivin strongly, 19% moderately, 28% weakly, and 44% lacked it. Loss of cytoplasmic survivin was seen in advanced tumor stage, higher Gleason score, preoperative PSA levels, and Ki-67 labeling index, and associated with earlier PSA recurrence (P < .0001). Survivin loss was significantly more common in cancers carrying TMPRSS2:ERG fusions (61% survivin negative) than in ERG wild-type cancers (32% survivin negative; P < .0001). Multivariate analysis revealed that reduced cytoplasmic survivin expression predicted poor prognosis independent from Gleason score, pT, pN, and serum PSA level. This was valid for ERG-positive and ERG-negative cancers. Survivin expression loss even retained its prognostic impact in 1020 PTEN deleted cancers, a group that is already characterized by dismal patient prognosis. In conclusion, reduced survivin expression is associated with more aggressive tumors and inferior prognosis in prostate cancer.

Contribution to characterization of skin field cancerization activity: morphometric, chromatin texture, proliferation, and apoptosis aspects.

BACKGROUND: A skin field cancerization is a cutaneous area with subclinical changes resultant from chronic sun exposure, with a higher predisposition to development of pre-neoplastic and neoplastic lesions. So far, there are no well-defined objective parameters that can indicate their degree of activity. OBJECTIVES: To describe and compare morphometric aspects and expression of factors related to apoptosis and cell proliferation in actinic keratosis (AK), in both photoexposed and photoprotected epidermis. METHODS: A cross-sectional study of patients with actinic keratosis in the forearms, biopsied at two points: the actinic keratosis and the axillary region. The biopsies of the actinic keratosis, perilesional area, and axilla were evaluated through keratinocyte intraepithelial neoplasia (KIN), and immunohistochemistry of p53, survivin, and Ki67. Nuclear morphometry of basal layer cells was performed through digital image analysis: entropy, area, perimeter, Ra, fractal dimension, circularity, color intensity, and largest diameter. RESULTS: There were 13 patients included and 38 actinic keratosis biopsied. In morphometry, 1039 nuclei were analyzed, of which 228 represented axillary skin, 396 demonstrated actinic keratosis, and 415 represented the perilesional area to the actinic keratosis. There was a significant difference (p<0.05) in all variables tested for the topographies evaluated. A significant correlation was identified between nucellar morphometric elements, KIN, proliferation markers, and apoptosis. Joint patterns of p53, Ki67, and KIN discriminated the topographies sampled. STUDY LIMITATIONS: This was a cross-sectional study with a small number of patients. CONCLUSIONS: There are patterns of proliferation, resistance to apoptosis, and different cellular morphometrics between photoprotected skin and photoexposed skin. The joint expression of p53, Ki67, and KIN can characterize skin field cancerization activity.

The role of Survivin as a biomarker and potential prognostic factor for breast cancer.

Breast cancer (BC) is one of the primary health problems worldwide. As the most common cancer in women in the world and in Brasil, behind only non-melanoma skin cancer, this neoplasm corresponds to approximately 28% of new cases per year in the country. BC also affects men, although the incidence corresponds to only 1% of total cases. Currently, most of the chemotherapeutic agents used in BC treatment are extremely toxic and cause long-term side effects. There is also a need to obtain earlier diagnoses, more accurate prognoses and make new therapies available that are more selective and effective in order to improve the current scenario. Therefore, this work sought to evaluate the importance of the biomarker survivin (Sur) in relation to BC, through the detailing of the role of Sur as a biomarker, the correlation between this protein and the prognosis of BC patients, and a summary of therapeutic strategies that target Sur for the development of new anticancer therapies.

The role of Survivin as a biomarker and potential prognostic factor for breast cancer

SUMMARY Breast cancer (BC) is one of the primary health problems worldwide. As the most common cancer in women in the world and in Brasil, behind only non-melanoma skin cancer, this neoplasm corresponds to approximately 28% of new cases per year in the country. BC also affects men, although the incidence corresponds to only 1% of total cases. Currently, most of the chemotherapeutic agents used in BC treatment are extremely toxic and cause long-term side effects. There is also a need to obtain earlier diagnoses, more accurate prognoses and make new therapies available that are more selective and effective in order to improve the current scenario. Therefore, this work sought to evaluate the importance of the biomarker survivin (Sur) in relation to BC, through the detailing of the role of Sur as a biomarker, the correlation between this protein and the prognosis of BC patients, and a summary of therapeutic strategies that target Sur for the development of new anticancer therapies.

RESUMO O câncer de mama (CM) é um dos principais problemas de saúde em todo o mundo. Como o câncer mais comum em mulheres no mundo e no Brasil, precedido apenas pelo câncer de pele não melanoma, essa neoplasia corresponde a aproximadamente 28% dos novos casos por ano no país. O CM também afeta homens, embora a incidência corresponda a apenas 1% do total de casos. Atualmente, a maioria dos agentes quimioterápicos utilizados no tratamento do CM são extremamente tóxicos e causam efeitos colaterais a longo prazo. Há também a necessidade de se obterem diagnósticos mais precoces, prognósticos mais precisos e disponibilizar novas terapias seletivas e efetivas, a fim de melhorar o cenário atual. Portanto, este trabalho buscou avaliar a importância do biomarcador Survivina (Sur) em relação ao CM, por meio do detalhamento do papel do Sur como biomarcador, da correlação entre essa proteína com o prognóstico de pacientes com CM e de um resumo do tratamento terapêutico e das estratégias que visam utilizar a Sur para o desenvolvimento de novas terapias anticâncer.

BioScore (B7-H1, survivin, and Ki-67) does not predict cancer-specific mortality in surgically treated patients with renal cell carcinoma: An external validation study.

BACKGROUND: To externally validate' BioScore', a biomarker-based scoring system using immunohistochemical tumor expression levels of B7-H1, survivin, and Ki-67, in a single-center cohort of renal cell carcinoma (RCC) patients. Additionally, we investigated the potential benefit of BioScore as compared to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score. MATERIALS AND METHODS: The validation cohort comprised 393 nonmetastatic RCC patients treated with radical nephrectomy or nephron-sparing surgery from 1999 to 2004. Kaplan-Meier estimators, the log-rank test, uni- and multivariable Cox regression models, and measures of discrimination were used to quantify the prognostic performance of BioScore regarding cancer-specific mortality (CSM). RESULTS: During a median follow-up of 7.8 years, 69/132 (52%) deaths were adjudicated to progressive disease. BioScore was weakly associated with CSM in univariable analysis (hazard ratio per 1 point increase = 1.12, 95% confidence interval = 1.02-1.23, P = 0.023). However, this association did not prevail after adjusting for other adverse prognostic factors as represented by the SSIGN score. The discriminative performance of BioScore was very modest (Harrell's C-Index = 0.60) and did not improve the SSIGN score (P = 0.341), which already showed an excellent discrimination, as evidenced by Harrell's C-Index of 0.81. In a sensitivity analysis regarding clear cell RCC patients only, B7-H1 positivity did not emerge as a statistically significant predictor of CSM. CONCLUSION: Although a higher BioScore was significantly associated with a higher CSM, the magnitude of this association was weak and not independent from other prognosticators. Moreover, BioScore did not improve the prognostic accuracy of the SSIGN score.

Correlation between SOX2 and Survivin clinical features in patients with salivary adenoid cystic carcinoma.

OBJECTIVE: In this study, expression of cancer stem cells (CSCs)-related factor-Sex-determining region of Y chromosome-related high-mobility-group box 2 (SOX2) and anti-apoptotic specific factor- Survivin in salivary adenoid cystic carcinoma (SACC) was detected to provide important clues for effective SACC prevention and treatment by combining clinical pathological parameters analysis. METHODS: Paraffin and fresh specimens were collected from SACC patients who underwent surgery at the Oral and Maxillofacial Surgery Department of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital. The experimental group was designed as SACC tissue, and the control group normal paracancerous normal gland tissue. (1) SOX2 and Survivin expression were detected using immunohistochemistry and analyzed by comnining clinical pathological parameter analysis. (2) mRNA and protein expression levels of SOX2 and Survivin were detected using RT-PCR, Western Blot. RESULTS: 1. Immunohistochemistry: (1) SOX2 was mainly expressed on the nucleus. The SOX2 positive rate was 28.57% in clinical stage I-II, and 76.92% in stage III-IV. (2) Survivin was mainly expressed in the cytoplasm. The Survivin positive rate was 61.90% in clinical stage I-II, and 76.92% in stage III-IV. (3) There was a clear correlation between SOX2 and Survivin. 2. RT-PCR and Western Blot: The mRNA and protein expression levels of SOX2 and Survivin were significantly higher in the experimental group than in the control group (P < 0.01). CONCLUSION: (1) The mRNA and protein expression level of SOX2 and Survivin was significantly higher in SACC tissues than in paracancerous normal salivary gland tissues, indicating that both of the two are tissue-specific and may become SACC oncogenes. (2) SOX2 and Survivin are significantly correlated in expression, which may coorinatively participate in SACC incidence and development.

High expression of survivin independently correlates with tumor progression and mortality in patients with skull base chordomas.

OBJECTIVE: The object of this study was to clarify the expression characteristics and prognostic value of survivin in skull base chordomas. METHODS: In this retrospective study, the authors measured the expression of survivin at the mRNA level in 81 samples from 71 patients diagnosed with skull base chordomas at their hospital in the period from July 2005 to January 2015. Clinical data collection, follow-up, and survival analyses were performed, and correlations were analyzed. RESULTS: Of the 71 patients, 50 had primary chordomas with a mean survivin expression level of 1.09; the other 21 patients had recurrent chordomas with a mean survivin expression level of 2.57, which was 2.36 times higher than the level in the primary chordoma patients (p < 0.001, Mann-Whitney U-test). In addition, an analysis of 18 paired samples derived from 9 patients showed that the expression level of survivin was 2.62 times higher in recurrent tumors than in primary tumors (p = 0.002, paired t-test). The Spearman rank correlation coefficient method showed that the expression level of survivin was positively correlated with the mean ratio of tumor signal intensity to the signal intensity of surrounding brainstem on T1-weighted sequences (RT1; rs = 0.274, p = 0.021) and was negatively correlated with the mean ratio of tumor signal intensity to the signal intensity of surrounding brainstem on T2-weighted sequences (RT2; rs = -0.389, p = 0.001). A multivariate Cox proportional-hazards model suggested that pathology (p = 0.041), survivin expression level (p = 0.018), preoperative Karnofsky Performance Status (KPS; p = 0.012), and treatment history (p = 0.009) were independent prognostic factors for tumor progression. Survivin expression level (p = 0.008), preoperative KPS (p = 0.019), tumor diameter (p = 0.027), and intraoperative blood loss (p = 0.015) were independent prognostic factors for death. CONCLUSIONS: Survivin expression level and preoperative KPS were independent significant prognostic factors for tumor progression and death in skull base chordoma patients. Recurrent skull base chordomas and chordomas with high RT1 and low RT2 were likely to have high survivin expression. Other independent risk factors related to tumor progression included conventional pathology and treatment history, whereas additional mortality-related risk factors included larger tumor diameter and greater intraoperative blood loss.

Integrative Histologic and Bioinformatics Analysis of BIRC5/Survivin Expression in Oral Squamous Cell Carcinoma.

Survivin is a well-known protein involved in the inhibition of apoptosis in many different cancer types. The aim of this study was to perform an integrated bioinformatic and histologic analysis in order to study the expression and prognostic role of Survivin and its related gene BIRC5 in oral cancer. Publicly available databases were accessed via Gene Expression Omnibus and Oncomine, in addition raw data from The Cancer Genome Atlas (TCGA) were also obtained in order to analyze the rate of gene mutation, expression and methylation in patients with oral squamous cells carcinoma (OSCC). Immunohistochemistry (IHC) was also performed in order to evaluate the nuclear and cytoplasmic expression of Survivin and their correlation with cell proliferation in samples from OSCC patients. Results of this study revealed that Survivin is rarely mutated in OSCC samples and upregulated when compared to non-cancerous tissue. A negative correlation between the methylation of the island cg25986496 and BIRC5 mRNA expression was detected from TCGA data. IHC staining revealed that cytoplasmic (and not nuclear) expression of Survivin is associated with poor overall survival in OSCC patients, while the nuclear expression correlates with higher proliferation rate. In addition, data from TCGA database revealed that BIRC5 gene expression is an independent prognostic factor for OSCC patients.

Targeting HSP60 by subcutaneous injections of jetPEI/HSP60-shRNA destabilizes cytoplasmic survivin and inhibits hepatocellular carcinoma growth.

Heat shock protein 60 (HSP60) overexpresses in various types of cancer, but its expression levels and functions in hepatocellular carcinoma (HCC) are still in dispute. We aim to clarify this issue and examine whether HSP60 could be a therapeutic target for HCC. We found drastically enhanced cell apoptosis and suppressed cell proliferation in two HCC cell lines with HSP60-silencing, and also indicated survivin was involved in this regulatory process in vitro and in vivo. However, HSP60-silencing in normal human hepatocytes only resulted in a minimal reduction of cell proliferation but without effects on cell apoptosis. We also showed HSP60 interacted with cytosolic but not mitochondrial survivin by immunoprecipitation assay. A rigorous method was used to standardize quantification from immunoblot assay to obtain more precise expression levels of HSP60 and survivin. The expression of HSP60 and survivin positively correlated in both cancerous and non-cancerous liver tissues (P < 0.001) after analyzing 145 surgically removed HCC tissues. A total of 56.6% of HCC patients overexpressed HSP60 in cancerous tissues, and 40.0% under-expressed HSP60. Higher expression of HSP60 and survivin in non-cancerous tissues both correlated with shorter overall survival (P = 0.029 and P < 0.001, respectively). Finally, we evaluated the therapeutic potential of HSP60 using extraneous delivery of jetPEI/shHSP60 complexes. The treatment results showed significant reduction of tumor weight by 44.3% (P < 0.05), accompanied by under-expression of survivin. These studies suggested that HSP60 not only served as a prognostic marker but also served as a novel therapeutic target for HCC.

Differentially localized survivin and STAT3 as markers of gastric cancer progression: Association with Helicobacter pylori.

BACKGROUND: Localization and differential expression of STAT3 and survivin in cancer cells are often related to distinct cellular functions. The involvement of survivin and STAT3 in gastric cancer has been reported in separate studies but without clear understanding of their kinetics in cancer progression. METHODS: We examined intracellular distribution of STAT3 and survivin in gastric adenocarcinoma and compared it with normal and precancer tissues using immunoblotting and immunohistochemistry. RESULTS: Analysis of a total of 156 gastric samples comprising 61 histologically normal, 30 precancerous tissues (comprising intestinal metaplasia and dysplasia), and 65 adenocarcinomas, collected as endoscopic biopsies from treatment naïve study participants, revealed a significant (P < .001) increase in overall protein levels. Survivin expression was detectable in both cytoplasmic (90.8%) and nuclear (87.7%) compartments in gastric adenocarcinomas lesions. Precancerous dysplastic gastric lesions exhibited a moderate survivin expression (56.7%) localized in cytoplasmic compartment. Similarly, STAT3 and pSTAT3 expression was detected at high level in gastric cancer lesions. The levels of compartmentalized expression of survivin and STAT3/pSTAT3 correlated in precancerous and adenocarcinoma lesions. Although overexpression of these proteins was found associated with the tobacco use and alcohol consumption, their expression invariably and strongly correlated with concurrent Helicobacter pylori infection. Receiver operating characteristic analysis of nuclear survivin, STAT3, and pSTAT3 in different study groups showed acceptable positive and negative predictive values with area under the curve above 0.8 (P < .001). CONCLUSION: Overall, our results suggest that overall increase in survivin and STAT3 and their subcellular localization are key determinants of gastric cancer progression, which can be collectively used as potential disease biomarkers and therapeutic targets for gastric cancer.

Clinicopathological variables of sporadic schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers.

OBJECTIVE While sporadic peripheral schwannomas (SPSs) are generally well treated with surgery, their biology is not well understood. Consequently, treatment options are limited. The aim of this study was to provide a comprehensive description of SPS. The authors describe clinicopathological features and treatment outcomes of patients harboring these tumors, and they assess expression of biomarkers using a clinically annotated tissue microarray. Together, these data give new insight into the biology and management of SPS. METHODS Patients presenting with a primary SPS between 1993 and 2011 (n = 291) were selected from an institutional registry to construct a clinical database. All patients underwent follow-up, and short- and long-term outcomes were assessed. Expression of relevant biomarkers was assessed using a new tissue microarray (n = 121). RESULTS SPSs were generally large (mean 5.5 cm) and frequently painful at presentation (55%). Most patients were treated with surgery (80%), the majority of whom experienced complete resolution (52%) or improvement (18%) of their symptoms. Tumors that were completely resected (85%) did not recur. Some patients experienced short-term (16%) and long-term (4%) complications postoperatively. Schwannomas expressed higher levels of platelet-derived growth factor receptor-ß (2.1) than malignant peripheral nerve sheath tumors (MPNSTs) (1.5, p = 0.004) and neurofibromas (1.33, p = 0.007). Expression of human epidermal growth factor receptor-2 was greater in SPSs (0.91) than in MPNSTs (0.33, p = 0.002) and neurofibromas (0.33, p = 0.026). Epidermal growth factor receptor was expressed in far fewer SPS cells (10%) than in MPNSTs (58%, p < 0.0001) or neurofibromas (37%, p = 0.007). SPSs more frequently expressed cytoplasmic survivin (66% of tumor cells) than normal nerve (46% of cells), but SPS expressed nuclear survivin in fewer tumor cells than in MPNSTs (24% and 50%, respectively; p = 0.018). CONCLUSIONS Complete resection is curative for SPS. Left untreated, however, these tumors can cause significant morbidity, and not all patients are candidates for resection. SPSs express a pattern of biomarkers consistent with the dysregulation of the tumor suppressor merlin observed in neurofibromatosis Type 2-associated schwannomas, suggesting a shared etiology. This SPS pattern is distinct from that of other tumors of the peripheral nerve sheath.

Targeting phosphorylation of STAT3 delays tumor growth in HPV-negative anal squamous cell carcinoma mouse model.

Although conventional chemoradiotherapy is effective for most anal squamous cell carcinoma (ASCC) patients, HPV-negative ASCC patients respond poorly to this treatment and new therapeutic approach is required. Our group has previously established an HPV-negative ASCC mouse model and demonstrated that signal transducer and activation of transcription 3 (STAT3) is hyper-activated in the model. Here, we show that in vivo inhibition of STAT3 by S3I-201 effectively delays tumor growth in ASCC mouse model indicated by significantly smaller tumor size and burden in the treatment group compared with control group at the same point. Further analysis shows that survivin and Ki67, important biomarkers for tumor cell survival and proliferation, are significantly reduced after S3I-201 treatment. Additionally, flow cytometry and immunohistofluorescent assays reveal decreased Myeloid-derived suppressor cell (MDSC) and tumor-associated macrophage (TAM) populations in the S3I-201 treatment group, which indicates a reversion of the immunosuppressive environment, unraveling the potential role for S3I-201 in immunosuppression in ASCC. Together these results for the first time demonstrated the anti-tumor effects of STAT3 inhibitor S3I-201 in HPV-negative ASCC mouse model and its multiple effects on cancer cells and immune system. Thus we conclude that S3I-201 may be a novel therapeutic approach for HPV-negative ASCC patients.