Investigation of YAP-1, OTX-2, and nestin protein expressions in neuroblastoma: a preliminary study.

OBJECTIVES: Neuroblastoma is the most common extracranial solid tumor in childhood. YAP (Yes-associated protein) is a highly expressed protein in NB. Nestin is an important marker of neuronal differentiation in NB. Orthodenticle homeobox (OTX) is a transcription factor and is overexpressed in blastoma-derived tumors. The aim of this study was to examine the potential roles of YAP-1, Nestin, and OTX-2 proteins in prognosis and risk stratification in neuroblastoma METHODS: Tumor sections of 56 patients with different NB risk groups were analyzed. YAP-1, Nestin, and OTX-2 protein expression levels were evaluated by immunohistochemical staining in NB patient tissue samples. RESULTS: YAP-1, Nestin, and OTX-2 protein expression levels were evaluated together with the clinical findings of NB patients. YAP-1 was expressed in 18% of all tissues, while Nestin was expressed in 20.4%. OTX-2 protein expression was found in 41.1% of the NB patients. YAP-1 was expressed in 26.9% of high-risk and 11.5% of low-risk patients. Nestin was expressed in 24.4% high-risk and 33.3% low-risk patients. OTX-2 was expressed in 68.2% high-risk and 60% low-risk patients.YAP-1 was shown to provide survival advantages among risk groups. INTERPRETATION: The findings of this study support that YAP-1 may be a potential prognostic biomarker for staging and risk-group assignment of NB patients. YAP-1 expression in neuroblastoma is associated with significantly poorer survival probabilities and should be considered as a potential therapeutic target. OTX-2 is a promising predictive biomarker candidate, but its mechanisms need further investigation in neuroblastoma, as nestin expression is not significantly linked to patient survival.

S-100 and MATH-1 Protein Expressions Can Be Useful for the Prediction of Clinical Outcome in Neuroblastoma Patients.

Neuroblastoma (NB) is the most frequent extracranial solid tumor of childhood, remarkable for its broad spectrum of clinical behavior. This diversity in behavior correlates closely with defined clinical and biological features and combinations of prognostic variables are used for risk-group assignment. S-100 proteins have roles in differentiation and were shown to be frequently dysregulated in NB. MATH-1 protein plays role in neuronal cell differentiation through development. However, up to date, there are no studies evaluating the relationship between MATH-1 and NB. Grb2-associated binding (Gab) proteins have roles in the regulation of cell growth and differentiation. Gab1 was reported to be related to poor survival of high-risk NB patients. The aim of this study was to investigate the relationship between differentiation-related S-100, MATH-1, and Gab1 proteins and risk group and/or stages of NB. A significant relation was found between S-100 and early stages of NB. This study also revealed a significant association between MATH-1 and low-risk groups. S-100 and MATH-1 were also shown to provide survival advantages among stages and risk groups. The findings of this study support the assumption that S-100 and MATH-1 can be potential prognostic biomarkers for staging and risk-group assignment of NB patients. These proteins can be useful tools for clinicians to guide through treatment options, especially for the evaluation of tumor differentiation.

Comparing Tribbles Homolog 3 (TRIB3) Protein Expression Levels with Clinicopathological Characteristics and Survival Among Neuroblastoma Patients.

Background: Tribbles Homolog 3 (TRIB3) is a member of the pseudokinase family of tribbles and acts as an adaptor protein to regulate different cellular processes. Upregulation of TRIB3 expression was shown either as a favorable or an adverse prognostic factor in various adult malignancies. However, TRIB3 expression has not been examined in pediatric cancers. Neuroblastoma is the most common malignant solid tumor of childhood, which affects mostly children under 5 years old. Risk stratification of patients defined by International Neuroblastoma Risk Group was used to determine prognosis and treatment of the disease. This study aimed to examine the relationship between TRIB3 protein expression levels and clinicopathological features and survival of patients. Methods: TRIB3 protein expression was analyzed using immunohistochemical staining on formalin-fixed paraffin-embedded tissue samples of neuroblastoma patients (n = 56). Survival analyses were performed with Kaplan-Meier method and log-rank tests. Association between TRIB3 expression and clinicopathological characteristics were analyzed with Spearman's correlation. Results: Of the patients, 32.1% were in the low-risk group, 21.4% in the medium-risk group, and 46.4% in the high-risk group. Survival analysis was performed in the entire neuroblastoma patient group and sub-risk groups of neuroblastoma patients. In the entire patient group, there was no significant difference in overall survival (P = .202) and event-free survival (P = .172) between TRIB3-positive and -negative patients. However, when survival analyses were performed in each risk group, TRIB3 expression was significantly associated with higher overall survival (P = .034) and event-free survival (P = .032) in low-risk group neuroblastoma patients. Nevertheless, no association was found between TRIB3 expression and overall survival (P = .799) and event-free survival (P = .448) in high-risk neuroblastoma patients. Furthermore, a significant correlation was identified between 1p36 loss-of-heterozygosity and TRIB3 expression (P = .030). However, TRIB3 expression did not correlate with other clinicopathological features. Conclusion: TRIB3 expression is a potential predictive biomarker for low-risk neuroblastoma patients.

Antioxidant effect of acetyl-l-carnitine against cisplatin-induced cardiotoxicity.

OBJECTIVE: Cisplatin (CDDP) toxicity is a dose-limiting clinical problem in clinical practice, mainly because of nephrotoxicity or ototoxicity. However, the mechanism of CDDP-induced cardiotoxicity is poorly understood. Acetyl-l-carnitine (ALCAR) is an antioxidant agent with protective effects against the side effects of various chemotherapeutics. CDDP-induced cardiotoxicity and the protective role of ALCAR were evaluated in this study. METHODS: Morphological changes were evaluated in hematoxylin and eosin-stained sections, and immunohistochemistry for caspase-3, superoxide dismutase-2 (SOD-2), inducible nitrite oxide synthase (iNOS), cyclooxygenase-2, and Bcl-2 was performed using the hearts of athymic nude mice carrying xenograft neuroblastoma tumors. Mice were randomized (six/group) to the control, CDDP (16 mg/kg), and ALCAR (200 mg/kg)+CDDP (16 mg/kg) groups. Results were analyzed using nonparametric tests. RESULTS: No difference was observed in the rates of cardiac necrosis, dilated/congested blood vessels, hemorrhage, polymorphonuclear leukocyte infiltration, edema, and pyknotic nuclei among the groups. SOD-2 expression was increased in the CDDP group but not in the ALCAR+CDDP group. iNOS, Bcl-2, and caspase-3 levels were not significantly different among the groups. CONCLUSIONS: ALCAR might be a candidate protective agent for CDDP-induced cardiotoxicity. SOD-2, as a member of the oxidant system, should be evaluated in further studies as a biomarker of cardiotoxicity.