An immunohistochemical study of interleukin-8 (IL-8) in breast cancer

The use of prognostic markers for breast cancer is important for routine diagnosis and research. Interleukin-8 is a chemotactic cytokine produced by several cell types in response to inflammation, however, its expression, regulation and function are poorly understood. Recent studies have associated angiogenesis and inflammatory processes with tumor malignancy. The present study investigated the correlation between interleukin-8 expression and breast cancer prognosis. Interleukin-8 expression was assessed in 72 women with mammary neoplasia by immunohistochemistry and the results were statistically correlated with clinical-pathological findings. There was an inverse correlation between interleukin-8 expression and metastasis (p = 0.03) and/or local recurrence (p = 0.02). In the patient group that received post-surgery chemotherapy and radiotherapy, a lower interleukin-8 expression was found in those women that showed local recurrence (p = 0.01). Multivariate logistic regression showed estrogen receptor negativity, progesterone positivity and metastasis with increased risk of death (p < 0.05). The data reflect the complexity of the role of interleukin-8 in tumor microenvironment and support its classification as a possible prognostic marker, although more studies are necessary for its inclusion in clinical practice.     

Expression of CD9 and CD82 in clear cell renal cell carcinoma and its clinical significance

CD9 and CD82, members of the tetraspanin family, act as metastasis suppressors in many human malignant tumors, but the role of these molecules is not well known in clear cell renal cell carcinoma (CCRCC). This study was designed to evaluate the immunohistochemical expression of CD9 and CD82 in 644 cases of CCRCC and to determine the clinicopathologic and prognostic significance of their expression. The percentage of positive tumor cells was evaluated, and the expression was classified into 2 categories: low expression (less than 10% positive cells) or high expression (more than 10% positive cells) for CD9 expression and negative (no positive cells) or positive for CD82 expression. CD9 high expression was found in 303 (47.0%) patients, and CD82 positivity was found in 98 (15.2%) patients. High expression of CD9 was statistically associated with older patients (p = 0.003). The cases showing positive immunoreactivity for CD82 exhibited a high stage (p < 0.001) and high nuclear grade (p < 0.001). The overall, cancer-specific and progression-free survival rates were significantly higher in patients with a CD82-negative profile compared to patients with a CD82-positive profile (p < 0.001). Although the biological function of CD82 in CCRCC remains unclear, the CCRCC patients with CD82 positive expression show poor prognosis.     

Circulating IL-35 in pancreatic ductal adenocarcinoma patients

IL-35 is a novel inhibitory cytokine that is mainly produced by regulatory T-cells (Tregs) and is required for Treg-mediated immunosuppression. However, the plasma levels of IL-35 in patients with pancreatic ductal adenocarcinoma (PDAC) have never been investigated. In this study, we found that plasma IL-35 levels more significantly increased in PDAC patients than in normal controls (134.53 ± 92.45 pg/mL vs. 14.26 ± 6.56 pg/mL). IL-35 mRNA levels were positively correlated with plasma IL-35 levels (EBI3, R = 0.925, p < 0.01; p35, R = 0.916, p < 0.01). Furthermore, IL-35 expression levels were associated with lymph node metastasis (p = 0.001) and late tumor stage (p = 0.002). For the resected patients, high IL-35 expression levels were associated with large tumor size (p < 0.01), higher TNM classification T staging (p < 0.05), and late tumor stage (p < 0.05). In conclusion, circulating IL-35 in PDAC patients significantly increased, suggesting that regulating the expression of IL-35 may provide a new possible target for the treatment of PDAC patients, especially for the resectable ones.     

Correlation of CpG island methylator phenotype with poor prognosis in hepatocellular carcinoma

CpG island methylator phenotype (CIMP), in which multiple genes are concurrently methylated, is an important mechanism in hepatocellular carcinoma development. We determined a hypermethylation profile in hepatocellular carcinoma (HCC).We examined the promoter methylation status of 10 genes in 60 cases of hepatocellular carcinoma (HCC), 60 cases of paired non-tumor tissues, and 6 cases of normal tissues by methylation-specific PCR.The average methylated gene numbers were significantly different between HCC and nontumor tissues (p < 0.001). We found metastasis, γ-glutamyl transpeptidase (GGT) and tumor node metastasis (TNM) stage were significantly different among patients with different CIMP status. Patients with high frequency CIMP tumors had significantly worse survival than patients with intermediate frequency or no CIMP tumors (p < 0.01 and p < 0.05, respectively).Our results suggested that CIMP could serve as a molecular marker of late stage and poorly prognostic HCC development.     

Imbalance in serum soluble CD30/CD30L and CD40/CD40L systems are associated with ovarian tumors

The aim of the study was to examine the concentrations of the soluble receptors and their ligands of CD30/CD30L and CD40/CD40L systems in the serum of women with ovarian tumor and in the ovarian cyst fluid of women with Cystadenoma serosum. The study included 120 women with ovarian tumors. As a control, sera were obtained from 60 healthy female volunteers. Concentrations of the sCD30, sCD30L, sCD40 and sCD40L in the serum and the ovarian cyst fluid were measured by ELISA enzyme-linked immunosorbent assay. Concentrations of both sCD30 and sCD30L in serum of women with ovarian tumors were significantly higher than in control (p < 0.0001). The highest serum receptor and its ligand levels were observed in women with ovarian cancer (p < 0.0001). Moreover, results showed significantly increased levels of sCD40 and sCD40L serum in women with ovarian tumors, as compared to the control group (p < 0.0001). The highest concentration of sCD40 in the serum of women with ovarian cancer and sCD40L in serum of women with Teratoma maturum (p < 0.0001) were observed. Impaired apoptosis among women with ovarian tumors is associated with the impairments of soluble CD30/CD30L and CD40/CD40L systems. Measurement of studied parameter concentrations in serum of women with ovarian tumors has been suggested to be a potential tool in monitoring of inflammatory. Evaluation of sCD30, sCD30L and sCD40 might be an early diagnostic marker in patients with the ovarian cancer. Concentrations of the studied parameters in the ovarian cyst fluid higher than the serum values suggest local suppression of the immune response. However, the final evaluation of the importance of measurement of serum levels of them requires further investigation.     

Prognostic importance of PAI-1 in node negative breast cancer patients--results after 10 years of follow up

The serine protease urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play key roles in the proteolytic cascade involved in physiological and pathological degradation of the extracellular matrix.The aim of this study was to determine the prognostic importance of PAI-1 expression in tumor cells in node-negative breast cancer patients that did not receive adjuvant chemotherapy. We used immunohistochemistry (IHC) as a detection method. The study retrospectively included 133 ductal invasive breast cancer patients from the Clinical Hospital Center Zagreb, Croatia, surgically treated in a two-year interval (1998-1999) with 10 years of follow up.The Cox proportional hazard regression test with stepwise variable selection was used to calculate the relative effect of investigated data on patients’ prognosis. Univariate analysis showed that all investigated factors, such as lymph node involvement (p = 0.025), tumor grade (p < 0.001), estrogen receptor status (p = 0.011), vascular invasion (p = 0.001), HER2 overexpression (p < 0.001), and proliferative index (p < 0.001), had a statistically significant influence on patients’ OS. Multivariate statistical analysis showed that only HER-2 (p < 0.001) can be considered an independent, statistically significant poor prognostic factor.In patients with negative lymph nodes that did not receive adjuvant chemotherapy, we found a significant correlation in overall survival (p = 0.009), which is favorable for PAI-1 negative tumors.In conclusion, it seems that PAI-1 in primary breast cancer tissue correlates with disease aggressiveness and has a strong prognostic impact on primary breast cancer, and is a strong prognostic factor for node-negative patients that did not receive chemotherapy.     

Mitochondrial UCP4 and bcl-2 expression in imprints of breast carcinomas: relationship with DNA ploidy and classical prognostic factors

Mitochondria are the bioenergetic and metabolic centers of cells and play an important role in the regulation of cell death. The mitochondrial apoptosis pathway is controlled by the bcl-2 protein family. Overexpression of mitochondrial uncoupling protein 4 (UCP4) can promote proliferation and inhibit apoptosis and differentiation. Imprint smears obtained from 124 tumors were studied immunocytochemically, and results were correlated with prognostic markers. There were 112 ductal and 12 lobular carcinomas. The positivity of UCP4 was correlated with lymph node metastases (p = 0.005), positive ER and PR expression (p < 0.0001 for both), as well as positivity for p53 (p < 0.0001) and Ki-67 (p < 0.0001). Decreased expression of bcl-2 correlated with increased expression of UCP4 (p = 0.001). Regarding DNA ploidy, UCP4 positivity was correlated with aneuploid tumors (p = 0.002). Negative expression of bcl-2 was correlated with poorly differentiated carcinomas (p < 0.0001), as well as with positive expression of p53 (p < 0.0001) and Ki-67 (p < 0.0001). Logistic regression revealed that ploidy and p53 expression had an impact on UCP4. These findings encourage future investigations regarding the potential role of UCPs not only into mechanisms underlying breast cancer, but also as a novel candidate to the design and development of more effective therapeutic strategies.     

E-cadherin expression in upper urothelial carcinoma in Balkan Endemic Nephropathy and non-endemic regions

There is a high incidence of upper urothelial carcinoma (UUC) in regions affected by Balkan Endemic Nephropathy (BEN). The aim of this study was to compare E-cadherin expression in UUC, in regions affected by BEN, and in control rural and city populations free of BEN. Another aim was to determine the influence of some morphological parameters on the E-cadherin status. In the samples of 85 UUC patients, of whom 40 lived in BEN settlements and 45 served as control subjects, immunoreactions were performed using monoclonal anti-human E-cadherin antibody. Aberrant expression of E-cadherin was more frequent in BEN tumors than in control tumors (p<0.01). Decreased E-cadherin expression was linked to high grade and solid growth in control and BEN tumors (p<0.0001 and <0.05 versus p<0.05 and <0.05, respectively), and to the stage in control tumors (p<0.01). However, BEN low grade and low stage tumors showed aberrant expression more often than did control tumors (p<0.05 and <0.005, respectively). In control tumors, using univariate analysis, E-cadherin status was found to be influenced by grade, stage, and tumor growth (p=0.001, 0.017, 0.015, respectively). In the same group, only the grade was significant according to multistep logistic regression analysis (Wald=6.429 and p=0.011). The growth pattern had a predominant influence on E-cadherin expression in BEN tumors (p=0.005). A significant influence on normal membranous or abnormal cytoplasmic expression of E-cadherin in UUC is exerted by tumor grade, stage, growth, and metaplastic change (p=0.002, 0.048, 0.019, 0.011, respectively), but only by tumor grade in the multistep logistic regression model. These results suggest that decreased expression of E-cadherin in BEN tumors may be linked to tumor growth, while expression of E-cadherin in control tumors may be associated with tumor grade.     

Overexpression of steroid receptor coactivator-3 in bone cancers: An in vivo immunohistochemical study with tissue microarray

Bone tissue is steroid-responsive and profoundly regulated by steroids and/or their receptors. Bone cancers (either primary or metastatic) belong to the most dangerous tumors. Previous studies have demonstrated overexpression of steroid receptor coactivator-3 (SRC-3) in many cancers, such as breast cancer, prostate cancer, thyroid cancer, functioning in the regulation of cancer cell proliferation, invasion, and metastasis. However, so far, the expression and function of SRC-3 in bone cancers have not yet been clarified. In this study, nickel-intensified immunohistochemistry was conducted using a commercial tissue microarray (with 94 cases of bone cancer tissue and 10 normal bone tissues), and the 4-scoring system was employed to evaluate the expression levels of SRC-3 immunoreactivity. The results showed that in normal bone tissue, levels of SRC-3 are almost negative (score = 0), the total positivity (score = 1–3) of SRC-3 immunoreactivities in bone cancers was 74.47%. There were no significant differences in gender, status (malignant or benign) or (mean) age (p > 0.05). The percentage of positivity was 77.78% in osteogenic tumors, 58.82% in cartilage tumors, 70% in giant cell tumors, 100% in hematopoietic tumors, 77.78% in miscellaneous lesions, and 75% in miscellaneous tumors. Age related differences of SRC-3 immunoreactivities were detected in cartilage tumors and giant cell tumors (p < 0.05). The above results clearly demonstrated a high frequency of overexpression of SRC-3 immunoreactivities in different bone cancers, indicating its potential roles in the prognosis and treatment of these cancers.     

Expression of Akt and Mdm2 in human esophageal squamous cell carcinoma

The Akt-Mdm2 pathway plays an important role in carcinogenesis in a variety of malignant tumors. However, the Akt-Mdm2 pathway in esophageal squamous cell carcinoma (ESCC) has not been fully studied. We investigated the proteins and mRNA expression of Akt and Mdm2 to elucidate the roles of these proteins in ESCC. We also examined the effect of Akt knockdown on Mdm2 expression in ESCC cells. ESCC tissue samples were obtained from 23 individuals who underwent surgical resection with no preoperative treatment. Akt1-3 and Mdm2 gene and protein expression were analyzed. The effect of siRNA-mediated Akt knockdown on Mdm2 expression was also studied, using ESCC cell lines. Akt1 and Mdm2 immunoreactivity was detected in 77.8 and 66.7% of tumor specimen from ESCC patients, respectively. Akt1 and Mdm2 mRNA expressions were correlated and significantly elevated in tumor tissue (p < 0.0001 and p < 0.05, respectively). The siRNA-targeted reduction of each Akt isoform reduced Mdm2 protein expression. The overexpression of Akt1 and Mdm2 may be related to esophageal carcinogenesis. Furthermore, Akt expression regulates Mdm2 expression, which may in turn regulate the function of wild-type p53. These results may provide the basis for future preventative or clinical therapies for esophageal cancer.     

Upregulation of matrix metalloproteinase-1 and proteinase-activated receptor-1 promotes the progression of human gliomas

Matrix metalloproteinases (MMPs) have been proposed to be involved in remodeling the tumor-stromal microenvironment. The protease-activated receptors (PARs) are the latest MMP targets. Recent studies have revealed that stromal-derived MMP-1 acts as a signaling molecule by cleaving PAR1 to cause tumor migration and invasion of various cancers. However, the involvement of MMP-1/PAR1 signaling pathway in the progression and prognosis of human gliomas remains to be identified.Immunohistochemical staining was performed to detect the expression patterns of MMP-1 and PAR1 in biopsies from 108 patients with primary gliomas. Kaplan-Meier survival and Cox regression analyzes were performed to evaluate the prognosis of patients.Immunostaining revealed MMP-1 to be expressed in 83.3% (90/108) and PAR1 in 76.9% (83/108) of the biopsies. PAR1 expression was significantly correlated with that of MMP-1 (r = 0.786, p < 0.0001). The total IHC scores for MMP-1 and PAR1 were significantly higher in high-grade tumors than in low-grade tumors (both p = 0.001). In addition, patients with high MMP-1 and high PAR1 expression have lower Karnofsky performance scale (KPS) scores than patients with low MMP-1 and low PAR1 expression (both p = 0.008). Moreover, MMP-1 and PAR1 expression was shown to be a strong prognostic marker for decreased overall survival (p = 0.002 and 0.003, respectively). Furthermore, Cox multi-factor analysis showed that KPS (p = 0.008), WHO grade (p = 0.006), MMP-1 (p = 0.006), and PAR1 (p = 0.008) were independent prognostic factors for human gliomas.Our results suggest that in gliomas, the upregulation of MMP-1 and PAR1 correlates with histological malignancy grade and clinical outcome. Also, MMP-1 and PAR1 immunostaining supplements the current histological grading by offering additional prognostic and predictive information.     

Expression of HAb18G/CD147 and its localization correlate with the progression and poor prognosis of non-small cell lung cancer

This study was designed to investigate the association of HAb18G/CD147 expression and localization with clinicopathological parameters and prognosis in NSCLC. Two hundred and eight (208) specimens of surgically resected NSCLC were stained by immunohistochemistry utilizing mouse anti-human HAb18G/CD147 monoclonal antibody. High levels of HAb18G/CD147 expression were associated with male gender, smoking history, tumor position, distant metastasis status, and clinical stage (p < 0.05) in squamous cell carcinoma. In adenocarcinomas, HAb18G/CD147 expression was associated with male gender, tumor diameter, differentiation, lymph node status, distant metastasis status, and clinical stage (p < 0.05). HAb18G/CD147 expression with higher PU was predominantly localized in the tumor cell membranes rather than in cytoplasms. In squamous cell carcinomas, membranous localization of HAb18G/CD147 was linked to distant metastasis status and TNM stage (p < 0.05). Cytoplasmic localization of HAb18G/CD147 was associated with male gender and smoking history. In adenocarcinomas, membranous localization of HAb18G/CD147 correlated with tumor diameter, differentiation and distant metastasis (p < 0.05). Univariate analysis indicated that patients with high HAb18G/CD147 expression and membranous localization predicted poor prognosis in both squamous cell carcinomas and adenocarcinomas. Multivariate analysis showed that lymph node status (HR = 1.762, 95%CI 1.105–2.811, p = 0.017), distant metastasis status (HR = 3.789, 95%CI 2.196–6.539, p = 0.000), expression (HR = 6.632, 95%CI 2.457–17.904, p = 0.000), and localization (HR = 0.520, 95%CI 0.341–0.794, p = 0.002) were good or excellent independent predictors of patient survival. HAb18G/CD147 is a biomarker characterizing progression and survival of NSCLC. More importantly, its cellular localizations should be considered in the analysis of clinicopathological characteristics and prognostic factors in NSCLC.     

Multiple sporadic gastrointestinal stromal tumors concomitant with ampullary adenocarcinoma: A case report with KIT and PDGFRA mutational analysis and miR-221/222 expression profile

GISTs originating multifocally at different GI sites, in patients lacking familial syndromes, could be interpreted as recurrent/metastatic disease. MiR-221/222 have recently been identified as regulators of KIT expression in GISTs. We report the first case of synchronous GISTs in the stomach and duodenum concomitant with an ampullary adenocarcinoma. Different CD117 expression patterns could be related to different KIT mutational status in the two lesions: gastric GIST showed a dot-like pattern and lacked KIT mutations; duodenal GIST had a strong membranous expression pattern, likely due to KIT exon 9 duplication, which is associated with lower response to imatinib. MiR-221/222 were downregulated in GISTs as compared with normal tissue (p < 0.05) and expressed increased levels in the gastric GIST as compared with duodenal one (p < 0.05). Our data support an independent origin of the two GISTs. Determining whether these tumors are multiple primaries or recurrencies is helpful to predict their malignancy and to select proper treatment.     

Ploidy and S-phase fraction as predictive markers of response to radiotherapy in cervical cancer

The aim of this study was to investigate the potential clinical utility of DNA flow cytometry biomarkers, ploidy, and S-phase fraction (SPF) in predicting overall survival in cervical cancer.This prospective study involved 159 patients with cervical carcinoma (median follow-up, 48 months). Pretreatment clinical staging was done according to the FIGO 2009 update classification. Biopsy tumor samples were used for flow cytometry analysis and histological examination. A prognostic study was performed using both Cox and Bayesian Weibull regression models.Eighty (50.3%) tumors presented DNA aneuploidy, mostly observed in adenosquamous (AS) cell carcinoma (8 of 9 cases) and adenocarcinoma (AC) (12 of 17 cases). The median SPF value (8.6%) was used for discriminating low vs. high tumor cell proliferation. High SPF significantly correlated with aneuploidy (p < 0.001). All AS carcinomas had SPF > 15%, while all ACs presented SPF < 10% (p < 0.001). Forty-three (27%) patients died of the disease during follow-up. Log-rank tests revealed significant differences between survival curves for older patients (≥44 years) (p = 0.029), advanced clinical staging (p < 0.001), and DNA diploidy in stage IIB of disease (p = 0.039). Both regression analyses showed that advanced clinical staging and low SPF independently predict worse overall survival of patients.The results suggest that DNA flow cytometry parameters can provide additional predictive information in cervical cancer management.     

Osteopontin is associated with decreased apoptosis and αv integrin expression in lung adenocarcinoma

Osteopontin (OPN) is a glycoprotein involved in invasion, progression and metastasis of many carcinomas. It contains several functional domains including binding sites for αv integrins, cell surface molecules playing a major role in mediating cell migration and adhesion. The aim of the study was to evaluate the expression of osteopontin in human non-small cell lung cancer (NSCLC) and to determine its possible prognostic significance as well as relation to apoptosis and αv integrin expression. We analyzed 111 surgically resected NSCLC for immunohistochemical expression of OPN and αv integrin. OPN expression was compared to apoptotic rate and clinicopathological parameters such as tumor size, histological grade, lymph node status, pT, and TNM stage. Apoptotic rate was measured by TUNEL staining method. OPN expression in NSCLC was significantly higher in lung adenocarcinomas (AC) then in squamous cell carcinomas (p < 0.001). There was no correlation between OPN expression and clinicopathological parameters. The level of OPN expression in AC was associated with decreased apoptotic activity of tumor cells (p = 0.006), and correlated with αv integrin expression (p = 0.048), particularly in low stage tumors (p = 0.013). Prolonged tumor cell survival in lung AC due to OPN and αv integrin overexpression may have an impact on tumor progression and resistance to therapy.     

Involvement of neuronal nitric oxide synthase in cognitive impairment in isoflurane-treated rats

The underlying causes of post-operative cognitive dysfunction (POCD) in elderly patients remain to be elucidated. In order to explore possible contributory mechanisms, we tested the effects of isoflurane anesthesia on (i) expression of hippocampal neuronal nitric oxide synthase (nNOS) and (ii) the relationship of changes in nNOS expression to cognitive dysfunction in isoflurane-treated aged rats. Our results indicate that isoflurane treatment leads to significant changes in correct reactions (F = 28.35, p < 0.001), initiative avoidances (F = 29.33, p < 0.001), and total reaction time (TRT) (F = 6.99, p < 0.05) of treated rats in the Y-maze test. Isoflurane-treated rats had fewer correct reactions and initiative avoidances in the Y-maze test 24 and 48 h after 2 h of isoflurane anesthesia compared with control group rats (p < 0.05). TRTs to complete 20 trials of the Y-maze test increased significantly 48 h after 2 h anesthesia. The number of nNOS-positive hippocampal neurons decreased 24 h after anesthesia, corresponding to an increased mean immunostaining grey-scale value. These data show that isoflurane causes a transient decrease in expression of hippocampal nNOS in aged rats during early post-anesthesia stages, and that the transient decrease of nNOS is closely correlated with cognitive impairment in isoflurane-treated aged rats.     

Trends in prostatic adenocarcinoma tumor volume by visual estimation in prostatectomy specimens

We retrospectively reviewed 1792 consecutive radical prostatectomies (RP) from 2003 to 2006 at a single institution to establish tumor volume reference values, to determine current trends in visually estimated prostate adenocarcinoma tumor volume, and to characterize cases with no residual cancer on RP. Tumor volumes were recorded and subsequently stratified as very low, 0–1%; low, 1.1–10%; intermediate, 10.1–20%; high, 20.1–50%; and very high, >50%, with incidences of 11.7%, 52.1%, 21.5%, 13.2%, and 1.5%, respectively. The incidence of very low volume tumors increased within the time period (p = 0.04). Seminal vesicle involvement was detected in 5.0% of cases and lymph node metastasis occurred in 1.4%. Volume categories statistically correlated with seminal vesicle invasion (p = 0) and lymph nodes metastases (p = 0). Eleven cases of no residual cancer (0.6%) were identified with a non-statically significant increase during the study (p = 0.07). The rising incidence of very low volume tumors should be considered by clinicians when discussing treatment options with patients. A discrete tumor volume should be provided for RP specimens as it may be an important prognostic factor.     

Trace elemental distribution in the scalp hair of bipolars using PIXE technique

Trace metals play a significant role in neurological disorders. There is very limited information available on the role of macro and trace elements in bipolar disorders. The objective of this investigation was to identification, quantification of essential trace elements in the scalp hair samples of the patients and compare with those of normal subjects. We made a hypothesis about the role played by essential trace metals whose concentrations are significantly different to those of normals in the disease process. The analysis was carried out in the scalp hair samples of 26 male and 26 female patients suffering from bipolar disorder (BD) by Particle Induced X-ray Emission Technique (PIXE). The concentration of Cu (p < 0.002) was found to be higher in the hair samples of male bipolar disorder patients while the concentrations of Mn (p < 0.001), Fe (p < 0.005), Zn (p < 0.0001) and Se (p < 0.005) were found to be lower than those in normal subjects. The concentration of Cu (p < 0.0001) was higher in the hair samples of female bipolar patients but depressed levels of Fe (p < 0.005), Ni (p < 0.05), Zn (p < 0.00001) and Se (p < 0.05) were observed compared to controls. Cu/Zn ratio was found to be higher in the hair samples of male and female patients compared with normals. While the imbalance of certain trace elements leads to generation of more free radicals, the imbalance of some other trace elements causes changes in dopamine (neurotransmitter) activity. It is essential to monitor before and periodically during treatment the levels of essential trace elements for effective treatment of bipolar disorder.     

B7-H1 and B7-H4 expression in colorectal carcinoma: Correlation with tumor FOXP3 regulatory T-cell infiltration

B7-H1 and B7-H4 are newly discovered members of the B7-CD28 family. They can inhibit T cell activation and proliferation and regulate T cell immune response negatively. Both B7-H1 and B7-H4 are expressed in many tumors and are classified as co-inhibitors of cell-mediated immunity. FOXP3⁺ regulatory T cells (Tregs) play an important role in the maintenance of tumor immunity tolerance. However, the implication of B7-H1 and B7-H4 expression and their interaction with Tregs infiltration in colorectal cancer are unknown. The present study aimed to determine the expression of B7-H1 and B7-H4 as well as Tregs infiltration in colorectal cancer and to explore the clinical and pathological implication of suppressor immune cells and molecules. Frozen sections and immunohistochemical assay were undertaken to assess B7-H1, B7-H4 expression and Tregs infiltration in fresh specimens collected from 56 patients with colorectal carcinoma. The results showed that expression of B7-H1 and B7-H4 in colorectal carcinoma tissues was significantly higher than in adjacent normal mucosa (P < 0.001). B7-H1 expression was positively correlated to the infiltration depth, lymph node metastasis and advanced Duke's stage (P < 0.05, P < 0.05 and P < 0.05, respectively), whereas B7-H4 expression was positively related to the infiltration depth and lymph node metastasis (P < 0.01 and P < 0.05, respectively). Furthermore, Tregs infiltration was more frequent in tumor tissue than in adjacent normal mucosa and was associated with poor differentiation and positive lymph node metastasis (P < 0.01, and P < 0.01, respectively). The statistical analysis indicated a significant correlation between Tregs infiltration and B7-H1 or B7-H4 expression respectively. These results suggest that over-expression of B7-H1 and B7-H4 has stronger prognostic significance and promote tumor tolerance, and they might contribute to Tregs development in the colorectal carcinoma tolerogenic milieu.     

Circulating estradiol defines the tumor phenotype in menopausal breast cancer patients

Objective

To correlate circulating hormone levels with the clinical and biological features of the tumors in menopausal breast cancer patients.

Design

Circulating hormone levels were measured in 161 previously untreated menopausal breast cancer patients within 72 h of their planned surgery. The obtained hormone levels were correlated with tumor size, histological and nuclear grade, histological score, axillary nodal status, DNA-ploidy and Ki67-, c-erb-B2-, p53, Bax-, VEGF- and Nup88-expression.

Results

The only statistically significant correlations found between circulating hormone levels and all tested variables were an inverse one between estradiol and the expression of the apoptosis-associated Bax gene (p = 0.009), and again an inverse correlation between estradiol and the expression of c-erb-B2 (p = 0.04). When comparing hormone levels with each other, a significant correlation between estradiol and progesterone (p < 0.0001), an inverse one between estradiol and FSH (p = 0.04) and a direct one between LH and prolactin (p = 0.001) were found.

Conclusion

Higher circulating estradiol levels in postmenopausal breast cancer patients are associated with molecular features usually defining a biologically less aggressive tumor phenotype.