Prognostic Significance and Correlation with Survival of bcl-2 and TGF-β RII in Colon Cancer

Bcl-2 and TGF-beta receptors type II (RII) in colon carcinomas were studied in a series of 113 patients, to determine their prognostic significance and to correlate their expression with other prognostic indicators. Bcl-2 expression in the tumor cells showed a reverse relation with tumor size (P = 0.018), histological grade (P = 0.04), and stage (P = 0.013). Univariate survival analysis using the log rank test showed that the survival of patients with bcl-2-positive tumors was significantly better than the survival of patients with bcl-2-negative tumors (P = 0.02). However, when entered into a multivariate analysis model, it was not found to be of independent prognostic significance. TGF-beta RII expression was correlated with stage (P = 0.03), while no statistically significant correlation was found between TGF-beta RII expression and histological grade or survival. In conclusion, these results provide additional evidence for the role of bcl-2 and TGF-beta RII in carcinogenesis of the colon, while they do not support the use of these factors as prognostic markers in patients with colon cancer.     

Pancreatic Cancer in the Faroe Islands: An Epidemiologic Study of Patients with Pancreatic Cancer in the Faroe Islands 1972–82

An epidemiologic study of pancreatic cancer was performed in the Faroe Islands, which have 44,000 inhabitants. All the patients with this diagnosis in the period 1972–82 were reviewed. The material comprised 57 patients. The diagnosis was confirmed microscopically in 67%, by explorative laporatomy in 28%, and by endoscopic retrograde cholangiopancreatography in 5% of the patients. The average annual age-standardized incidence per 100,000 inhabitants (world standard) was 10.7 among men and 7.9 among women. The incidence of pancreatic cancer on the Faroe Islands is at the same high level as in the other Scandinavian countries, suggesting that industrial pollution has no pathogenic role. Nor could diseases or environmental, occupational, or familial factors be identified in the development of pancreatic cancer. High intake of lipids, available carbohydrates, and alcohol can be a contributory cause of developing pancreatic cancer.     

Concomitant Expression of IL-6 and TGF-β Cytokines and their Receptors in Peripheral Blood of Patients with Multiple Sclerosis: The Effects of INFβ Drugs

Background: Concomitant signals from IL-6 and TGF-β have a central role in the Th17 cells development and differentiation, and these cells are the main promoters of demyelinating inflammation in the central nervous system (CNS) resulting in multiple sclerosis (MS). Objectives: To evaluate the simultaneous IL-6 and TGF-β gene and their receptor protein expression in patients with Relapsing-Remitting (RR)-MS. Materials and methods: IL-6 and TGF-β mRNA and their receptor expression on the surface of CD4+T cells were evaluated using real-time PCR (RT-PCR) and flow cytometry, respectively. Results: The IL-6 mRNA expression in patients with RRMS was significantly higher than in the controls (p= 0.019). When patients who did not receive any other treatment were compared with the controls, the significant difference was substantial (p=0.006). The TGF-β mRNA expression in patients was lower than in the controls (p = 0.03). However, in patients receiving IFNβ, it increased compared with the other patients (p= 0.036). There was no difference in cytokine receptor expression between patients and the control group. Conclusion: Our data conclude an increase and decrease in mRNA expression levels of IL-6 and TGF-β in patients with RRMS, respectively. Moreover, there were no significant differences in receptor expression of either cytokines. Based on our data the balance of TGF and IL-6 appears to have a positive impact on the disease control.     

Pancreatic Cancer Cells Resistant to Chemoradiotherapy Rich in “Stem-Cell-Like” Tumor Cells

Background  

Tumor resistance to chemoradiation therapy is partly attributed to the presence of apoptosis-resistant cancer stem cells (CSCs). Chemoradiation therapy can enrich CSCs by killing apoptosis-susceptible cancer cells.     

The Role of Tumor Necrosis Factor-α Receptors in Atherosclerosis

Tumor necrosis factor (TNF-α)-α is a cytokine exhibiting a plethora of activities involved in inflammation, immune regulation, and energy metabolism. TNF is produced by many cell types, including cells found in atherosclerotic lesions, such as activated monocytes or macrophages, T and B lymphocytes, mast cells, and smooth muscle cells. Two receptors mediate the functions of TNF, and both receptors are also present on cells of the artery wall and on cells involved in lesion development. Mice genetically engineered to lack expression of TNF and each of its receptors are now available and are being used to dissect the role of these molecules in protection from or development of atherosclerosis. The role of TNF receptors in atherosclerosis is the primary focus of this review.     

Association of Single Nucleotide Polymorphisms in the Human Tumor Necrosis Factor-α and Interleukin 1-β Genes in Patients with Pre-eclampsia

Pre-eclampsia is a pregnancy-specific syndrome that may be dangerous especially to the fetus. Different cytokines have been found to be elevated in women with pre-eclampsia and may have possible roles in the development of this disorder. Alleles of the interleukin-l-beta (IL-lβ) and tumor necrosis factor alpha (TNF-α) genes are associated with pr-eeclampsia in several studies in different populations. The aim of the present study was to investigate the relationship between IL-lβ (C+3954T) and TNF-α (G-308A) gene polymorphisms with pre-eclampsia in north east of Iran (Khorasan province).This study included 54 diagnosed patients with pre-eclampsia and 50 normal pregnant women as control group. DNA was extracted from peripheral blood and the polymorphisms were determined by PCR-RFLP method. Data was analyzed using chi-square and Fisher's exact tests.There was significant association between TNF-α (G-308A) genotype and pre-eclampsia (p=0.001) but we did not find any significant association between IL-lβ (C+3954T) genotype and pre-eclampsia (p=0.39).The present study might suggest a role for TNF-α in the development of pre-eclampsia; however, IL-lβ (C+3954T) polymorphism could not be considered as a marker of susceptibility to preeclampsia in our population.     

TGF-β and p53 Staining in CT-Guided and Endoscopic Ultrasound Fine-Needle Aspirates of Pancreatic Adenocarcinoma

Our purpose was to determine if fine-needle aspirates of pancreatic adenocarcinoma would produce material amenable to tumor marker staining and to correlate the expression of TGF-beta and p53 with patient and tumor data. One hundred twenty specimens were analyzed. TGF-beta was positive in 26% of cases and had no correlation with patient's age, sex, survival, stage, grade, or size. p53 was positive in 22% of the cases and correlated only with grade 1 tumors. Expression of TGF-beta and p53 can be tested on preserved cytologic specimens. This is the largest study to date correlating TGF-beta and p53 expression in pancreatic adenocarcinoma and patient demographics, prognosis, and tumor attributes. This is also the first study that did not select for surgical candidates. TGF-beta expression does not appear to have prognostic significance in pancreatic cancer. p53 was more common in well-differentiated tumors and may be an early mutation lost in more poorly differentiated tumors.     

Functional Expression of μ-Opioid Receptors in the Human Colon Cancer Cell Line,HT-29, and their Localization in Human Colon

We have investigated the functional expression of μ-opioid receptors (MORs) in the human colon cancer cell line, HT-29. As revealed by immunocytochemistry, immunoreactivity was present in both the cytoplasm and nuclei of the cells. Challenge with morphine for 24 h (1 nM to 1 μM) barely affected cell proliferation, while the secretion of urokinase type plasminogen activator (a protease involved in invasion/metastasis) was markedly augmented by a concentration of 0.1 μM. Human colon cancer tissue from 14 consecutively operated patients was investigated by immunohistochemistry. MORs were found in the nuclei of colonocytes and immune cells of the lamina propria in tumor-free tissue. In tumor tissue, immunoreactivity was found in the membrane and often in the nuclei of tumor cells. The current findings suggest that morphine administration could affect tumor progression by interfering with, for example, invasive properties. Our demonstration of a nuclear expression of the MORs appears to be a novel finding.     

Primers on Molecular Pathways: Lipopolysaccharide Signaling — Potential Role in Pancreatitis and Pancreatic Cancer

The innate immune system recognizes the presence of bacterial pathogens through the expression of a family of membrane receptors known as Toll-like receptors (TLRs). Lipopolysaccharide (LPS) is specifically recognized by TLR4. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. LPS can act not only on immune cells but also on some types of epithelial cells including cancer cells and promote its transformed phenotype. Specifically, LPS can activate NF-κB signaling in pancreatic cancer cells, thus connecting inflammation with cancer progression. The TLR4 signaling pathway may offer a useful therapeutic target for patients with pancreatitis or pancreatic cancer associated with inflammation.     

Serum cytokines in follicular lymphoma. Correlation of TGF-β and VEGF with survival

The prognosis of follicular lymphoma could vary with the tumor immune microenvironment. We evaluated the prognostic value of serum levels of ten cytokines. Our study cohort included 60 follicular lymphoma patients and 20 controls. Serum was available at diagnosis in 31 patients, at first relapse in 18, and complete remission in 11. Bioplex technology was used for determination of nine cytokines [interleukin (IL)-1Ra, IL-6, IL-7, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (b-FGF)]. Transforming growth factor beta (TGF-β) was measured by sandwich enzyme-linked immunosorbent assay. IL-1Ra, IL-6, IL-7, IL-10, IL-13, TNF-α, VEGF, and PDGF levels were found increased in follicular lymphoma patients compared to controls. Multivariate analysis identified early stage and high TGF-β levels as independent predictors of overall survival associated with improved outcome. High lactate dehydrogenase and VEGF levels were independently associated with poorer progression-free survival. These results show the prognostic value of TGF-β and VEGF in follicular lymphoma and suggest their contribution to tumor microenvironment alterations.     

TGF-β and IL-23 gene expression in unstimulated PBMCs of patients with diabetes

The protective effects of TGF-β have been documented in various autoimmune diseases, mostly in organ-specific autoimmunity including type 1 diabetes mellitus (T1DM). However, TGF-β also plays a role as a pro-inflammatory mediator by induction of Th17 cytokine production. IL-23 also plays a key role in differentiation of Th17 cells, which are implicated in pathogenesis of autoimmune conditions including T1DM. The aim of this study was to investigate and compare the difference in the level of TGF-β1 and IL-23 gene expression in unstimulated peripheral blood mononuclear cells (PBMCs) of patients with different forms of diabetes compared with normal healthy controls subjects. Patients with T1DM were grouped as early-onset T1DM (N?=?20) with age at diagnosis <18?years and late-onset T1DM (N?=?20) with the age at onset >18?years. Patients with T2DM (N?=?20) and normal healthy controls (N?=?20) were recruited from the same area. TGF-β1 and IL-23 gene expression in fresh unstimulated PBMCs was determined in each group using quantitative real-time PCR. The results confirmed that a significant difference in TGF-β1 and IL-23 gene expression was observed in both forms of juvenile-onset T1DM and adult-onset T1DM compared to the controls and T2DM patients. There was no significant difference for TGF-β gene expression in patients with T2DM and controls. We therefore conclude that our results support the previous data on TGF-β gene down-regulation in T1DM. Also up-regulation of IL-23 has been observed in T1DM whilst it was down-regulated in T2DM. We also found no significant difference between juvenile-onset and adult-onset T1DM indicating same mechanism might be involved in the pathogenesis of both types. More studies on different cytokines in Th17 pathways are required to further confirm our finding.     

Imbalance of serum IL-10 and TGF-β in patients with pollen food syndrome

BackgroundPollen food syndrome is one of the main causes of food allergies in adults. However, the intrinsic immunological mechanisms remain unclear.MethodsForty pollinosis sufferers [23 with a food allergy (PSFA) and 17 without a food allergy (PS)] and 17 non-atopic healthy controls were included in this study. The PSFA group was subdivided into an oral allergy syndrome group, a systemic reaction group, and an anaphylactic reaction group according to their symptoms after eating the suspected foods. Serum IL-10 and TGF-β levels of all participants were determined by ELISA. Clinical characteristics of the patients were also evaluated.ResultsThere were no significant differences in age, sex, pollen-associated symptoms, duration of respiratory disease, and positive parental history of atopy between the PSFA and PS groups. Compared to healthy controls, serum IL-10 levels of both the PSFA group and PS group were significantly lower (p ≤ 0.01), but TGF β levels were significantly higher in the PSFA group (35.3 ± 5.6 ng/ml vs. 31.2 ± 6.6 ng/ml, respectively; p = 0.037). Within the PSFA group, IL-10 levels in the anaphylactic reaction subgroup were significantly lower compared to oral allergy syndrome subgroup (1.87 ± 0.47 pg/ml vs. 1.40 ± 0.30 pg/ml, respectively; p = 0.027). More severe food allergy symptoms were associated with lower serum IL-10 levels. In contrast, the highest serum levels of TGF-β were found in patients from the anaphylactic reaction subgroup.ConclusionsWith the exception of a defect in regulatory cells represented by the reduction of IL-10, other potential immunological mechanisms (e.g., Th17 or IL-23 together with TGF-β) may be involved in the development of pollen food syndrome.     

Suppression of the Epidermal Growth Factor Receptor Inhibits Epithelial–Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells

Background  

Aberrant expression of epidermal growth factor receptor (EGFR) has been detected in pancreatic cancer; however, the mechanisms of EGFR in inducing pancreatic cancer development have not been adequately elucidated. The objective of this study was to determine the role of EGFR in mediating epithelial–mesenchymal transition (EMT) in pancreatic cancer cells.     

ZNF281 Promotes Growth and Invasion of Pancreatic Cancer Cells by Activating Wnt/β-Catenin Signaling

Digestive Diseases and Sciences - Zinc finger protein 281 (ZNF281) has been identified to be involved in embryonic stem cell differentiation and tissue development. Also, ZNF281 was found in...     

The Differential Effects of Statins on the Risk of Developing Pancreatic Cancer: A Case–Control Study in Two Centres in the United Kingdom

Introduction

There are plausible biological mechanisms for how statins may prevent pancreatic cancer, although the evidence from epidemiological studies in the general population is conflicting. This study aims to clarify whether statins exert their effects in specific sub-groups, namely, gender, smoking status and diabetes.

Methods

A matched case–control study was conducted in patients diagnosed with pancreatic cancer, and a group of dermatology patients of similar ages and gender, diagnosed with basal cell carcinoma. Participants’ medical records were reviewed for information on statin use prior to diagnosis. Odds ratios and 95 % CIs for the development of pancreatic cancer were estimated using conditional logistic regression. Subgroup analysis was performed in men, women, smokers and those with type 2 diabetes.

Results

Two hundred fifty-two cases (median age 71 years, range 48–73 years, 51 % women) and 504 controls were identified, of which 23 % of cases were regular statin users versus 21 % of controls. In the general study population there was no association between pancreatic cancer and regular statin use (OR 0.82, 95 % CI 0.53–1.23, p = 0.33). However, in male smokers, regular statin use was associated with significantly reduced odds of pancreatic cancer compared to male smokers not prescribed a statin (OR 0.11, 95 % CI 0.01–0.96, p = 0.05). In patients with type 2 diabetes statins use was not associated with reduced odds (OR 0.92, 95 % CI 0.35–2.45, p = 0.80), with no gender effects.

Conclusions

In male smokers, statins may reduce the odds of pancreatic cancer. Statin use should be measured in aetiological studies of pancreatic cancer but analysed in specific sub-groups. Future work should investigate statins as chemopreventative agents in this high risk sub-group.