Role of the Ghrelin System in Colitis and Hepatitis as Risk Factors for Inflammatory-Related Cancers.

It is not known exactly what leads to the development of colorectal cancer (CRC) and hepatocellular carcinoma (HCC), but there are specific risk factors that increase the probability of their occurrence. The unclear pathogenesis, too-late diagnosis, poor prognosis as a result of high recurrence and metastasis rates, and repeatedly ineffective therapy of both cancers continue to challenge both basic science and practical medicine. The ghrelin system, which is comprised of ghrelin and alternative peptides (e.g., obestatin), growth hormone secretagogue receptors (GHS-Rs), and ghrelin-O-acyl-transferase (GOAT), plays an important role in the physiology and pathology of the gastrointestinal (GI) tract. It promotes various physiological effects, including energy metabolism and amelioration of inflammation. The ghrelin system plays a role in the pathogenesis of inflammatory bowel diseases (IBDs), which are well known risk factors for the development of CRC, as well as inflammatory liver diseases which can trigger the development of HCC. Colitis-associated cancer serves as a prototype of inflammation-associated cancers. Little is known about the role of the ghrelin system in the mechanisms of transformation of chronic inflammation to low- and high-grade dysplasia, and, finally, to CRC. HCC is also associated with chronic inflammation and fibrosis arising from different etiologies, including alcoholic and nonalcoholic fatty liver diseases (NAFLD), and/or hepatitis B (HBV) and hepatitis C virus (HCV) infections. However, the exact role of ghrelin in the progression of the chronic inflammatory lesions into HCC is still unknown. The aim of this review is to summarize findings on the role of the ghrelin system in inflammatory bowel and liver diseases in order to better understand the impact of this system on the development of inflammatory-related cancers, namely CRC and HCC.

Changes in Inflammatory Markers after Administration of Tocilizumab in COVID-19: A Single-Center Retrospective Study.

The COVID-19 pandemic requires the development of effective methods for the treatment of severe cases. We aimed to describe clinical outcomes and changes in inflammatory markers in Polish patients treated with tocilizumab. The medical charts of SARS-CoV-2-positive patients treated in the Department of Infectious Diseases between 4 March and 2 September 2020 were retrospectively analyzed. The patients who received tocilizumab according to the Polish Association of Epidemiologists and Infectiologists guidelines were selected for the study. We identified 29 individuals who received tocilizumab, out of whom 11 (37.9%) died. The individuals who died had significantly higher maximal interleukin-6 (IL-6) and lactate dehydrogenase (LDH) serum levels than survivors. After administration of tocilizumab, further increase in LDH and IL-6 was a prognostic factor for unfavorable outcomes. Among inflammatory markers, 7-day mean of IL-6 serum concentration was the best predictor of death (cut-off: ≥417 pg/mL; area under ROC curve = 0.81 [95% Confidence Interval: 0.63-0.98]). The serum concentrations of inflammatory markers before administration of tocilizumab did not predict the outcome, whereas IL-6 and LDH measurements after administration of tocilizumab seemed to be of predictive value.

The Neuropeptide System and Colorectal Cancer Liver Metastases: Mechanisms and Management.

Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, remains to be a clinical and research challenge. It is estimated that ~50% of CRC patients die from distant metastases, with treatment of this complication still posing significant difficulties. While liver metastasis (LM) cascade is known in the literature, its mechanisms are still unclear and remain studied in different research models. A connection is suggested between nervous system dysfunctions and a range of Neurotransmitters (Nts) (including Neuropeptides, NPs), Neurotrophins (Ntt) and their receptors (Rs) in CRC liver metastasis development. Studies on the role of NP/NP-Rs in the progression and metastasis of CRC, show the complexity of brain-tumor interactions, caused by their different forms of release to the extracellular environment (endocrine, autocrine, paracrine and neurocrine). Many stages of LM are connected to the activity of pro-inflammatory, e.g., Corticotropin-releasing Hormone Receptor 1 (CRHR1), Neuropeptide Y (NPY) and Neurotensin (NT), anti-inflammatory, e.g., Calcitonin Gene-related Peptide (CGRP), CRHR2 and Vasoactive Intestinal Polypeptide (VIP) or dual role neuropeptides, e.g., Substance P (SP). The regulation of the local immunological profile (e.g., CRH/CRHRs), dysfunctions of enteroprotective role of NPs on epithelial cells (e.g., NT/NT-R), as well as structural-functional changes in enteric nervous system innervation of the tumor are also important. More research is needed to understand the exact mechanisms of communication between the neurons and tumor cells. The knowledge on the mechanisms regulating tumor growth and different stages of metastasis, as well as effects of the action of a numerous group of Nts/NPs/Ntt as growth factors, have implications for future therapeutic strategies. To obtain the best treatment outcomes, it is important to use signaling pathways common for many NPs, as well to develop a range of broad-spectrum antagonists. This review aims to summarize the current knowledge on the importance of neuroactive molecules in the promotion of the invasion-metastasis cascade in CRC, as well as the improvements of clinical management of CRC liver metastasis.

Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer-From Basic Research to Potential Clinical Applications.

Colorectal cancer (CRC) is one of the most common cancers in men and women worldwide as well as is the leading cause of death in the western world. Almost a third of the patients has or will develop liver metastases. While genetic as well as epigenetic mechanisms are important in CRC pathogenesis, the basis of the most cases of cancer is unknown. High spatial and inter-patient variability of the molecular alterations qualifies this cancer in the group of highly heterogeneous tumors, which makes it harder to elucidate the mechanisms underlying CRC progression. Determination of highly sensitive and specific early diagnosis markers and understanding the cellular and molecular mechanism(s) of cancer progression are still a challenge of the current era in oncology of solid tumors. One of the accepted risk factors for CRC development is overexpression of insulin-like growth factor 2 (IGF2), a 7.5-kDa peptide produced by liver and many other tissues. IGF2 is the first gene discovered to be parentally imprinted. Loss of imprinting (LOI) or aberrant imprinting of IGF2 could lead to IGF2 overexpression, increased cell proliferation, and CRC development. IGF2 as a mitogen is associated with increased risk of developing colorectal neoplasia. Higher serum IGF2 concentration as well as its tissue overexpression in CRC compared to control are associated with metastasis. IGF2 protein was one of the three candidates for a selective marker of CRC progression and staging. Recent research indicates dysregulation of different micro- and long non-coding RNAs (miRNAs and lncRNAs, respectively) embedded within the IGF2 gene in CRC carcinogenesis, with some of them indicated as potential diagnostic and prognostic CRC biomarkers. This review systematises the knowledge on the role of genetic and epigenetic instabilities of IGF2 gene, free (active form of IGF2) and IGF-binding protein (IGFBP) bound (inactive form), paracrine/autocrine secretion of IGF2, as well as mechanisms of inducing dysplasia in vitro and tumorigenicity in vivo. We have tried to answer which molecular changes of the IGF2 gene and its regulatory mechanisms have the most significance in initiation, progression (including liver metastasis), prognosis, and potential anti-IGF2 therapy in CRC patients.

Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis.

Mucins are large O-glycoproteins with high carbohydrate content and marked diversity in both the apoprotein and the oligosaccharide moieties. All three mucin types, trans-membrane (e.g., MUC1, MUC4, MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, MUC6) and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, MUC20), are critical in maintaining cellular functions, particularly those of epithelial surfaces. Their aberrant expression and/or altered subcellular localization is a factor of tumour growth and apoptosis induced by oxidative stress and several anti-cancer agents. Abnormal expression of mucins was observed in human carcinomas that arise in various gastrointestinal organs. It was widely believed that hepatocellular carcinoma (HCC) does not produce mucins, whereas cholangiocarcinoma (CC) or combined HCC-CC may produce these glycoproteins. However, a growing number of reports shows that mucins can be produced by HCC cells that do not exhibit or are yet to undergo, morphological differentiation to biliary phenotypes. Evaluation of mucin expression levels in precursors and early lesions of CC, as well as other types of primary liver cancer (PLC), conducted in in vitro and in vivo models, allowed to discover the mechanisms of their action, as well as their participation in the most important signalling pathways of liver cystogenesis and carcinogenesis. Analysis of mucin expression in PLC has both basic research and clinical value. Mucins may act as oncogenes and tumour-promoting (e.g., MUC1, MUC13), and/or tumour-suppressing factors (e.g., MUC15). Given their role in promoting PLC progression, both classic (MUC1, MUC2, MUC4, MUC5AC, MUC6) and currently tested mucins (e.g., MUC13, MUC15, MUC16) have been proposed to be important diagnostic and prognostic markers. The purpose of this review was to summarize and update the role of classic and currently tested mucins in pathogenesis of PLC, with explaining the mechanisms of their action in HCC carcinogenesis. It also focuses on determination of the diagnostic and prognostic role of these glycoproteins in PLC, especially focusing on HCC, CC and other hepatic tumours with- and without biliary differentiation.

Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy.

The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor ß (TGF-ß) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.

Insulin-Like Growth Factor (IGF) System in Liver Diseases.

Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2) act in response to growth hormone (GH). Other IGF family components include at least six binding proteins (IGFBP1 to 6), manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R). The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth), and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD), lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC) stage. These changes result in well-known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma). Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD.

Tissue expression of ß-catenin and E- and N-cadherins in chronic hepatitis C and hepatocellular carcinoma.

INTRODUCTION: The role of Wnt/ ß -catenin signaling pathway in HCV-associated hepatocellular carcinogenesis is still unknown. MATERIAL AND METHODS: This study aimed to perform quantitative analysis of immuno- and hybridocytochemical expression of ß -catenin, E- and N-cadherins and HCV proteins (C, NS3, NS5A) in long-lasting (≥ 20 years) chronic hepatitis C (CH-C) (n = 54), hepatocellular carcinoma (HCC) (n = 61), and control liver samples (n = 8). RESULTS: Typical membranous expression of ß -catenin in the control liver was higher than in the CH-C and HCC (p = 0.06). The mean ß -catenin tissue expression in CH-C was similar to controls, and significantly higher than that of HCC (p = 0.005). E-cadherin expression was lower in CH-C than in the control (p = 0.045) and HCC (p < 0.001). In HCC both ß -catenin and E-cadherin expressions were significantly lower in comparison to controls (p = 0.02, p = 0.001, respectively). Positive correlations were found between ß -catenin and E-cadherin (in CH-C and HCC), ß -catenin and N-cadherin (HCC), E- and N-cadherins expressions (HCC) (p < 0.05 in all cases). In CH-C the positive correlation was demonstrated between NS5A protein and ß -catenin, and between the all HCV proteins (C, NS3, NS5A) and E-cadherin expression (p < 0.05 in all cases). CONCLUSIONS: Alterations in cellular locations of ß -catenin and E-cadherin in CH-C and HCC pointed to structural disturbances in intercellular junctions in the livers and presence of the transcriptionally inactive form of ß -catenin. The reduced expression of E-cadherin in long-lasting CH-C may represent an early indicator of the epithelial-mesenchymal transition. The most important role in modulation of the Wnt/ ß -catenin pathway in vivo is probably played by the NS5A viral protein.

Insulin-like growth factor (IGF) axis in cancerogenesis.

Determination of the role of insulin-like growth factor (IGF) family components in carcinogenesis of several human tumors is based on numerous epidemiological and pre-clinical studies, experiments in vivo and in vitro and on attempts at application of drugs affecting the IGF axis. Investigative hypotheses in original studies were based on biological functions manifested by the entire family of IGF (ligands, receptors, linking proteins, adaptor molecules). In the context of carcinogenesis the most important functions of IGF family involve intensification of proliferation and inhibition of cell apoptosis and effect on cell transformation through synthesis of several regulatory proteins. IGF axis controls survival and influences on metastases of cells. Interactions of IGF axis components may be of a direct or indirect nature. The direct effects are linked to activation of PI3K/Akt signaling pathway, in which the initiating role is first of all played by IGF-1 and IGF-1R. Activity of this signaling pathway leads to an increased mitogenesis, cell cycle progression, and protection against different apoptotic stresses. Indirect effects of the axis depend on interactions between IGF and other molecules important for cancer etiology (e.g. sex hormones, products of suppressor genes, viruses, and other GFs) and the style of life (nutrition, physical activity). From the clinical point of view, components of IGF system are first of all considered as diagnostic serous and/or tissue biomarkers of a given cancer, prognostic factors and attractive target of modern anti-tumor therapies. Several mechanisms in which IGF system components act in the process of carcinogenesis need to be clarified, mainly due to multifactorial etiology of the neoplasms. Pin-pointing of the role played in carcinogenesis by any single signaling pathway remains particularly difficult. The aim of this review is to summarize the current data of several epidemiological studies, experiments in vitro and on animal models, to increase our understanding of the complex role of IGF family components in the most common human cancers.

The prevalence of mixed genotype infections in Polish patients with hepatitis C.

OBJECTIVES: Hepatitis C virus (HCV) genotype has been described as an independent predictor of the response to therapy. A mixed infection with two types of HCV is probably an uncommon event. The aim of this study was to determine the occurrence of mixed infection with two different HCV genotypes in adult patients with chronic hepatitis C eligible for treatment. METHODS: Plasma samples and clinical and demographic data were collected from 1159 patients with hepatitis C. The INNO-LiPA HCV assay was used to identify the HCV genotypes. RESULTS: The dominant genotype was genotype 1, which was found to be responsible for 83.9% of infections, with subtype 1b being the most common. A mixed genotype infection was detected in 26 patients (2.2%). The most common mixed genotype was 1a+1b detected in 17/26 patients (65%). Antiviral therapy led to complete elimination of both genotypes in 50% of patients with 1b+3a infection and in 33% of patients with 1b+4a infection. CONCLUSIONS: The results obtained showed that infection with mixed HCV genotypes in Polish patients with hepatitis C is uncommon. The selective elimination of genotypes 3a and 4a after therapy confirms the greater resistance to treatment of genotype 1b. In the context of new anti-HCV drug development, further investigations are needed to determine the clinical importance of mixed HCV infection.

Insulin-like growth factor-1 mRNA isoforms and insulin-like growth factor-1 receptor mRNA expression in chronic hepatitis C.

AIM: To evaluate the expression of different insulin-like growth factor (IGF)-1 mRNA isoforms and IGF-1 receptor (IGF-1R) mRNA in hepatitis C virus (HCV)-infected livers. METHODS: Thirty-four liver biopsy specimens from chronic hepatitis C (CH-C) patients were obtained before anti-viral therapy. Inflammatory activity (grading) and advancement of fibrosis (staging) were evaluated using a modified point scale of METAVIR. The samples were analyzed using quantitative real-time PCR technique. From fragments of liver biopsies and control liver that were divided and ground in liquid nitrogen, RNA was isolated using RNeasy Fibrous Tissue Mini Kit according to the manufacturer's instruction. Expression levels of IGF-1 mRNA isoforms (IGF-1A, IGF-1B, IGF-1C, P1, and P2) and IGF-1R mRNA were determined through normalization of copy numbers in samples as related to reference genes: glyceraldehyde-3-phosphate dehydrogenase and hydroxymethylbilane synthase. Results on liver expression of the IGF-1 mRNA isoforms and IGF-1R transcript were compared to histological alterations in liver biopsies and with selected clinical data in the patients. Statistical analysis was performed using Statistica PL v. 9 software. RESULTS: The study showed differences in quantitative expression of IGF-1 mRNA variants in HCV-infected livers, as compared to the control. Higher relative expression of total IGF-1 mRNA and of IGF-1 mRNAs isoforms (P1, A, and C) in HCV-infected livers as compared to the control were detected. Within both groups, expression of the IGF-1A mRNA isoform significantly prevailed over expressions of B and C isoforms. Expression of P1 mRNA was higher than that of P2 only in CH-C. Very high positive correlations were detected between reciprocal expressions of IGF-1 mRNA isoforms P1 and P2 (r = 0.876). Expression of P1 and P2 mRNA correlated with IGF-1A mRNA (r = 0.891; r = 0.821, respectively), with IGF-1B mRNA (r = 0.854; r = 0.813, respectively), and with IGF-1C mRNA (r = 0.839; r = 0.741, respectively). Expression of IGF-1A mRNA significantly correlated with isoform B and C mRNA (r = 0.956; r = 0.869, respectively), and B with C isoforms (r = 0.868) (P < 0.05 in all cases). Lower expression of IGF-1A and B transcripts was noted in the more advanced liver grading (G2) as compared to G1. Multiple negative correlations were detected between expression of various IGF-1 transcripts and clinical data (e.g., alpha fetoprotein, HCV RNA, steatosis, grading, and staging). Expression of IGF-1R mRNA manifested positive correlation with grading and HCV-RNA. CONCLUSION: Differences in quantitative expression of IGF-1 mRNA isoforms in HCV-infected livers, as compared to the control, suggest that HCV may induce alteration of IGF-1 splicing profile.

The insulin-like growth factor-1 and expression of its binding protein­3 in chronic hepatitis C and hepatocellular carcinoma.

The role of growth factors produced by the liver, including insulin-like growth factor-1 (IGF-1) and its main binding protein, IGF binding protein-3 (IGFBP-3), in hepatitis C virus (HCV)-associated carcinogenesis has only partially been recognized and there is not much data available on the local expression of IGF-1 and IGFBP-3 in chronic hepatitis C (CH­C). Therefore, the aim of the present study was to evaluate the IGF­1 and IGFBP­3 serum levels and tissue expression in liver biopsies of CH­C patients (n=37) and hepatocellular carcinoma (HCC) samples (n=61) as related to age- and gender-matched control serum samples (n=15) and healthy liver samples (n=10). Serum concentrations of IGF-1 (S-IGF-1) and IGFBP­3 (S-IGFBP­3) were measured by the ELISA method. Tissue expression of proteins was detected using ABC immunocytochemistry and evaluated applying a spatial visualization technique. Concentrations of S-IGF-1 and hepatic expression of IGF-1 (H-IGF-1) proved to be lower in CH-C compared to the controls. No significant differences were detected in the concentration of S-IGFBP-3 between the studied groups but the S-IGF-1/IGFBP-3 ratio in the CH-C group was significantly lower compared to the control. H-IGFBP-3 was higher in CH-C compared to those in the control and HCC. In HCC, lower expression of H-IGF-1 was detected compared to the control and a higher H-IGF-1/IGFBP-3 ratio compared to CH-C. A negative correlation was detected between S-IGF-1 and S-IGF-1/IGFBP-3 ratio, on the one hand, and age, grading and concentration of α-fetoprotein (AFP) on the other, while H-IGFBP-3 was negatively correlated with BMI in the CH­C group. In patients with CH­C, the H­IGF­1/IGFBP­3 ratio was higher compared to that of the S­IGF­1/IGFBP­3 ratio. The studies documented a disturbed H­IGF­1 and H­IGFBP­3 in CH­C, which may be of significance in carcinogenesis. Examination of serum concentration and tissue expression of the two proteins and, first of all, estimation of the IGF­1/IGFBP­3 ratio may provide additional (to the estimation of IGF­1 and AFP) non-invasive markers in HCV­related liver injury.

Distribution of HCV genotypes in Poland.

UNLABELLED: Available data on prevalence of HCV genotypes in Poland are insufficient. The aim of the study was the analysis of distribution of HCV genotypes in Poland over the period of recent 10 years regarding the age of patients and the regions of the country. MATERIAL AND METHODS: Analysis of HCV genotypes in Poland was carried out between 2003 and 2012, and included 14 651 patients from 22 centers where patients with chronic viral hepatitis C are diagnosed and treated. Genotypes were analyzed in age groups (< 20 years of age, 20-40 years of age, > 40 years of age) as well as in populations of HBV and HIV co-infections. RESULTS: Genotype (G) 1 infection was demonstrated in 79.4%, G2 -0.1%, G3- 13.8%, G4- 4.9%, G6-0.09% and mixed infections in 1.6%. There was no infection with genotype 5. The highest prevalence of G1 was observed in the Lódzkie voivodship (89.2%) and the Slaskie voivodship (86.7%) while the lowest one in the Warminsko-mazurskie (62.0%) and the Podlaskie voivodships (68.2%). Genotype 3 most commonly occurs in the Warminsko-mazurskie (28.1%), and the Podlaskie voivodships (23.0%) and is least common in the Malopolskie (7.9%) and the Lódzkie voivodships (9.0%). Genotype 4 is more common in the Kujawsko-pomorskie (11.7%) and the Podlaskie voivodships (8.6%) and relatively less common in the Lubelskie (1.1%) and the Lódzkie voivodships (1.8%). Prevalence of G1 infection in 2003-2004 was 72% and increased up to 85.6% in 2011-2012, that was accompanied by decrease of G3 prevalence from 17% to 8% in this period. In HBV co-infected (n = 83), G1 infection was demonstrated in 85.5%, G3 - in 7.2%, G4 -4.8%, and mixed genotypes in 6%. Among HIV co-infected (n = 391), a much lower prevalence of G1 (33.0%) and a high of G3 (40.4%) as well as G4 (24.0%) were observed. CONCLUSIONS: There is a geographic variability of HCV genotypes prevalence in Poland. Increase of HCV G1 infections and decrease of G3 and G4 were observed in the last 10 years. Genotypes G3 and G4 occur more often in HCV/HIV co-infected than in HCV mono-infected patients.

The insulin-like growth factor (IGF) signaling axis and hepatitis C virus-associated carcinogenesis (review).

Insulin-like growth factor (IGF) signaling plays an important autocrine, paracrine and endocrine role in growth promotion involving various tissues and organs. Synthesis of both IGFs (IGF-1 and IGF-2) in normal conditions takes place mainly in the liver even if the proteins can be produced in every cell of the human body. The alterations in the IGF signaling axis in human hepatocarcinogenesis are described, but mechanisms of the interactions between expression of oncogenic hepatitis C virus (HCV) proteins and components of the IGF system in progression of chronic hepatitis C to primary hepatocellular carcinoma (HCC) have been poorly recognised. In advanced stages of liver diseases, lowered serum levels of IGF-1 and IGF-2 have been documented. This was supposed to reflect significant damage to liver parenchyma, a decreased number of growth hormone receptors and a decreased genomic expression of IGF binding proteins (IGF BPs). In HCC, a decreased tissue expression of IGF-1, and an increased expression of IGF-1 receptor (IGF-1R) were noted, compared to the control. Potential mechanisms of augmented IGF-2 expression in HCC were also described and dysregulation of IGF signaling in HCC was concluded to occur predominantly at the level of IGF-2 bioavailability. The review aimed at presentation of involvement of IGF-1, IGF-1R and IGF BPs (mostly IGF BP-3 and IGF BP-6) in HCV-related hepatocarcinogenesis. Manifestation of various mRNA transcripts and IGF-1 proteins and their potential involvement in carcinogenesis are also discussed.

Results of antiviral treatment of patients with chronic hepatitis C: experience of Poznan centre.

INTRODUCTION: Hepatitis C virus (HCV) infection in Poland affects approximately 750 thousand persons. The prevention of cirrhosis and hepatocellular carcinoma, of which approximately 20% of patients with chronic hepatitis C virus are at risk, aims at eradication of the virus by applying antiviral treatment with pegylated interferon alpha with ribavirin. MATERIAL/METHODS: In this paper the results of the standard treatment of chronic hepatitis C in a population of 169 adult patients in whom it was started in the period of 01.01.2007-30.06.2008 are analyzed. Moreover, the influence of various clinical, biochemical and viral factors on achieving therapeutic success in the form of the sustained virological response (SVR) was studied. RESULTS: In the group of 128 patients who received the full course of antiviral treatment, the SVR was achieved by 67.2% of patients (86 persons), whereas regarding all 169 patients who started the therapy, the sustained disappearance of viremia was found in 53.2% of patients (90 persons). Regarding 155 persons in whom the treatment was not interrupted for reasons others than virology, this value was 55.5%. For the sustained disappearance of viremia the following was favorable: genotype 3 virus, age under 40 years, body mass up to 75 kg, correct value of body mass index (BMI), low gamma-glutamyl transpeptidase (GGTP) activity before the treatment, minimum advancement of liver fibrosis in a liver biopsy (S1), complete early biochemical response (cEBR), and moreover, the achievement of negation of viremia after 12 weeks of the treatment in a group of patients infected with genotype 1 (complete early virological response, cEVR). These factors were strongly correlated with each other and that is why an analysis by the method of logistic multiple regression was impossible. Adverse reactions to the treatment and other health problems were the reasons for earlier discontinuation of the standard therapeutic scheme in 14 patients, whereby the lack of an SVR occurred in 10 of them (71.5% which is 5.9% of the studied population).

Seroprevalence of hepatitis A virus antibodies (anti-HAV) in adult inhabitants of Wielkopolska region, Poland--the role of simple demographic factors.

INTRODUCTION AND OBJECTIVE: Based on the available epidemiologic data, Poland currently has the features typical for areas of very low endemicity for hepatitis A. The incidence of hepatitis A in the Wielkopolska region in years 2006-2008 was 0.68/100,000 inhabitants or significantly lower. The aim of this cross-sectional analysis was to evaluate the seroprevalence of anti-HAV antibodies in inhabitants of the Wielkopolska region of western Poland regarding some demographic factors. MATERIAL AND METHODS: In addition to testing anti-HAV antibodies, the medical history and demographic data, such as age, gender, place of residence, and level of education of 680 patients and 105 healthy blood donors were analyzed. RESULTS: Anti-HAV antibodies were observed in 235 cases (29.9%). In univariate regression analysis, the covariates correlated with positive anti-HAV testing were age, female gender and lower level of education. Only 6.2% of young adults were seropositive. Among study participants above the age of 50, anti-HAV antibodies were present in 64-100% of cases. An icteric disease consistent with hepatitis A diagnosis was identified in the histories of 10.2% of seropositive patients. CONCLUSIONS: The risk for contracting disease after exposure to HAV in young (<40 years old) inhabitants of the Wielkopolska region is high. Apart from older individuals, also women and people with a lower level of education are more frequently seropositive. A low level of immunity to HAV should be an indication for vaccination against HAV , especially in selected groups.

Alterations of insulin-like growth factor I (IGF-I) and estradiol serum levels in chronic hepatitis C.

AIM OF THE STUDY: Deregulation of insulin-like growth factor I (IGF-I) production and decreased hepatic estrogen levels were associated with development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) infected cirrhotic patients. The aim of our study was to determine serum levels of IGF-I, insulin and 17-ß estradiol (17-ßE) in relation to other markers of liver injury in chronic hepatitis C (CHC) patients. MATERIAL AND METHODS: Thirty anti-viral treatment-naïve CHC patients and 10 healthy subjects were examined. HCV infection was confirmed by presence of anti-HCV and HCV-RNA in serum. Serum levels of IGF-I, insulin and of 17-ßE were evaluated using ELISA methods. RESULTS: Serum levels of IGF-I and 17-ßE were significantly lower in CHC patients than in controls while insulin levels were similar in both groups. A lower IGF-I level (but not the level of 17-ßE) was observed in cirrhotic CHC patients in comparison to non-cirrhotic ones. Decreased serum level of IGF-I was associated with more advanced staging and liver steatosis, higher levels of alpha-fetoprotein (AFP) and gamma globulin levels, and higher aspartate transaminase (AST) activity in CHC patients. Insulin and 17-ßE levels positively correlated with patient's age. A positive correlation was observed between insulin level on one hand and staging, liver steatosis and levels of gamma globulins in CHC patients on the other. A negative correlation between IGF-I and insulin levels was noted only in HCV infected patients. CONCLUSIONS: Decreased IGF-I levels and increased levels of insulin better than estradiol serum levels characterize staging and liver steatosis in CHC patients. The lower serum level of 17-ßE in the CHC group than in control patients suggests that CHC patients carry higher risk of liver injury and of HCC development.

Polysaccharides and mucin 5AC (MUC5AC) expression in gallbladder mucosa of young patients with gallstones as evaluated by spatial visualization and quantification.

The study aimed at examination of tissue expression of polysaccharides and secretory mucin 5AC (MUC5AC) in young patients (up to 25 years of age) with a symptomatic gallstones. For comparison, patients most frequently subjected to cholecystectomy were studied, i.e. patients of approximately 50 years of age with the same diagnosis. In quantitative studies on tissue expression of both mucus components, the modern technique of spatial visualization was applied for the first time. Application of the technique permitted to demonstrate significant positive relationships between expression of glycoproteins (immunocytochemical ABC technique for detection of MUC5AC) and expression of sugar components in mucus (PAS technique) and to confirm suitability of the technique for quantitative appraisal of both histochemical and immunocytochemical reactions. An even higher expression of polysaccharides in the entire mucosa and of MUC5AC was detected in gallbladder epithelium of 50-year-old patients, as compared to young patients with symptomatic gallstones. In the young patients, expression of polysaccharides correlated with inflammatory activity (grading), width of gallbladder wall and PLT level in peripheral blood. A significantly higher expression of polysaccharides in gallbladder epithelium was demonstrated in young patients admitted in the emergency mode to the hospital. These correlations in young patients may suggest a role of both mucus components in pathogenesis of cholelithiasis in this age group. A quantitative appraisal of mucus component expression in the two parts of gallbladder mucosa (epithelium vs. entire mucosa) using spatial visualization technique permitted to more accurately compare production of glycoproteins and of polysaccharides in patients with cholelithiasis and to demonstrate additional correlations of a potential clinical significance.

p53 immunocytochemistry and TP53 gene mutations in patients with chronic hepatitis C virus (HCV) infection.

Chronic infection with hepatitis C virus (HCV) is regarded as a risk factor for hepatocellular carcinoma (HCC), mostly in patients with liver cirrhosis. Present study aimed at evaluation of cellular expression of p53 protein, genetic TP53 changes in liver samples and anti-p53 in serum of patients with chronic hepatitis C virus infection. The expression of p53 protein were analysed by immunocytochemistry in liver biopsies from adult patients with chronic, long-lasting hepatitis C. In order to detect TP53 mutations, PCR/SSCP and sequencing were performed. Antibodies against p53 in serum were determined using enzyme immunoassay (ELISA).In two out of 14 examined patients TP53 point mutations were detected in the liver samples. In the first patient, a substitution of C to T was demonstrated in position 1 of the codon 250, resulting in substitution of proline by serine. The other patient carried a substitution of C to G in position 13274 of the intron 6. The patient carrying mutation in the codon 250 demonstrated morphological traits of liver cirrhosis and had high number of p53-immunoreactive cell nuclei in tissue. None of the patients manifested elevated titres of serum anti-p53. In the liver, significant positive correlations were disclosed between expression of p53 on one hand and grading and staging on the other. A negative correlation was disclosed between cellular expression of p53 and duration time of infection. In conclusions, genetic changes in TP53 can be detected also in non-neoplastic lesions linked to chronic HCV infection.