Review of genetic and epigenetic alterations in hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is associated with multiple risk factors and is believed to arise from pre-neoplastic lesions, usually in the background of cirrhosis. However, the genetic and epigenetic events of hepatocarcinogenesis are relatively poorly understood. HCC display gross genomic alterations, including chromosomal instability (CIN), CpG island methylation, DNA rearrangements associated with hepatitis B virus (HBV) DNA integration, DNA hypomethylation and, to a lesser degree, microsatellite instability.

Low level microsatellite instability may be associated with reduced cancer specific survival in sporadic stage C colorectal carcinoma.

Background: Colorectal cancers (CRCs) may be categorised according to the degree of microsatellite instability (MSI) exhibited, as MSI-high (MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS). MSI-H status confers a survival advantage to patients with sporadic CRC.

Aims: To determine if low levels of MSI are related to the clinicopathological features and prognosis of sporadic stage C CRC.

CCR5-Delta32 mutation is strongly associated with primary sclerosing cholangitis.

CCR5 plays a key role in the distribution of CD45RO+ T cells and contributes to generation of a T helper 1 immune response. CCR5-Delta32 is a 32-bp deletion associated with significant reduction in cell surface expression of the receptor. We investigated the role of CCR5-Delta32 on susceptibility to ulcerative colitis (UC), Crohn's disease (CD) and primary sclerosing cholangitis (PSC).

Cadherin/catenin complex appears to be intact in hepatocellular carcinomas from Australia and South Africa.

Background And Aim: E-cadherin binds to beta-catenin to form the cadherin/catenin complex required for strong cell adhesion. Inactivation of this complex in tumors facilitates invasion into surrounding tissues. Alterations of both proteins have been reported in hepatocellular carcinomas (HCC).

Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer.

Colorectal cancer (CRC) has traditionally been classified into two groups: microsatellite stable/low-level instability (MSS/MSI-L) and high-level MSI (MSI-H) groups on the basis of multiple molecular and clinicopathologic criteria. Using methylated in tumor (MINT) markers 1, 2, 12, and 31, we stratified 77 primary CRCs into three groups: MINT++ (>2), MINT+ (1-2), and MINT- (0 markers methylated). The MSS/MSI-L/MINT++ group was indistinguishable from the MSI-H/MINT++ group with respect to methylation of p16(INK4a), p14(ARF), and RIZ1, and multiple morphological features.

Occult axillary lymph node metastases in breast cancer do matter: results of 10-year survival analysis.

Axillary lymph node status is one of the most powerful prognostic factors for patients with breast cancer and is often critical in stratifying patients into adjuvant treatment regimens. In 203 apparently node-negative cases of breast cancer, a combination of immunohistochemical staining and step-sectioning identified occult metastases in 25% of cases. Ten-year follow-up information is available for these patients.

Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells.

Background: The response of hepatocellular carcinoma (HCC) to therapy is often disappointing and new modalities of treatment are clearly needed. Active immunotherapy based on the injection of autologous dendritic cells (DC) co-cultured ex vivo with tumor antigens has been used in pilot studies in various malignancies such as melanoma and lymphoma with encouraging results.

Methods: In the present paper, the preparation and exposure of patient DC to autologous HCC antigens and re-injection in an attempt to elicit antitumor immune responses are described.

When is molecular genetic testing for colorectal cancer indicated?

The genetic mutations causing many of the syndromes which confer a high inherited risk of colorectal cancer have now been identified. These include familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, Peutz-Jeghers syndrome, Cowden's syndrome and juvenile polyposis. In all these diseases, the precise mutation is nearly always unique to a particular family; there are few mutation hot spots.

Reciprocal relationship between methylation status and loss of heterozygosity at the p14(ARF) locus in Australian and South African hepatocellular carcinomas.

Chromosome 9p21, a locus comprising the tumor suppressor genes (TSG) p16(INK4a) and p14(ARF), is a common region of loss of heterozygosity (LOH) in hepatocellular carcinoma (HCC). p14(ARF) shares exon 2 with p16 in a different reading frame. p14 binds to MDM2 resulting in a stabilization of functional p53.

A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene. It is characterised by the appearance of hundreds to thousands of colorectal adenomas in adolescence and the subsequent development of colorectal cancer. Various extracolonic malignancies are associated with FAP, including desmoids and neoplasms of the stomach, duodenum, pancreas, liver, and brain.

A molecular comparison of T lymphocyte populations infiltrating the liver and circulating in the blood of patients with chronic hepatitis B: evidence for antigen-driven selection of a public complementarity-determining region 3 (CDR3) motif.

Despite a large number of T cells infiltrating the liver of patients with chronic hepatitis B, little is known about their complexity or specificity. To characterize the composition of these T cells involved with the pathogenesis of chronic hepatitis B (CHB), we have studied the clonality of VbetaT cell receptor (TCR)-bearing populations in liver tissue by size spectratyping the complementarity-determining region (CDR3) lengths of TCR transcripts. We have also compared the CDR3 profiles of the lymphocytes infiltrating the liver with those circulating in the blood to see whether identical clonotypes may be detected that would indicate a virus-induced expansion in both compartments.

A novel variant genotype C of hepatitis B virus identified in isolates from Australian Aborigines: complete genome sequence and phylogenetic relatedness.

There have been no reports of DNA sequences of hepatitis B virus (HBV) strains from Australian Aborigines, although the hepatitis B surface antigen (HBsAg) was discovered among them. To investigate the characteristics of DNA sequences of HBV strains from Australian Aborigines, the complete nucleotide sequences of HBV strains were determined and subjected to molecular evolutionary analysis. Serum samples positive for HBsAg were collected from five Australian Aborigines.

Sodium iodide symporter (NIS) gene expression in human placenta.

The placenta must allow the passage of iodide from the maternal to the fetal circulation for synthesis of thyroxine by the fetal thyroid. The thyroid sodium iodide symporter (NIS) was cloned in 1996 and, although widely distributed among epithelial tissues, early studies failed to detect it in placenta. We demonstrated NIS mRNA in human placenta and in the human choriocarcinoma cell line, JAr.

Different transporters for tri-iodothyronine (T(3)) and thyroxine (T(4)) in the human choriocarcinoma cell line, JAR.

We investigated transport systems for tri-iodothyronine (T(3)) and thyroxine (T(4)) in the human choriocarcinoma cell line, JAR, using a range of structurally similar compounds to determine whether these thyroid hormones are transported by common or different mechanisms. Saturable T(3) but not saturable T(4) uptake was inhibited by a wide range of aromatic compounds (nitrendipine, nifedipine, verapamil, meclofenamic acid, mefenamic acid, diazepam, phenytoin). Nitrendipine and diazepam were the most effective inhibitors of saturable thyroid hormone uptake.

Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer.

Background: Colorectal cancers exhibiting microsatellite instability (MSI) appear to have unique biological behaviour. This study analyses the association between extensive MSI (MSI-H), clinicopathological features and survival in an unselected group of patients with sporadic Australian Clinico-Pathological Stage (ACPS) C (tumour node metastasis stage III) colorectal cancer.

Methods: Some 255 patients who underwent resection for sporadic ACPS C colorectal cancer between 1986 and 1992 were studied.

What did we learn from the Shanghai hepatitis A epidemic?

A major outbreak of hepatitis A (HAV), associated with consumption of raw clams, occurred in Shanghai, China in 1988. Over 300 000 cases were reported, of which 47 (0.015%) were fatal.

Consensus statement on the role of hepatitis A vaccination in patients with chronic liver disease.

Hepatitis A virus (HAV) is a ubiquitous, easily transmitted virus that can cause severe hepatitis, particularly in the adult population. Improvements in sanitation and hygiene in the developing world have led to a decline in immunity against HAV. A growing number of adults are now susceptible to infection, with those who have not been vaccinated against hepatitis B virus (HBV) being at risk of dual infection and potentially more severe illness.

p73 is up-regulated in a subset of hepatocellular carcinomas.

Loss of heterozygosity (LOH) at 1p36 occurs in a number of solid tumors including hepatocellular carcinoma (HCC). Recently, a novel gene, p73, has been identified at 1p36.33.

Cell death mediated by amino acid transmitter receptors in human alcoholic brain damage: conflicts in the evidence.

Human alcoholics have reduced neuronal counts in certain brain regions, such as superior frontal cortex (SFC), where the form and quantity of synaptic gamma-aminobutyric acid type A (GABAA) receptor sites are atypical. We measured the expression of GABAA receptor isoform mRNA and protein, since GABAA receptor pharmacology is strongly influenced by its subunit composition. Cortex samples were obtained at autopsy; whole-tissue extracts were assayed for mRNA by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), while synaptic membranes were studied for both GABAA receptor pharmacology and subunit protein levels by Western blots with isoform-specific antibodies.

Expression of GABA(A) receptor isoform genes in the cerebral cortex of cirrhotic and alcoholic cases assessed by S1 nuclease protection assays.

Pathogenic processes underlying the localized reduction in neuronal number in cerebral cortex in human alcoholics have been reported to be associated with selective variations in the parameters of GABA(A) receptor site binding. Since the properties of the receptor complex depend on its isoform composition, we studied how the expression of GABA(A) receptor subunit isoform genes varied with alcoholism. Cerebral cortex tissue was obtained at autopsy from chronic human alcoholics (average ethanol intake > 80 g/day for most of their adult lives; n = 17) and matched controls (< 20 g/day ethanol; n = 15).

Composition of peripheral blood lymphocyte populations during different stages of chronic infection with hepatitis B virus.

To characterize the immunological populations associated with different stages of chronic infection with hepatitis B virus (HBV), we performed flow cytometric analyses on the peripheral blood leucocytes of 29 patients with various forms of chronic hepatitis B. The clinical spectrum of the patients ranged from asymptomatic infections, in the presence of high virus production, to intermittent or recurrent exacerbations of liver injury alternating with relatively normal liver function. Patients with partial resolution of disease who experienced an initial acute flare followed by prolonged seroconversion showed decreased percentages of CD3+ cells during the seroconversion phase when levels of serum alanine transferase (ALT) had normalized.

Distinct patterns of T cell receptor distribution of peripheral blood CD8+ cells during different stages of chronic infection with hepatitis B virus.

We compared the Vbeta TCR repertoires of CD8+ peripheral blood lymphocytes between 21 patients with chronic hepatitis B (CHB) and 9 healthy individuals, using RT-PCR analysis. Several differences were seen between CHB patients and controls, including a marked increase in the expression of two to five Vbeta families in the CHB patients. There was no evidence for a superantigen effect, although an increase in Vbeta7 was seen in 64% of patients.

Regional development of glutamate-N-methyl-D-aspartate receptor sites in asphyxiated newborn infants.

The N-methyl-D-aspartate (NMDA) subclass of glutamate receptors was examined in newborn infants dying between 25 weeks' gestation and term, either from acute cerebral hypoxia, or from other noncerebral conditions incompatible with life. Frontal, occipital, temporal, and motor cortex tissue samples were obtained at autopsy (post mortem delay: median, 45.9 hr; range, 24-96 hr) and frozen for subsequent [3H]MK801 homogenate binding assays.