Molecular pathogenesis of intraductal papillary mucinous neoplasms of the pancreas

Over the last 3 decades, there have been substantial improvements in diagnostic imaging and sampling techniques to evaluate pancreatic diseases. The modern technology has helped us to recognize premalignant conditions of pancreas including mucinous cystic neoplasms and intraductal papillary mucinous neoplasms (IPMNs). Differentiation between benign and malignant lesions and early detection of any malignant transformation in premalignant lesion are extremely important for further management decisions. Diagnostic cytology has limited sensitivity to further differentiate between benign, premalignant, and malignant lesions of the pancreas. There is limited information about the epidemiological risk factors and molecular mechanisms leading to development and further progression to malignancy of IPMNs. Several studies have shown that pancreatic juice and pancreatic tissue from the lesion can be tested for molecular markers including K-ras, p53, and p16 to differentiate between cancer and chronic inflammatory process. We review cellular signaling pathways that contribute to pathogenesis of IPMNs of the pancreas to further identify potential biomarkers and molecular targets.     

Variations in the functional domain of basal core promoter of hepatitis B virus among Eastern Indian patients with prevalence of genotypes A, C, and D among the same ethnic population

Mutations in the basal core promoter (BCP) and precore (PC) regions are associated with persistent and intermittently high hepatitis B virus (HBV) replication in several patients. The variability in the functional domains of BCP and PC region of HBV and their association with disease progression and clinical outcome were assessed in Eastern India, an unique region where three HBV genotypes, A, D, and C are prevalent among the same ethnic group. PCR amplification and direct sequencing of BCP and PC region was done on sera obtained from 130 HBsAg positive subjects with different clinical presentations. Associations of the apparent risk factors with clinical advancement were evaluated by statistical methods including multiple logistic regression analyses (MLR). HBV genotype A was present in 33.08%, C in 25.38%, and D in 41.54% cases. Genotypes A and C were associated with higher rate of T1762/A1764 mutations than the most predominant genotype D. HBeAg negative state was associated with considerably higher rate of C1753 mutation. T1762/A1764 along with C1753 was common among cirrhosis and T1762/A1764 without C1753 was frequent among chronic liver disease cases. No significant association was found between A1896 point mutation and clinical status. Multivariate analysis revealed that T1762/A1764 double mutation, HBV/A, age ≥25 years, C1753 and A1899 were critical factors for clinical advancement while age ≥25 years and C1753 as significant predictor for cirrhosis in comparison with chronic liver disease. In conclusion, the analysis of the BCP variability may help in monitoring the progression towards advanced liver disease in Eastern Indian patients.     

Malignancy in common variable immune deficiency: report of two rare cases of gastrointestinal malignancy and a review of the literature

Patients can develop malignancies due to various reasons including genetic factors, chemical carcinogens, radiation, and defects in their immune system. The immune system is postulated to carry out routine surveillance for malignancy. Patients who have defective immune responses may be susceptible to malignancies due to complicated underlying mechanisms. These include defective immune response to cancer-causing bacteria, transforming viruses, and concomitant molecular, cellular and immunoregulatory defects. Common variable immune deficiency (CVID) is characterized by hypogammaglobulinemia, impaired antibody responses and an increased susceptibility to infections. A disorderly immune response, or immune dysregulation, may also lead to autoimmune complications and possibly to malignancy. The treatment of CVID involves infusion of replacement doses of immunoglobulin, either intravenously (IGIV) or subcutaneously (SCIG). However, it is unclear whether adequate replacement of immunoglobulins is sufficient to prevent the increased risk of malignancy seen in this disease. We present two cases of unusual solid tumors complicating CVID treated with adequate doses of intravenous immunoglobulins. In this study we review the occurrence of malignancy in patients with CVID and postulate mechanisms that may be involved indigent to this disease. We will also review the role of replacement immunoglobulin and discuss cancer screening in these high risk individuals.     

Genome‐wide high‐resolution analysis of DNA copy number alterations in NF1‐associated malignant peripheral nerve sheath tumors using 32K BAC array

Neurofibromatosis Type I (NF1) is an autosomal dominant disorder characterized by the development of both benign and malignant tumors. The lifetime risk for developing a malignant peripheral nerve sheath tumor (MPNST) in NF1 patients is ～10% with poor survival rates. To date, the molecular basis of MPNST development remains unclear. Here, we report the first genome‐wide and high‐resolution analysis of DNA copy number alterations in MPNST using the 32K bacterial artificial chromosome microarray on a series of 24 MPNSTs and three neurofibroma samples. In the benign neurofibromas, apart from loss of one copy of the NF1 gene and copy number polymorphisms, no other changes were found. The profiles of malignant samples, however, revealed specific loss of chromosomal regions including 1p35‐33, 1p21, 9p21.3, 10q25, 11q22‐23, 17q11, and 20p12.2 as well as gain of 1q25, 3p26, 3q13, 5p12, 5q11.2‐q14, 5q21‐23, 5q31‐33, 6p23‐p21, 6p12, 6q15, 6q23‐q24, 7p22, 7p14‐p13, 7q21, 7q36, 8q22‐q24, 14q22, and 17q21‐q25. Copy number gains were more frequent than deletions in the MPNST samples (62% vs. 38%). The genes resident within common regions of gain were NEDL1 (7p14), AP3B1 (5q14.1), and CUL1 (7q36.1) and these were identified in >63% MPNSTs. The most frequently deleted locus encompassed CDKN2A, CDKN2B, and MTAP genes on 9p21.3 (33% cases). These genes have previously been implicated in other cancer conditions and therefore, should be considered for their therapeutic, prognostic, and diagnostic relevance in NF1 tumorigenesis. © 2009 Wiley‐Liss, Inc.     

Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1

Dendritic cells (DCs) efficiently capture HIV-1 and mediate transmission to T cells, but the underlying molecular mechanism is still being debated. The C-type lectin DC-SIGN is important in HIV-1 transmission by DCs. However, various studies strongly suggest that another HIV-1 receptor on DCs is involved in the capture of HIV-1. Here we have identified syndecan-3 as a major HIV-1 attachment receptor on DCs. Syndecan-3 is a DC-specific heparan sulfate (HS) proteoglycan that captures HIV-1 through interaction with the HIV-1 envelope glycoprotein gp120. Syndecan-3 stabilizes the captured virus, enhances DC infection in cis, and promotes transmission to T cells. Removal of the HSs from the cell surface by heparinase III or by silencing syndecan-3 by siRNA partially inhibited HIV-1 transmission by immature DCs, whereas neutralizing both syndecan-3 and DC-SIGN completely abrogated HIV-1 capture and subsequent transmission. Thus, HIV-1 exploits both syndecan-3 and DC-SIGN to mediate HIV-1 transmission, and an effective microbicide should target both syndecan-3 and DC-SIGN on DCs to prevent transmission.     

Association of Tagging Single Nucleotide Polymorphisms on 8 Candidate Genes in Dopaminergic Pathway with Schizophrenia in Croatian Population

Aim

To perform a comprehensive evaluation of association of common genetic variants in candidate genes in the dopaminergic pathway with schizophrenia in a sample from Croatian population.

Methods

A case-control association study was performed on 104 unrelated patients with schizophrenia recruited from a psychiatric hospital in Zagreb and 131 phenotypically normal Croatian subjects. Forty-nine tagging single nucleotide polymorphisms (tagSNPs) in 8 candidate genes in the dopaminergic pathway were identified from the HapMap database and tested for association. Genotyping was performed using the SNPlex platform. Statistical analysis was conducted to assess allelic and genotypic associations between cases and controls using a goodness of fit χ² test and trend test, respectively; adjustment for multiple testing was done by permutation based analysis.

Results

Significant allele frequency differences between schizophrenia cases and controls were observed at 4 tagSNPs located in the genes DRD5, HTR1B1, DBH, and TH1 (P < 0.005). A trend test also confirmed the genotypic association (P < 0.001) of these 4 tagSNPs. Additionally, moderate association (P < 0.05) was observed with 8 tagSNPs on SLC6A3, DBH, DRD4, SLC6A4, and COMT.

Conclusions

Common genetic variants in genes involved in the dopaminergic pathway are associated with schizophrenia in the populations of Caucasian descent.Schizophrenia is a chronic, severe, and disabling brain disease affecting about 1% of the global population (1). There is substantial evidence that genetic factors are involved in the etiology of the disease (2). High heritability (~ 80%) and higher concordance in monozygotic (~ 50%) than in dizygotic (~ 17%) twins are strong indicators for an inherited basis of schizophrenia (3-5). During the past decade, numerous loci and plausible candidate genes have been identified by linkage and association studies. However, the findings have remained inconclusive (2,6). Like other complex diseases, a complex genetic etiology compounded by involvement of other non-genetic factors has hindered the precise identification of schizophrenia gene variants. Second, a major limitation in most association studies has been testing of a few variants within a gene of interest rather than a thorough assessment of the entire gene region. With the availability of the sequence of the genome and large body of data on human genetic variation from the HapMap project (7), it is now possible to undertake more comprehensive association studies.Genes involved in the dopamine pathway are biologically plausible candidates in schizophrenia susceptibility. In this study, we report on the association of single nucleotide polymorphisms (SNPs) in 8 dopaminergic genes (DRD4, DRD5, SLC6A3, SLC6A4, HTR1B, DBH, TH, and COMT) with schizophrenia in a Caucasian sample from Croatia. We performed a comprehensive association study using tagging SNPs (tagSNPs). Overall, 49 tagSNPs were identified from the HapMap database (7), 4 of which showed strong evidence of association with schizophrenia susceptibility.     

The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas

Neurofibromatosis type 1 (NF1) is a common inherited complex multi-system disorder associated with the growth of various benign and malignant tumors. About 40% of NF1 patients develop spinal tumors, of whom some have familial spinal neurofibromatosis (FSNF), a variant form of NF1 in which patients present with multiple bilateral spinal tumors but have few other clinical features of the disease. We have studied 22 spinal neurofibromas derived from 14 unrelated NF1 patients. Seven of these patients satisfied the diagnostic criteria of NF1 while the remaining seven had only few features of NF1. The latter group defined as FSNF harbored significantly higher number of missense or missense and splice-site germline mutations compared to the group with classical NF1. This is the first study to describe NF1 somatic mutations in spinal neurofibromas. Loss-of-heterozygosity (LOH) was identified in 8/22 of the spinal tumors, 75% of LOH observed was found to result from mitotic recombination, suggesting that this may represent a frequent mutational mechanisms in these benign tumors. No evidence for LOH of the TP53 gene was found in these tumors.     

Beta blockers in coronary artery disease with and without hypertension

Beta-adrenergic blockers (BB) were developed to treat angina. Trials of BB with myocardial infarction (MI) setting were highly successful in the pre-thrombolytic era. Subsequently BB proved to be beneficial in post-thrombolytic MI in long-term use. In stable angina BB gives good symptomatic relief primarily by reducing myocardial oxygen demand. In the set-up of unstable angina/non-ST elevation MI they prevent arrhythmia and progression to ST elevation MI. BB have also been shown to retard the progression of atherosclerosis. In congestive cardiac failure (CCF) they are now the first-line drugs with ACE inhibitors to impart prognostic benefit. Their role in improving outcome of cardiac and non-cardiac surgeries has found good evidence and recommendation. But in the field where BB have scored maximally, ie, in hypertension, their role is recently debated. But the unchallenged fact remains that in presence of any form of coronary artery disease, BB are the most preferred class of drugs to treat hypertension.