Expression of MK-1 and RegⅣ and its clinicopathological significances in the benign and malignant lesions of gallbladder

<p>Abstract</p> <p>Background</p> <p>To study the expression of MK-1 and RegⅣ and to detect their pathological significances in benign and malignant lesions of gallbladder.</p> <p>Methods</p> <p>The expression of MK-1 and RegⅣ was detected by immunohistochemical method in paraffin-embedded sections of surgical resected specimens from gallbladder adenocarcinoma (n = 108), peritumoral tissues (n = 46), adenomatous polyp (n = 15), and chronic cholecystitis (n = 35).</p> <p>Results</p> <p>The positive rate of MK-1 or RegⅣ expression was significantly higher in gallbladder adenocarcinoma than that in peritumoral tissues (χ²_MK-1= 18.76, <it>P </it>< 0.01; χ²_RegⅣ= 9.92, <it>P </it>< 0.01), denomatous polyp (χ²_MK-1= 9.49, <it>P </it>< 0.01; χ²_RegⅣ= 8.59, <it>P </it>< 0.01) and chronic cholecystitis (χ²_MK-1= 24.11, <it>P </it>< 0.01; χ²_RegⅣ= 19.24, <it>P </it>< 0.01). The positive cases of MK-1 and/or RegⅣ in the benign lesions showed moderately- or severe-atypical hyperplasia of gallbladder epitheli. The positive rates of MK-1 were significantly higher in the cases of well-differentiated adenocarcinoma, no-metastasis of lymph node, and no-invasiveness of regional tissues than those in the ones of differentiated adenocarcinoma, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma (<it>P </it>< 0.05 or <it>P </it>< 0.01). On the contrary, the positive rates of RegⅣ were significantly lower in the cases of well-differentiated adenocarcinoma, no-metastasis of lymph node, and no-invasiveness of regional tissues than those in the ones of differentiated adenocarcinoma, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma (<it>P </it>< 0.05 or <it>P </it>< 0.01). Univariate Kaplan-Meier analysis showed that decreased expression of MK-1 (<it>P </it>= 0.09) or increased expression of RegⅣ (<it>P </it>= 0.003) was associated with decreased overall survival. Multivariate Cox regression analysis showed that decreased expression of MK-1 (<it>P </it>= 0.033) and increased expression of RegⅣ (<it>P </it>= 0.008) was an independent prognostic predictor in gallbladder adenocarcinoma.</p> <p>Conclusions</p> <p>The expression of MK-1 and/or RegⅣ might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.</p

Co-expression of nuclear and cytoplasmic HMGB1 is inversely associated with infiltration of CD45RO+ T cells and prognosis in patients with stage IIIB colon cancer

<p>Abstract</p> <p>Background</p> <p>The intratumoral infiltration of T cells, especially memory T cells, is associated with a favorable prognosis in early colorectal cancers. However, the mechanism underlying this process remains elusive. This study examined whether high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, is involved in the infiltration of T cells and disease progression in locally advanced colon cancer.</p> <p>Methods</p> <p>Seventy-two cases of pathologically-confirmed specimens were obtained from patients with stage IIIB (T3N1M0) colon cancer who underwent radical resection between January 1999 and May 2002 at the Cancer Center of Sun Yat-Sen University. The density of tumor-infiltrating lymphocytes (TILs) within the tumor tissue and the expression of HMGB1 in the cancer cells were examined via immunohistochemical analysis. The phenotype of CD45RO+ cells was confirmed using a flow cytometric assay. The association between HMGB1 expression, the density of TILs, and the 5-year survival rate were analyzed.</p> <p>Results</p> <p>The density of CD45RO+ T cells within the tumor was independently prognostic, although a higher density of CD3+ T cells was also associated with a favorable prognosis. More importantly, the expression of HMGB1 was observed in both the nucleus and the cytoplasm (co-expression pattern) in a subset of colon cancer tissues, whereas nuclear-only expression of HMGB1 (nuclear expression pattern) existed in most of the cancer tissues and normal mucosa. The co-expression pattern of HMGB1 in colon cancer cells was inversely associated with the infiltration of both CD3+ and CD45RO+ T cells and 5-year survival rates.</p> <p>Conclusions</p> <p>This study revealed that the co-expression of HMGB1 is inversely associated with the infiltration of CD45RO+ T cells and prognosis in patients with stage IIIB colon cancer, indicating that the distribution patterns of HMGB1 might contribute to the progression of colon cancer via modulation of the local immune response.</p

The reg4 Gene, Amplified in the Early Stages of Pancreatic Cancer Development, Is a Promising Therapeutic Target

BACKGROUND: The aim of our work was to identify the genes specifically altered in pancreatic adenocarcinoma and especially those that are altered early in cancer development. METHODOLOGY/PRINCIPAL FINDINGS: Gene copy number was systematically assessed with an ultra-high resolution CGH oligonucleotide microarray in DNA from samples of pancreatic cancer. Several new cancer-associated variations were observed. In this work we focused on one of them, involving the reg4 gene. Gene copy number gain of the reg4 gene was confirmed by qPCR in 14 cancer samples. It was also found with increased copy number in most PanIN3 samples. The relationship betweena gain in reg4 gene copy number and cancer development was investigated on the human pancreatic cancer cell line Mia-PaCa2 xenografted under the skin of nude mice. When cells were transfected with a vector allowing reg4 expression, they generated tumors almost twice larger in size. In addition, these tumors were more resistant to gemcitabine treatment than control tumors. Interestingly, weekly intraperitoneal administration of a monoclonal antibody to reg4 halved the size of tumors generated by Mia-PaCa2 cells, suggesting that the antibody interfered with a paracrine/autocrine mechanism involving reg4 and stimulating cancer progression. The addition of gemcitabine resulted in further reduction, tumors becoming 5 times smaller than control. Exposure to reg4 antibody resulted in a significant decrease in intra-tumor levels of pAkt, Bcl-xL, Bcl-2, survivin and cyclin D1. CONCLUSIONS/SIGNIFICANCE: It was concluded that adjuvant therapies targeting reg4 could improve the standard treatment of pancreatic cancer with gemcitabine

Outer Membrane Vesicles of Porphyromonas gingivalis Elicit a Mucosal Immune Response

We previously reported that mutation of galE in Porphyromonas gingivalis has pleiotropic effects, including a truncated lipopolysaccharide (LPS) O-antigen and deglycosylation of the outer membrane protein OMP85 homolog. In the present study, further analysis of the galE mutant revealed that it produced little or no outer membrane vesicles (OMVs). Using three mouse antisera raised against whole cells of the P. gingivalis wild type strain, we performed ELISAs to examine the reactivity of these antisera with whole cells of the wild type or the galE mutant. All three antisera had significantly lower reactivity against the galE mutant compared to wild type. OMVs, but not LPS, retained the immunodominant determinant of P. gingivalis, as determined by ELISAs (with wild type LPS or OMVs as antigen) and absorption assays. In addition, we assessed the capacity of OMVs as a vaccine antigen by intranasal immunization to BALB/c mice. Synthetic double-stranded RNA polyriboinosinic polyribocytidylic acid [Poly (I∶C)], an agonist of Toll-like receptor 3 (TLR3), was used as the mucosal adjuvant. Vaccination with OMV elicited dramatically high levels of P. gingivalis-specific IgA in nasal washes and saliva, as well as serum IgG and IgA. In conclusion, the OMVs of P. gingivalis have an important role in mucosal immunogenicity as well as in antigenicity. We propose that P. gingivalis OMV is an intriguing immunogen for development of a periodontal disease vaccine

Is Adipose Tissue a Place for Mycobacterium tuberculosis Persistence?

BACKGROUND: Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), has the ability to persist in its human host for exceptionally long periods of time. However, little is known about the location of the bacilli in latently infected individuals. Long-term mycobacterial persistence in the lungs has been reported, but this may not sufficiently account for strictly extra-pulmonary TB, which represents 10–15% of the reactivation cases. METHODOLOGY/PRINCIPAL FINDINGS: We applied in situ and conventional PCR to sections of adipose tissue samples of various anatomical origins from 19 individuals from Mexico and 20 from France who had died from causes other than TB. M. tuberculosis DNA could be detected by either or both techniques in fat tissue surrounding the kidneys, the stomach, the lymph nodes, the heart and the skin in 9/57 Mexican samples (6/19 individuals), and in 8/26 French samples (6/20 individuals). In addition, mycobacteria could be immuno-detected in perinodal adipose tissue of 1 out of 3 biopsy samples from individuals with active TB. In vitro, using a combination of adipose cell models, including the widely used murine adipose cell line 3T3-L1, as well as primary human adipocytes, we show that after binding to scavenger receptors, M. tuberculosis can enter within adipocytes, where it accumulates intracytoplasmic lipid inclusions and survives in a non-replicating state that is insensitive to the major anti-mycobacterial drug isoniazid. CONCLUSIONS/SIGNIFICANCE: Given the abundance and the wide distribution of the adipose tissue throughout the body, our results suggest that this tissue, among others, might constitute a vast reservoir where the tubercle bacillus could persist for long periods of time, and avoid both killing by antimicrobials and recognition by the host immune system. In addition, M. tuberculosis-infected adipocytes might provide a new model to investigate dormancy and to evaluate new drugs for the treatment of persistent infection

Predicting Survival within the Lung Cancer Histopathological Hierarchy Using a Multi-Scale Genomic Model of Development

BACKGROUND: The histopathologic heterogeneity of lung cancer remains a significant confounding factor in its diagnosis and prognosis—spurring numerous recent efforts to find a molecular classification of the disease that has clinical relevance. METHODS AND FINDINGS: Molecular profiles of tumors from 186 patients representing four different lung cancer subtypes (and 17 normal lung tissue samples) were compared with a mouse lung development model using principal component analysis in both temporal and genomic domains. An algorithm for the classification of lung cancers using a multi-scale developmental framework was developed. Kaplan–Meier survival analysis was conducted for lung adenocarcinoma patient subgroups identified via their developmental association. We found multi-scale genomic similarities between four human lung cancer subtypes and the developing mouse lung that are prognostically meaningful. Significant association was observed between the localization of human lung cancer cases along the principal mouse lung development trajectory and the corresponding patient survival rate at three distinct levels of classical histopathologic resolution: among different lung cancer subtypes, among patients within the adenocarcinoma subtype, and within the stage I adenocarcinoma subclass. The earlier the genomic association between a human tumor profile and the mouse lung development sequence, the poorer the patient's prognosis. Furthermore, decomposing this principal lung development trajectory identified a gene set that was significantly enriched for pyrimidine metabolism and cell-adhesion functions specific to lung development and oncogenesis. CONCLUSIONS: From a multi-scale disease modeling perspective, the molecular dynamics of murine lung development provide an effective framework that is not only data driven but also informed by the biology of development for elucidating the mechanisms of human lung cancer biology and its clinical outcome

A survey and classification of storage deduplication systems

The automatic elimination of duplicate data in a storage system commonly known as deduplication is increasingly accepted as an effective technique to reduce storage costs. Thus, it has been applied to different storage types, including archives and backups, primary storage, within solid state disks, and even to random access memory. Although the general approach to deduplication is shared by all storage types, each poses specific challenges and leads to different trade-offs and solutions. This diversity is often misunderstood, thus underestimating the relevance of new research and development. The first contribution of this paper is a classification of deduplication systems according to six criteria that correspond to key design decisions: granularity, locality, timing, indexing, technique, and scope. This classification identifies and describes the different approaches used for each of them. As a second contribution, we describe which combinations of these design decisions have been proposed and found more useful for challenges in each storage type. Finally, outstanding research challenges and unexplored design points are identified and discussed.This work is funded by the European Regional Development Fund (EDRF) through the COMPETE Programme (operational programme for competitiveness) and by National Funds through the Fundacao para a Ciencia e a Tecnologia (FCT; Portuguese Foundation for Science and Technology) within project RED FCOMP-01-0124-FEDER-010156 and the FCT by PhD scholarship SFRH-BD-71372-2010

Lipophilic Compound-Mediated Gene Expression and Implication for Intervention in Reactive Oxygen Species (ROS)-Related Diseases: Mini-review

In addition to exhibiting antioxidant properties, conjugated linoleic acid (CLA) and vitamin E may modulate gene expression of endogenous antioxidant enzymes. Depending on cellular microenvironments, such modulation reflects either antioxidant or prooxidant outcomes. Although epidemiological/experimental studies have indicated that CLA and vitamin E have health promoting properties, recent findings from clinical trials have been inconclusive. Discrepancies between the results found from prospective studies and recent clinical trials might be attributed to concentration-dependent cellular microenvironment alterations. We give a perspective of possible molecular mechanisms of actions of these lipophilic compounds and their implications for interventions of reactive oxygen species (ROS)-related diseases