In Silico Transcriptomic Analysis of Wound-Healing-Associated Genes in Malignant Pleural Mesothelioma.

Background and objectives: Malignant pleural mesothelioma (MPM) is a devastating malignancy with poor prognosis. Reliable biomarkers for MPM diagnosis, monitoring, and prognosis are needed. The aim of this study was to identify genes associated with wound healing processes whose expression could serve as a prognostic factor in MPM patients. Materials and Methods: We used data mining techniques and transcriptomic analysis so as to assess the differential transcriptional expression of wound-healing-associated genes in MPM. Moreover, we investigated the potential prognostic value as well as the functional enrichments of gene ontologies relative to microRNAs (miRNAs) of the significantly differentially expressed wound-healing-related genes in MPM. Results: Out of the 82 wound-healing-associated genes analyzed, 30 were found significantly deregulated in MPM. Kaplan-Meier analysis revealed that low ITGAV gene expression could serve as a prognostic factor favoring survival of MPM patients. Finally, gene ontology annotation enrichment analysis pointed to the members of the hsa-miR-143, hsa-miR-223, and the hsa-miR-29 miRNA family members as important regulators of the deregulated wound healing genes. Conclusions: 30 wound-healing-related genes were significantly deregulated in MPM, which are potential targets of hsa-miR-143, hsa-miR-223, and the hsa-miR-29 miRNA family members. Out of those genes, ITGAV gene expression was a prognostic factor of overall survival in MPM. Our results highlight the role of impaired tissue repair in MPM development and should be further validated experimentally

Membrane testosterone binding sites in prostate carcinoma as a potential new marker and therapeutic target: Study in paraffin tissue sections

BACKGROUND: Steroid action is mediated, in addition to classical intracellular receptors, by recently identified membrane sites, that generate rapid non-genomic effects. We have recently identified a membrane androgen receptor site on prostate carcinoma cells, mediating testosterone rapid effects on the cytoskeleton and secretion within minutes. METHODS: The aim of this study was to investigate whether membrane androgen receptors are differentially expressed in prostate carcinomas, and their relationship to the tumor grade. We examined the expression of membrane androgen receptors in archival material of 109 prostate carcinomas and 103 benign prostate hyperplasias, using fluorescein-labeled BSA-coupled testosterone. RESULTS: We report that membrane androgen receptors are preferentially expressed in prostate carcinomas, and they correlate to their grade using the Gleason's microscopic grading score system. CONCLUSION: We conclude that membrane androgen receptors may represent an index of tumor aggressiveness and possibly specific targets for new therapeutic regimens

The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment

PACT-mediated pkr activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation

The inability of cells to adapt to increased environmental tonicity can lead to inflammatory gene expression and pathogenesis. The Rel family of transcription factors TonEBP and NF-κB p65 play critical roles in the switch from osmoadaptive homeostasis to inflammation, respectively. Here we identified PACT-mediated PKR kinase activation as a marker of the termination of adaptation and initiation of inflammation in Mus musculus embryonic fibroblasts. We found that high stress-induced PACT-PKR activation inhibits the interaction between NF-κB c-Rel and TonEBP essential for the increased expression of TonEBP-dependent osmoprotective genes. This resulted in enhanced formation of TonEBP/NF-κB p65 complexes and enhanced proinflammatory gene expression. These data demonstrate a novel role of c-Rel in the adaptive response to hyperosmotic stress, which is inhibited via a PACT/PKR-dependent dimer redistribution of the Rel family transcription factors. Our results suggest that inhibiting PACT-PKR signaling may prove a novel target for alleviating stress-induced inflammatory diseases

The Complete Mitochondrial Genome Sequence of the Planthopper, Sivaloka damnosus

The complete mitochondrial genome (mitogenome) sequence was determined from the plant hopper, Sivaloka damnosus Chow and Lu (Hemiptera: Issidae), a representative of the insect family Issidae. The genome is a circular molecule of 15,287 bp with a total A+T content of 76.5%. The gene content, order, and structure are identical to that in Drosophila melanogaster, which is considered ancestral for insects. All 13 protein-coding genes of the S. damnosus mitogenome have a putative inframe ATR methionine or ATT isoleucine codons as start signals. The usual termination codons (TAA and TAG) were found in 11 protein-coding genes. However, atp6, and nad4 have incomplete termination codons. All tRNAs show stable canonical clover-leaf structures similar to other insect mitochondrial tRNAs, except for tRNASer(AGN), which has a reduced DHU arm. The A+T-rich region or putative control region includes two extensive repeat regions. The first repeat region is composed of two sets of complicated repeat units, and these repetitive sequences are arranged alternately; the second contains ten 20 bp tandemly repetitive sequences. In the phylogenetic analyses based on protein-coding genes, Cicadomorpha is a sister to Fulgoromorpha+Sternorrhyncha, and Heteroptera is a sister to all other Hemiptera

A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling

A BAFF receptor mutation associated with non-Hodgkin lymphoma provides new insight into the proximal players of normal BAFF-R signaling

Expression of TNF-superfamily members BAFF and APRIL in breast cancer: Immunohistochemical study in 52 invasive ductal breast carcinomas

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest an association between chronic inflammation, modulating the tissue microenvironment, and tumor biology. Tumor environment consists of tumor, stromal and endothelial cells and infiltrating macrophages, T lymphocytes, and dendritic cells, producing an array of cytokines, chemokines and growth factors, accounting for a complex cell interaction and regulation of differentiation, activation, function and survival of tumor and surrounding cells, responsible for tumor progression and spreading or induction of antitumor immune responses and rejection. Tumor Necrosis Factor (TNF) family members (19 ligands and 29 receptors) represent a pleiotropic family of agents, related to a plethora of cellular events from proliferation and differentiation to apoptosis and tumor reduction. Among these members, BAFF and APRIL (CD257 and CD256 respectively) gained an increased interest, in view of their role in cell protection, differentiation and growth, in a number of lymphocyte, epithelial and mesenchymal structures.</p> <p>Methods</p> <p>We have assayed by immunohistochemistry 52 human breast cancer biopsies for the expression of BAFF and APRIL and correlated our findings with clinicopathological data and the evolution of the disease.</p> <p>Results</p> <p>BAFF was ubiquitely expressed in breast carcinoma cells, DCIS, normal-appearing glands and ducts and peritumoral adipocytes. In contrast, APRIL immunoreactive expression was higher in non-malignant as compared to malignant breast structures. APRIL but not BAFF immunoreactivity was higher in N+ tumors, and was inversely related with the grade of the tumors. Neither parameter was related to DFS or the OS of patients.</p> <p>Conclusion</p> <p>Our data show, for the first time, an autocrine secretion of BAFF and APRIL from breast cancer cells, offering new perspectives for their role in neoplastic and normal breast cell biology and offering new perspectives for possible selective intervention in breast cancer.</p

Can a single model explain both breast cancer and prostate cancer?

<p>Abstract</p> <p>Background</p> <p>The Estradiol-Dihydrotestosterone model of prostate cancer (PC) showed how the interaction of hormones with specific hormone receptors affected apoptosis. The same hormone can produce different effects, depending on which hormone receptor it interacts with.</p> <p>Model</p> <p>This model proposes that the first step in the development of most PC and breast cancer (BC) occurs when aromatase converts testosterone to estradiol (E2). A sufficiently high enough local level of E2 results in telomerase activity. The telomerase activity allows cell division and may lead to BC or PC, which will proliferate if the rate of cell division is greater than the rate of cell death. The effect of hormones on their hormone receptors will affect the rate of cell death and determine whether or not the cancer proliferates.</p> <p>Conclusion</p> <p>By minimizing bcl-2 and maximizing apoptotic proteins, new systemic treatments for BC and PC can be developed that may be more effective than existing treatments.</p