Prostate-specific PTen deletion in mice activates inflammatory microRNA expression pathways in the epithelium early in hyperplasia development

PTen loss is one of the most frequent events in prostate cancer both at the initiation stage and during late stage metastatic development. The mouse model of prostate-specific probasin-mediated Pten deletion leads to prostate intraepithelial neoplasia (PIN) leading to adenocarcinoma. Using this model, we analysed the miR and mRNA transcriptome profile of Pten−/− PIN versus wild type age-matched prostate tissues and analysed the effects of Pten loss on miR expression in the early neoplastic process. At the PIN stage, Pten loss significantly changed the expression of over 20 miRNAs and over 4000 genes. The observed miR expression indicated a strong immunological cohort, which is seen in many human and mouse cancers and is thought to derive from infiltrating B and T immune cells. However, upon in situ hybridisation, these immunologically related miRs did not correlate with immune cell location, and emanated from the prostate epithelium itself and not from the associated immune cells present. Growing Pten−/− prostate cells in culture showed that the overexpressed miRNAs seen in Pten−/− were directly in response to the overactive PI3 kinase pathway and were in part responsible in reducing target gene expression levels. Inhibition of PI3 kinase downstream regulators, or re-introducing wild type PtencDNA reduced miR overexpression resulting in increased miR target gene expression. MiR inhibitors also showed this pattern, and synergised with an mTORC1 inhibitor. Overall, Pten deletion in the prostate epithelium activated a cohort of inflammation-related miRs usually associated with immune responses from B and T cells. These oncomiRs may then accelerate carcinogenesis

Prohibitin Links Cell Cycle, Motility and Invasion in Prostate Cancer Cells

Prohibitin (PHB) is a tumour suppressor gene with several different molecular activities. PHB overexpression leads to G1/S-phase cell cycle arrest, and PHB represses the androgen receptor (AR) in prostate cancer cells. PHB interacts with and represses members of the E2F family in a manner that may also be AR-linked, therefore making the AR:PHB:E2F interaction axis highly complex. PHB siRNA increased the growth and metastatic potential of LNCaP mouse xenografts in vivo. Conversely, PHB ectopic cDNA overexpression affected several hundred genes in LNCaP cells. Furthermore, gene ontology analysis showed that in addition to cell cycle regulation, several members of the WNT family were significantly downregulated (WNT7B, WNT9A and WNT10B), as well as pathways for cell adhesion. Online GEO data studies showed PHB expression to be decreased in clinical cases of metastatic prostate cancer, and to be correlated with higher WNT expression in metastasis. PHB overexpression reduced prostate cancer cell migration and motility in wound-healing assays, reduced cell invasion through a Matrigel layer and reduced cellular attachment. In LNCaP cells, WNT7B, WNT9A and WNT10B expression were also upregulated by androgen treatment and downregulated by androgen antagonism, indicating a role for AR in the control of these WNT genes. However, these WNTs were strongly cell cycle regulated. E2F1 cDNA ectopic expression and PHB siRNA (both cell cycle promoting effects) increased WNT7B, WNT9A and WNT10B expression, and these genes were also upregulated as cells were released from G1 to S phase synchronisation, indicating further cell cycle regulation. Therefore, the repressive effects of PHB may inhibit AR, E2F and WNT expression and its loss may increase metastatic potential in human prostate cancer

Wnt-11 expression promotes invasiveness and correlates with survival in human pancreatic ductal adeno carcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, proving difficult to manage clinically. Wnt-11, a developmentally regulated gene producing a secreted protein, has been associated with various carcinomas but has not previously been studied in PDAC. The present study aimed to elucidate these aspects first in vitro and then in a clinical setting in vivo. Molecular analyses of Wnt-11 expression as well as other biomarkers involved qRT-PCR, RNA-seq and siRNA. Proliferation was measured by MTT; invasiveness was quantified by Boyden chamber (Matrigel) assay. Wnt-11 mRNA was present in three different human PDAC cell lines. Wnt-11 loss affected epithelial-mesenchymal transition and expression of neuronal and stemness biomarkers associated with metastasis. Indeed, silencing Wnt-11 in Panc-1 cells significantly inhibited their Matrigel invasiveness without affecting their proliferative activity. Consistently with the in vitro data, human biopsies of PDAC showed significantly higher Wnt-11 mRNA levels compared with matched adjacent tissues. Expression was significantly upregulated during PDAC progression (TNM stage I to II) and maintained (TNM stages III and IV). Wnt-11 is expressed in PDAC in vitro and in vivo and plays a significant role in the pathophysiology of the disease; this evidence leads to the conclusion that Wnt-11 could serve as a novel, functional biomarker PDA

Size Dependence of Residual Thermal Stresses in Micro Multilayer Ceramic Capacitors by Using Finite Element Unit Cell Model Including Strain Gradient Effect

The residual thermal stresses induced by the high-temperature sintering process in multilayer ceramic capacitors (MLCCs) are investigated by using a finite element unit cell model, in which the strain gradient effect is considered. The numerical results show that the residual thermal stresses depend on the lateral margin length, the thickness ratio of the dielectrics layer to the electrode layer, and the MLCC size. At a given thickness ratio, as the MLCC size is scaled down, the peak shear stress reduces significantly and the normal stresses along the length and thickness directions change slightly with the decrease in the ceramic layer thickness td as td >1 μm, but as td <1 μm, the normal stress components increase sharply with the increase in td. Thus, the residual thermal stresses induced by the sintering process exhibit strong size effects and, therefore, the strain gradient effect should be taken into account in the design and evaluation of MLCC devices.Розглянуто задачу про залишкові температурні напруження в багатошарових керамічних конденсаторах, викликані високотемпературним процесом спікання. Застосовано модель одиничної чарунки в методі скінченних елементів, де враховано вплив градієнта деформацій. Отримані числові результати показують, що залишкові температурні напруження залежать від довжини поздовжнього краю, відношення товщини діелектричних шарів до товщини електродних шарів і розміру конденсатора. При заданому відношенні товщин, коли розмір конденсатора зменшується, то найвищі зсувні напруження зменшуються суттєво і нормальні напруження вздовж довжини та в напрямку зміни товщини змінюються незначно зі зменшенням товщини керамічного шару до величини, меншої 1 мікрона. Коли ця величина є більшою 1 мікрона, то нормальні напруження зростають різко зі збільшенням товщини керамічного шару. Таким чином, залишкові температурні напруження, викликані високотемпературним процесом спікання, виявляють сильний вплив розміру конденсатора і тому вплив градієнта деформації повинен братися до уваги в процесі створення і оцінювання роботи багатошарових керамічних конденсаторів

Black Hole Entropy: From Shannon to Bekenstein

In this note we have applied directly the Shannon formula for information theory entropy to derive the Black Hole (Bekenstein-Hawking) entropy. Our analysis is semi-classical in nature since we use the (recently proposed [8]) quantum mechanical near horizon mode functions to compute the tunneling probability that goes in to the Shannon formula, following the general idea of [5]. Our framework conforms to the information theoretic origin of Black Hole entropy, as originally proposed by Bekenstein.Comment: 9 pages Latex, Comments are welcome; Thoroughly revised version, reference and acknowledgements sections enlarged, numerical error in final result corrected, no major changes, to appear in IJT

Single gluino production in the R-parity lepton number violating MSSM at the LHC

We examine the $R_{p}$-violating signal of single gluino production associated with a charged lepton or neutrino at the large hadron collider (LHC), in the model of R-parity relaxed supersymmetric model. If the parameters in the ${\rlap/R}_p$ supersymmetric interactions are not too small, and the mass of gluino is considered in the range from several GeV (as the Lightest Supersymmetric Particle) to 800 GeV, the cross section of the single gluino production via Drell-Yan processes can be in the order of $10^2 \sim 10^3$ femto barn, and that via gluon fusion in the order of $10^{-1} \sim 10^3$ femto barn. If the gluino decay can be well detected in the CERN LHC, this process provides a prospective way to probe supersymmetry and $R_p$ violation.Comment: LaTex, 22 pages, 5 EPS file

Thermodynamics Inducing Massive Particles' Tunneling and Cosmic Censorship

By calculating the change of entropy, we prove that the first law of black hole thermodynamics leads to the tunneling probability of massive particles through the horizon, including the tunneling probability of massive charged particles from the Reissner-Nordstr\"om black hole and the Kerr-Newman black hole. Novelly, we find the trajectories of massive particles are close to that of massless particles near the horizon, although the trajectories of massive charged particles may be affected by electromagnetic forces. We show that Hawking radiation as massive particles tunneling does not lead to violation of the weak cosmic-censorship conjecture

Electroweak Corrections to the Charged Higgs Boson Decay into Chargino and Neutralino

The electroweak corrections to the partial widths of the $H^+ \to \tilde{\chi}^+_i \tilde{\chi}_j^0 (i=1,j=1,2)$ decays including one-loop diagrams of the third generation quarks and squarks, are investigated within the Supersymmetric Standard Model. The relative corrections can reach the values about 10%, therefore they should be taken into account for the precise experimental measurement at future colliders.Comment: 21 pages, 6 eps figures, 1 Latex fil

Tissue invasion and metastasis: Molecular, biological and clinical perspectives

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks