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Lin Zhang Joseph JY Sung Jun Yu Siew C Ng Sunny H Wong Chi H Cho Simon SM Ng Francis KL Chan William KK Wu 《The Journal of pathology》2014,233(2):103-112
Helicobacter pylori and Epstein–Barr virus (EBV) account for roughly 80% and 10%, respectively, of gastric carcinomas worldwide. Autophagy is an evolutionarily conserved and intricately regulated cellular process that involves the sequestration of cytoplasmic proteins and organelles into double‐membrane autophagosomes that eventually fuse with lysosomes for degradation of the engulfed content. Emerging evidence indicates that xenophagy, a form of selective autophagy, plays a crucial role in the pathogenesis of H. pylori‐ and EBV‐induced gastric cancer. Xenophagy specifically recognizes intracellular H. pylori and EBV and physically targets these pathogens to the autophagosomal–lysosomal pathway for degradation. In this connection, H. pylori or EBV‐induced dysregulation of autophagy may be causally linked to gastric tumourigenesis and therefore can be exploited as therapeutic targets. This review will discuss how H. pylori and EBV infection activate autophagy and how these pathogens evade recognition and degradation by the autophagic pathway. Elucidating the molecular aspects of H. pylori‐ and EBV‐induced autophagy will help us better understand the pathogenesis of gastric cancer and promote the development of autophagy modulators as antimicrobial agents. Published by John Wiley & Sons, Ltd 相似文献
994.
Mandeep Singh Ruchi Jha Jonathan Melamed Ellen Shapiro Simon W. Hayward Peng Lee 《The American journal of pathology》2014,184(10):2598-2607
The androgen receptor (AR) in stromal cells contributes significantly to the development and growth of prostate during fetal stages as well as during prostate carcinogenesis and cancer progression. During prostate development, stromal AR induces and promotes epithelial cell growth, as observed from tissue recombinant and mouse knockout studies. During prostate carcinogenesis and progression, the stromal cells begin to lose AR expression as early as at the stage of high-grade prostatic intraepithelial neoplasia. The extent of loss of stromal AR is directly proportional to the degree of differentiation (Gleason grade) and progression of prostate cancer (PCa). Co-culture studies suggested that stromal AR inhibits the growth of malignant epithelial cells, possibly through expression of certain paracrine factors in the presence of androgens. This functional reversal of stromal AR, from growth promotion during fetal prostate development to mediating certain growth-inhibiting effects in cancer, explains to some extent the reason that loss of AR expression in stromal cells may be crucial for development of resistance to androgen ablation therapy for PCa. From a translational perspective, it generates the need to re-examine the current therapeutic options and opens a fundamental new direction for therapeutic interventions, especially in advanced PCa.CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.Prostate cancer (PCa) is the most common non-skin malignancy in the male population within the United States and is the second most common cancer in men worldwide.1 It is also one of the leading causes of cancer-related deaths in males in the United States.Normal human prostate is composed of an epithelial tissue and an adjacent stroma. The epithelium is composed of two principal cell types, the tall columnar secretory luminal cells that line the glandular ducts and the flattened basal cells surrounding them. In addition, some rare neuroendocrine cells are also present. Often, the terms mesenchyme and stroma are loosely used. Herein, mesenchyme refers to the mesodermal-derived fetal or newborn tissues with instructive induction potential. The word stroma describes the tissues surrounding the prostatic epithelium, later in development. In the adult human prostate, the stroma is composed mainly of smooth muscle cells. However, it also includes some fibroblasts, nerves, blood vessels, and various infiltrating immune and inflammatory cell types.Circulating androgens mediate the development and function of prostate by stimulating the androgen receptor (AR). Rat studies have shown that in stroma, AR is expressed in mesenchymal cells of the urogenital sinus (UGS), especially those adjacent to the epithelium, concurrent with the formation of prostatic buds.2,3 As the prostate develops and the mesenchymal cells differentiate to form smooth muscle, AR expression is widespread, but not universal, throughout the muscle. In the past, investigators have mainly focused on studying epithelial AR function in prostate. Relatively limited data are available to describe the expression and function of stromal AR in prostate development2–14 and cancer. Stromal AR is involved in both prostate development and prostate carcinogenesis, with distinct functions in these two processes. We examine the current knowledge and understanding of stromal AR function, including its translational significance. 相似文献
995.
Simon D?hrmann Sabina Anik Joshua Olson Ericka L. Anderson Neelou Etesami Hyewon No Joshua Snipper Victor Nizet Cheryl Y. M. Okumura 《Infection and immunity》2014,82(10):4011-4020
Streptococcal collagen-like protein 1 (Scl-1) is one of the most highly expressed proteins in the invasive M1T1 serotype group A Streptococcus (GAS), a globally disseminated clone associated with higher risk of severe invasive infections. Previous studies using recombinant Scl-1 protein suggested a role in cell attachment and binding and inhibition of serum proteins. Here, we studied the contribution of Scl-1 to the virulence of the M1T1 clone in the physiological context of the live bacterium by generating an isogenic strain lacking the scl-1 gene. Upon subcutaneous infection in mice, wild-type bacteria induced larger lesions than the Δscl mutant. However, loss of Scl-1 did not alter bacterial adherence to or invasion of skin keratinocytes. We found instead that Scl-1 plays a critical role in GAS resistance to human and murine phagocytic cells, allowing the bacteria to persist at the site of infection. Phenotypic analyses demonstrated that Scl-1 mediates bacterial survival in neutrophil extracellular traps (NETs) and protects GAS from antimicrobial peptides found within the NETs. Additionally, Scl-1 interferes with myeloperoxidase (MPO) release, a prerequisite for NET production, thereby suppressing NET formation. We conclude that Scl-1 is a virulence determinant in the M1T1 GAS clone, allowing GAS to subvert innate immune functions that are critical in clearing bacterial infections. 相似文献
996.
Antonino Missineo Antonella Di Poto Joan A. Geoghegan Simonetta Rindi Simon Heilbronner Valentina Gianotti Carla Renata Arciola Timothy J. Foster Pietro Speziale Giampiero Pietrocola 《Infection and immunity》2014,82(6):2448-2459
Staphylococcus lugdunensis is a coagulase-negative staphylococcus that is a commensal of humans and an opportunistic pathogen. It can cause a spectrum of infections, including those that are associated with the ability to form biofilm, such as occurs with endocarditis or indwelling medical devices. The genome sequences of two strains revealed the presence of orthologues of the ica genes that are responsible for synthesis of poly-N-acetylglucosamine (PNAG) that is commonly associated with biofilm in other staphylococci. However, we discovered that biofilm formed by a panel of S. lugdunensis isolates growing in iron-restricted medium was susceptible to degradation by proteases and not by metaperiodate, suggesting that the biofilm matrix comprised proteins and not PNAG. When the iron concentration was raised to 1 mM biofilm formation by all strains tested was greatly reduced. A mutant of strain N920143 lacking the entire locus that encodes iron-regulated surface determinant (Isd) proteins was defective in biofilm formation under iron-limited conditions. An IsdC-null mutant was defective, whereas IsdK, IsdJ, and IsdB mutants formed biofilm to the same level as the parental strain. Expression of IsdC was required both for the primary attachment to unconditioned polystyrene and for the accumulation phase of biofilm involving cell-cell interactions. Purified recombinant IsdC protein formed dimers in solution and Lactococcus lactis cells expressing only IsdC adhered to immobilized recombinant IsdC but not to IsdJ, IsdK, or IsdB. This is consistent with a specific homophilic interaction between IsdC molecules on neighboring cells contributing to accumulation of S. lugdunensis biofilm in vivo. 相似文献
997.
Pierre‐Simon Bellaye Guillaume Wettstein Olivier Burgy Valérie Besnard Audrey Joannes Julien Colas Sébastien Causse Joëlle Marchal‐Somme Aurélie Fabre Bruno Crestani Martin Kolb Jack Gauldie Philippe Camus Philippe Bonniaud 《The Journal of pathology》2014,232(4):458-472
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix (ECM) in the lungs. TGF‐β1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. αB‐crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of αB‐crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad‐dependent pathway. We demonstrate here that αB‐crystallin is strongly expressed in fibrotic lung tissue from IPF patients and in vivo rodent models of pulmonary fibrosis. We also show that αB‐crystallin‐deficient mice are protected from bleomycin‐induced fibrosis. Similar protection from fibrosis was observed in αB‐crystallin KO mice after transient adenoviral‐mediated over‐expression of IL‐1β or TGF‐β1. We show in vitro in primary epithelial cells and fibroblasts that αB‐crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF‐β1–Smad pathway and the consequent activation of TGF‐β1 downstream genes. αB‐crystallin over‐expression disrupts Smad4 mono‐ubiquitination by interacting with its E3–ubiquitin ligase, TIF1γ, thus limiting its nuclear export. Conversely, in the absence of αB‐crystallin, TIF1γ can freely interact with Smad4. Consequently, Smad4 mono‐ubiquitination and nuclear export are favoured and thus TGF‐β1–Smad4 pro‐fibrotic activity is inhibited. This study demonstrates that αB‐crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
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Simon J. Sonntag Wei Li Michael Becker Wiebke Kaestner Martin R. Büsen Nikolaus Marx Dorit Merhof Ulrich Steinseifer 《Annals of biomedical engineering》2014,42(5):971-985
Mitral regurgitation (MR) is one of the most frequent valvular heart diseases. To assess MR severity, color Doppler imaging (CDI) is the clinical standard. However, inadequate reliability, poor reproducibility and heavy user-dependence are known limitations. A novel approach combining computational and experimental methods is currently under development aiming to improve the quantification. A flow chamber for a circulatory flow loop was developed. Three different orifices were used to mimic variations of MR. The flow field was recorded simultaneously by a 2D Doppler ultrasound transducer and Particle Image Velocimetry (PIV). Computational Fluid Dynamics (CFD) simulations were conducted using the same geometry and boundary conditions. The resulting computed velocity field was used to simulate synthetic Doppler signals. Comparison between PIV and CFD shows a high level of agreement. The simulated CDI exhibits the same characteristics as the recorded color Doppler images. The feasibility of the proposed combination of experimental and computational methods for the investigation of MR is shown and the numerical methods are successfully validated against the experiments. Furthermore, it is discussed how the approach can be used in the long run as a platform to improve the assessment of MR quantification. 相似文献