Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis.

Chemotherapy has been widely used in cancer treatment. However, the prognosis of the cancer patients following chemotherapy has not been substantially improved. Alternative strategies such as immunotherapy and their combinations with chemotherapy are now being considered.

Up-regulation of LOX-1 expression by TNF-alpha promotes trans-endothelial migration of MDA-MB-231 breast cancer cells.

Adhesion of cancer cell to endothelial cells and the subsequent trans-endothelial migration are key steps in metastasis. However, the identities of the molecules mediating cancer cell/endothelial cell interaction are still not fully understood. In this study, we tested the hypothesis that lectin-like oxidized-low-density lipoprotein (oxLDL) receptor-1 (LOX-1), a key mediator of vascular inflammation and atherosclerosis expressed on endothelial cell surface, mediates breast cancer cell/endothelial cell interactions.

The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells.

Aging is associated with reduced numbers of all thymocyte sub-populations, including early T-cell progenitors. However, it is unclear if this is due to inadequate recruitment of lymphohematopoietic progenitor cells (LPCs) to the aged thymus or to abnormal development of T cells within the thymus. We found that LPCs from young mice were recruited equally well to the thymi of young or aged mice and that thymic stromal cells (TSCs) from young and old mice expressed similar levels of P-selectin and CCL25, which are believed to mediate recruitment of LPCs to the adult thymus.

Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution.

It has been speculated that aging lymphohematopoietic progenitor cells (LPC) including hematopoietic stem cells (HSC) and early T-cell progenitors (ETP) have intrinsic defects that trigger age-related thymic involution. However, using a different approach, we suggest that that is not the case. We provided a young thymic microenvironment to aged mice by transplanting a fetal thymus into the kidney capsule of aged animals, and demonstrated that old mouse-derived LPCs could re-establish normal thymic lymphopoiesis and all thymocyte subpopulations, including ETPs, double negative subsets, double positive, and CD4(+) and CD8(+) single positive T cells.

p38 mitogen-activated protein kinase mediates sidestream cigarette smoke-induced endothelial permeability.

Second-hand smoke is associated with increased risk of cardiovascular diseases. So far, little is known about the signaling mechanisms of second-hand smoke-induced vascular dysfunction. Endothelial junctions are fundamental structures important for maintaining endothelial barrier function.

Vascular endothelial growth factor (VEGF)-induced up-regulation of CCN1 in osteoblasts mediates proangiogenic activities in endothelial cells and promotes fracture healing.

Angiogenesis is indispensable during fracture repair, and vascular endothelial growth factor (VEGF) is critical in this process. CCN1 (CYR61) is an extracellular matrix signaling molecule that has been implicated in neovascularization through its interactions with several endothelial integrin receptors. CCN1 has been shown to be up-regulated during the reparative phase of fracture healing; however, the role of CCN1 therein remains unclear.

Regulation of the alpha-crystallin gene acr2 by the MprAB two-component system of Mycobacterium tuberculosis.

Coordinated regulation of molecular chaperones is an important feature of the bacterial stress response. The small molecular chaperone gene acr2 of Mycobacterium tuberculosis is activated by exposure to several stresses, including heat and the detergent sodium dodecyl sulfate (SDS). In this study, we show that acr2 is directly regulated by the MprAB two-component system, and that MprAB has both positive and negative effects on acr2 expression.

Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA.

We found that p53-deficient (p53(-/-)) lung carcinoma (H1299) cells express robust levels of cell surface uPAR and uPAR mRNA. Expression of p53 protein in p53(-/-) cells suppressed basal and urokinase (uPA)-induced cell surface uPAR protein and increased uPAR mRNA degradation. Inhibition of p53 by RNA silencing in Beas2B human airway epithelial cells conversely increased basal as well as uPA-mediated uPAR expression and stabilized uPAR mRNA.

Therapy of nontuberculous mycobacterial disease.

Purpose Of Review: Nontuberculous mycobacterial disease, especially pulmonary disease, is increasingly encountered by clinicians. Therapy of the most common nontuberculous mycobacterial pathogen, Mycobacterium avium complex, improved with the introduction of macrolide-containing regimens, but treatment for this and most other nontuberculous mycobacterial pathogens remains difficult.

Recent Findings: Treatment trials with macrolide-containing regimens for Mycobacterium avium complex lung disease have yielded generally favorable outcomes.

Ethical considerations in the interpretation and communication of clinical trial results.

The ethical interpretation and communication of research results is essential to ensure the validity, timeliness, and accessibility of new knowledge for patients, physicians, and regulatory agencies. Failure to adhere to ethical principles may cause adverse outcomes for patients because of overestimation of benefit, underestimation of harm, and lack of timely awareness of benefit or harm. Although fabrication, falsification, and plagiarism are the traditional criteria for research misconduct, other more subtle behaviors may cause greater threats to public safety and trust in the research enterprise.

Modulation of tissue factor-factor VIIa signaling by lipid rafts and caveolae.

Objective: Coagulation factor VIIa (VIIa) binding to its cellular receptor, tissue factor (TF), not only initiates the coagulation cascade but also induces cell signaling by activating G-protein coupled protease-activated receptors. The objective of the present study is to investigate the role of lipid rafts and caveolae in modulating TF-VIIa signaling and coagulant functions.

Methods And Results: TF-VIIa coagulant function was measured in factor X activation assay and the signaling function was evaluated in phosphoinositide hydrolysis and IL-8 gene induction.

Effect of wine phenolics on cytokine-induced C-reactive protein expression.

Background: Elevation of C-reactive protein (CRP) levels in blood was recognized as one of the cardiac disease risk factors. Consumption of wine is shown to reduce the risk from heart disease and improve longevity.

Objectives: In the present study, we evaluated the effect of various wine polyphenolic compounds and several active synthetic derivatives of resveratrol on the inflammatory cytokines (IL-1beta + IL-6)-induced CRP expression in Hep3B cells.

Evidence for complex interactions of stress-associated regulons in an mprAB deletion mutant of Mycobacterium tuberculosis.

Two-component systems are important constituents of bacterial regulatory networks. Results of this investigation into the role of the MprAB two-component system of Mycobacterium tuberculosis indicate that it is associated with the regulation of several stress-responsive regulons. Using a deletion mutant lacking portions of the response regulator, MprA, and the histidine kinase, MprB, it was demonstrated by real-time PCR, primer extension analyses and DNA microarrays that MprAB activates sigma factor genes sigE and sigB, under SDS stress and during exponential growth.

Suppression of memory CD8 T cell generation and function by tryptophan catabolism.

Dendritic cell-derived indoleamine 2,3-dioxygenase (IDO) suppresses naive T cell proliferation and induces their apoptosis by catalyzing tryptophan, and hence is essential for the maintenance of peripheral tolerance. However, it is not known whether memory T cells are subject to the regulation by IDO-mediated tryptophan catabolism, as memory T cells respond more rapidly and vigorously than their naive counterparts and are resistant to conventional costimulatory blockade. In this study, we present the evidence that memory CD8+ T cells are susceptible to tryptophan catabolism mediated by IDO.

Predictors of depressive symptoms in patients with COPD and health impact.

While depression is a common co-morbid condition among patients with COPD, little is known about predictors or health impact of depression among these patients. To address these gaps in knowledge we conducted a cross-sectional survey of 207 patients with COPD cared for in a network of primary care clinics affiliated with an urban academic health center. A standardized questionnaire was used to measure demographic characteristics, smoking status, co-morbid medical conditions, current medications, self-efficacy, social support, illness intrusiveness, and self-reported health care utilization during the previous 6 months.

Racial/ethnic differences in multiple self-care behaviors in adults with diabetes.

Objective: To assess racial/ethnic differences in multiple diabetes self-care behaviors.

Design: Cross-sectional study.

Participants: 21,459 participants with diabetes in the 2003 Behavioral Risk Factor Surveillance survey.

Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer.

Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells.

Endothelial cell protein C receptor acts as a cellular receptor for factor VIIa on endothelium.

Although factor VII/factor VIIa (FVII/FVIIa) is known to interact with many non-vascular cells, activated monocytes, and endothelial cells via its binding to tissue factor (TF), the interaction of FVII/FVIIa with unperturbed endothelium and the role of this interaction in clearing FVII/FVIIa from the circulation are unknown. To investigate this, in the present study we examined the binding of radiolabeled FVIIa to endothelial cells and its subsequent internalization. (125)I-FVIIa bound to non-stimulated human umbilical vein endothelial cells (HUVEC) in time- and dose-dependent manner.

The role of sphingosine 1-phosphate in the TNF-alpha induction of IL-8 gene expression in lung epithelial cells.

Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine involved in the pathogenesis of inflammatory diseases of the lung. Interleukin-8 (IL-8), a C-X-C chemokine, is induced by TNF-alpha and initiates injury by acting as a chemoattractant for neutrophils and other immune cells. Although sphingolipids such as ceramide and sphingosine 1-phosphate (S1-P) have been shown to serve as signaling molecules in the TNF-alpha inflammatory response, their role in the TNF-alpha induction of IL-8 gene expression in lung epithelial cells is not known.

Children's health in the rural environment.

The rural environment is not as wholesome as some might think. In fact, smoking, drinking, illicit drug use, and obesity are more prevalent in rural than in urban youngsters. Childhood mortality is higher in rural areas, with drowning, motor vehicle accidents, firearm injuries, and farm machinery accidents as the leading causes.

Bax and Bak genes are essential for maximum apoptotic response by curcumin, a polyphenolic compound and cancer chemopreventive agent derived from turmeric, Curcuma longa.

Curcumin, an active ingredient of turmeric (Curcuma longa), inhibits proliferation and induces apoptosis in cancer cells, but the sequence of events leading to cell death is poorly defined. The objective of this study was to examine the molecular mechanisms by which multidomain pro-apoptotic Bcl-2 family members Bax and Bak regulate curcumin-induced apoptosis using mouse embryonic fibroblasts (MEFs) deficient in Bax, Bak or both genes. Curcumin treatment resulted an increase in the protein levels of both Bax and Bak, and mitochondrial translocation and activation of Bax in MEFs to trigger drop in mitochondrial membrane potential, cytosolic release of apoptogenic molecules [cytochrome c and second mitochondria-derived activator of caspases (Smac)/direct inhibitor of apoptosis protein-binding protein with low isoelectric point], activation of caspase-9 and caspase-3 and ultimately apoptosis.

Thrombin-thrombomodulin inhibits prourokinase-mediated pleural mesothelial cell-dependent fibrinolysis.

Fibrin deposition is a hallmark of pleural inflammation and loculation but understanding of mechanisms by which mesothelial cells regulate intrapleural fibrinolysins remains incomplete. We speculated that pleural mesothelial cells regulate local fibrinolytic capacity via processing of single chain urokinase type plasminogen activator (scuPA). Pretreatment of human pleural mesothelial (MeT-5A) cells with TGF-beta or thrombin, either alone or in combination, inhibited urokinase (uPA)-mediated fibrinolysis by MeT-5A.

Expression of glutathione S-transferase pi and glutathione synthase correlates with survival in early stage non-small cell carcinomas of the lung.

The glutathione S-transferase (GST) family of genes encode for detoxification enzymes that protect against reactive oxygen species and influence host susceptibility to carcinogens, including tobacco smoke. It has not been determined whether isoenzyme GST-pi or glutathione synthase (GSH2) expression by tumor cells bears a relationship to survival. A total of 201 non-small cell lung cancers (NSCLC) with long-term follow-up were immunostained with antibodies to GST-pi and GSH2 using standard immunostaining techniques.

Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira.

Augmentation therapy with a plasma derived alpha l-Proteinase Inhibitor (alpha1 -PI) has been demonstrated to be effective in restoring serum Alpha1 -antitrypsin (AAT)* levels in individuals with AAT Deficiency (note: alpha1 PI and AAT are synonymous). The objective of this study was to demonstrate that the steady-state trough serum alphal-PI levels, achieved by a new plasma derived alpha,-PI (Zemaira, study drug, ZLB Behring LLC, King of Prussia, Pennsylvania, USA), were bioequivalent to those achieved by the currently available alpha-PI therapy, Prolastin (control drug, Bayer Corporation, Berkeley, California, USA), and maintained weekly trough serum antigenic alpha1-PI levels above the protective threshold of 11 microM. This multi-center, controlled study randomized a total of 44 subjects to receive either study or control drug for a 10-week double-blind phase.

Activity and regulation of factor VIIa analogs with increased potency at the endothelial cell surface.

Background: Variants of recombinant factor VIIa (rFVIIa) with increased intrinsic activity have been developed to improve efficacy in the treatment of bleeding disorders in the future. The increased potency of FVIIa variants was demonstrated in limited in vitro and in vivo studies. However, further characterization of FVIIa variants is needed to evaluate their potential clinical use.