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Oxygen use has extended from inpatient to outpatient settings for patients with chronic pulmonary diseases and complications of hypoxaemia. This article presents an overview of oxygen devices (oxygen concentrators, compressed gas cylinders and liquid oxygen) and delivery systems (high- and low-flow). The indications, advantages and disadvantages of each device and delivery system are presented, aiming to offer updated knowledge to the multidisciplinary team members managing patients with respiratory failure, and therefore allowing appropriate selection of devices and delivery systems that are tailored to the needs of each patient.
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Giving and receiving effective feedback are skills that are central in healthcare settings http://ow.ly/zZ1C30eVrH1.
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Clinical record keeping is integral to good professional practice and the delivery of quality healthcare http://ow.ly/TicN305wiyc.
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BACKGROUND: Minnelide, a pro-drug of triptolide, has recently emerged as a potent anticancer agent. The precise mechanisms of its cytotoxic effects remain unclear. METHODS: Cell viability was studied using CCK8 assay. Cell proliferation was measured real-time on cultured cells using Electric Cell Substrate Impedence Sensing (ECIS). Apoptosis was assayed by Caspase activity on cultured lung cancer cells and TUNEL staining on tissue sections. Expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA, APAF-1) was estimated by qRTPCR. Effect of Minnelide on proliferative cells in the tissue was estimated by Ki-67 staining of animal tissue sections. RESULTS: In this study, we investigated in vitro and in vivo antitumor effects of triptolide/Minnelide in non-small cell lung carcinoma (NSCLC). Triptolide/Minnelide exhibited anti-proliferative effects and induced apoptosis in NSCLC cell lines and NSCLC mouse models. Triptolide/Minnelide significantly down-regulated the expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA) and up-regulated pro-apoptotic APAF-1 gene, in part, via attenuating the NF-κB signaling activity. CONCLUSION: In conclusion, our results provide supporting mechanistic evidence for Minnelide as a potential in NSCLC.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Organophosphates/pharmacology , Phenanthrenes/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Diterpenes , Epoxy Compounds , Mice , NF-kappa B/metabolism , Signal Transduction/drug effects , Transcription, Genetic/drug effects , Transcriptional Activation/drug effects , Up-Regulation/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The Apaf-1 interacting protein (APIP) and the uveal autoantigen with coiled coil domains and ankyrin repeats (UACA) belong to endogenous regulators of the apoptosome apparatus, but their role in tumourigenesis and progression of non-small cell lung carcinoma (NSCLC) is not known. Previous studies demonstrated that APIP inhibits the apoptosome-mediated procaspase-9 activation while UACA induces translocation of Apaf-1 from the cytoplasm into the nucleus. Here, we report for the first time that the expression of APIP and UACA genes is down-regulated on the level of both mRNA and protein in NSCLC cells and tumours. In particular, the expression of APIP protein was strikingly decreased and the expression of UACA mRNA and protein was frequently down-regulated in NSCLC tumours of different histopathological types. Moreover, stage IA NSCLC tumours showed significantly lower expression of UACA mRNA compared to higher stage tumours. The weak increase of both APIP and UACA mRNA levels in the 5-aza-2'-deoxycytidine-treated NSCLC cells indicates that mechanisms other than DNA methylation are involved in the regulation of APIP and UACA gene expression in these cancer cells. Taken together, the down-regulation of APIP and UACA expression suggests that the threshold to activate the apoptosome apparatus may be decreased in NSCLC cells due to the lack of APIP-mediated suppression and UACA-assisted Apaf-1 nuclear entry. Moreover, the loss of UACA-assisted Apaf-1 nuclear translocation may underlie the failure of DNA damage checkpoint activation in NSCLC cells leading to their genomic instability.
Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis/genetics , Autoantigens/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Down-Regulation , Lung Neoplasms/metabolism , Adult , Aged , Apoptosis Regulatory Proteins/metabolism , Autoantigens/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Statistics, Nonparametric , Transcription, GeneticABSTRACT
The granzyme B-induced cell death has been traditionally viewed as a primary mechanism that is used by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to eliminate harmful target cells including allogeneic, virally infected and tumour cells. Granzyme B (GrB) is the most abundant serine protease which is stored in secretory granules of CTLs and NK cells. After recognition of the target cell, the engaged CTLs and NK cells vectorially secrete GrB along with other granule proteins including perforin into the immunological synapse. From this submicroscopic intercellular cleft GrB translocates into the cytoplasm of the target cell. Although several models have been proposed to explain the GrB delivery mechanism, conclusive understanding of this process remains still elusive. Once in the cytoplasm, GrB cleaves and activates, or inactivates, multiple protein substrates, resulting eventually into apoptotic demise of the target cell. This review is focused on the gene structure and expression of GrB, its biosynthesis and activation, delivery mechanisms into the target cell cytoplasm, direct proteolytic involvement in activation of several pro-apoptotic pathways, and on regulation of its activity in cancer cells. Moreover, emphasis is given to the GrB-mediated anticancer effects and future clinical applications of the GrB-based and tumour-targeted recombinant fusion constructs.
Subject(s)
Apoptosis/genetics , Granzymes/genetics , Granzymes/physiology , Neoplasms/genetics , Animals , Enzyme Activation , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Granzymes/metabolism , Humans , Models, Biological , Neoplasms/enzymology , Neoplasms/metabolism , Tissue DistributionABSTRACT
Human proteinase inhibitor-9 (PI-9)/serpinB9 is an intracellular ovalbumin-family serpin with nucleocytoplasmic distribution which is expressed in certain normal cell types and cancer cells of different origin. Due to binding and inactivating of granzyme B (GrB), PI-9 can protect the cells from GrB-mediated apoptosis. High levels of PI-9 expression in certain cancer cells may contribute to their resistance against the immune mediated killing. So far, it is not known whether non-small cell lung cardinomas (NSCLCs) express PI-9 mRNA and a functional PI-9 protein. Herein we report for the first time that NSCLC cells express both PI-9 mRNA and protein and that there is a subset of NSCLC cells with upregulated PI-9 mRNA and protein expression. Futhermore, our work revealed that the PI-9 protein expressed in NSCLC cells can inhibit the active GrB. Finally, analysis of PI-9 mRNA expression in NSCLC tumours from surgically treated patients showed that the expression of this transcript is upregulated in the less-differentiated lung adenocarcinomas. We suggest, that the upregulated expression of PI-9 in NSCLC cells may serve to protect them from apoptosis induced by GrB.
