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Deep Proteome Profiling Reveals Common Prevalence of MZB1-Positive Plasma B Cells in Human Lung and Skin Fibrosis.

Tue, 12/05/2017 - 13:45
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Deep Proteome Profiling Reveals Common Prevalence of MZB1-Positive Plasma B Cells in Human Lung and Skin Fibrosis.

Am J Respir Crit Care Med. 2017 Nov 15;196(10):1298-1310

Authors: Schiller HB, Mayr CH, Leuschner G, Strunz M, Staab-Weijnitz C, Preisendörfer S, Eckes B, Moinzadeh P, Krieg T, Schwartz DA, Hatz RA, Behr J, Mann M, Eickelberg O

Abstract
RATIONALE: Analyzing the molecular heterogeneity of different forms of organ fibrosis may reveal common and specific factors and thus identify potential future therapeutic targets.
OBJECTIVES: We sought to use proteome-wide profiling of human tissue fibrosis to (1) identify common and specific signatures across end-stage interstitial lung disease (ILD) cases, (2) characterize ILD subgroups in an unbiased fashion, and (3) identify common and specific features of lung and skin fibrosis.
METHODS: We collected samples of ILD tissue (n = 45) and healthy donor control samples (n = 10), as well as fibrotic skin lesions from localized scleroderma and uninvolved skin (n = 6). Samples were profiled by quantitative label-free mass spectrometry, Western blotting, or confocal imaging.
MEASUREMENTS AND MAIN RESULTS: We determined the abundance of more than 7,900 proteins and stratified these proteins according to their detergent solubility profiles. Common protein regulations across all ILD cases, as well as distinct ILD subsets, were observed. Proteomic comparison of lung and skin fibrosis identified a common upregulation of marginal zone B- and B1-cell-specific protein (MZB1), the expression of which identified MZB1+/CD38+/CD138+/CD27+/CD45-/CD20- plasma B cells in fibrotic lung and skin tissue. MZB1 levels correlated positively with tissue IgG and negatively with diffusing capacity of the lung for carbon monoxide.
CONCLUSIONS: Despite the presumably high molecular and cellular heterogeneity of ILD, common protein regulations are observed, even across organ boundaries. The surprisingly high prevalence of MZB1-positive plasma B cells in tissue fibrosis warrants future investigations regarding the causative role of antibody-mediated autoimmunity in idiopathic cases of organ fibrosis, such as idiopathic pulmonary fibrosis.

PMID: 28654764 [PubMed - indexed for MEDLINE]

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer.

Tue, 12/05/2017 - 13:45
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Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer.

Am J Respir Crit Care Med. 2017 Nov 15;196(10):1275-1286

Authors: Morrison TJ, Jackson MV, Cunningham EK, Kissenpfennig A, McAuley DF, O'Kane CM, Krasnodembskaya AD

Abstract
RATIONALE: Acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure in critically ill patients. Mesenchymal stromal cells (MSCs) are a promising candidate for a cell-based therapy. However, the mechanisms of MSCs' effects in ARDS are not well understood. In this study, we focused on the paracrine effect of MSCs on macrophage polarization and the role of extracellular vesicle (EV)-mediated mitochondrial transfer.
OBJECTIVES: To determine the effects of human MSCs on macrophage function in the ARDS environment and to elucidate the mechanisms of these effects.
METHODS: Human monocyte-derived macrophages (MDMs) were studied in noncontact coculture with human MSCs when stimulated with LPS or bronchoalveolar lavage fluid (BALF) from patients with ARDS. Murine alveolar macrophages (AMs) were cultured ex vivo with/without human MSC-derived EVs before adoptive transfer to LPS-injured mice.
MEASUREMENTS AND MAIN RESULTS: MSCs suppressed cytokine production, increased M2 macrophage marker expression, and augmented phagocytic capacity of human MDMs stimulated with LPS or ARDS BALF. These effects were partially mediated by CD44-expressing EVs. Adoptive transfer of AMs pretreated with MSC-derived EVs reduced inflammation and lung injury in LPS-injured mice. Inhibition of oxidative phosphorylation in MDMs prevented the modulatory effects of MSCs. Generating dysfunctional mitochondria in MSCs using rhodamine 6G pretreatment also abrogated these effects.
CONCLUSIONS: In the ARDS environment, MSCs promote an antiinflammatory and highly phagocytic macrophage phenotype through EV-mediated mitochondrial transfer. MSC-induced changes in macrophage phenotype critically depend on enhancement of macrophage oxidative phosphorylation. AMs treated with MSC-derived EVs ameliorate lung injury in vivo.

PMID: 28598224 [PubMed - indexed for MEDLINE]

Differences in systemic adaptive immunity contribute to the 'frequent exacerbator' COPD phenotype.

Tue, 12/05/2017 - 13:45
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Differences in systemic adaptive immunity contribute to the 'frequent exacerbator' COPD phenotype.

Respir Res. 2016 Oct 28;17(1):140

Authors: Geerdink JX, Simons SO, Pike R, Stauss HJ, Heijdra YF, Hurst JR

Abstract
BACKGROUND: Some COPD patients are more susceptible to exacerbations than others. Mechanisms underlying these differences in susceptibility are not well understood. We hypothesized that altered cell mediated immune responses may underlie a propensity to suffer from frequent exacerbations in COPD.
METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from 24 stable COPD patients, eight frequent exacerbators (≥3 diary-card exacerbations/year) and 16 infrequent exacerbators (< 3 diary-card exacerbations/year). Detailed multi-parameter flow cytometry was used to study differences in innate and adaptive systemic immune function between frequent and infrequently exacerbating COPD patients.
RESULTS: The 24 COPD patients had a mean (SD) age of 76.3 (9.4) years and FEV1 1.43 (0.60)L, 53.3 (18.3)% predicted. PBMCs of frequent exacerbators (FE) contained lower frequencies of CD4+ T central memory cells (CD4+ Tcm) compared to infrequent exacerbators (IE) (FE = 18.7 %; IE = 23.9 %; p = 0.035). This observation was also apparent in absolute numbers of CD4+ Tcm cells (FE = 0.17 × 10^6/mL; IE = 0.25 × 10^6/mL; p = 0.035). PBMCs of FE contained a lower frequency of CD8+ T effector memory cells expressing HLA-DR (Human Leukocyte Antigen - D Related) compared to IE COPD patients (FE = 22.7 %; IE = 31.5 %; p = 0.007).
CONCLUSION: Differences in the adaptive systemic immune system might associate with exacerbation susceptibility in the 'frequent exacerbator' COPD phenotype. These differences include fewer CD4+ T central memory cells and CD8+ T effector memory cells.
TRIAL REGISTRATION: Not applicable.

PMID: 27793198 [PubMed - indexed for MEDLINE]

Painful and swollen hands 3 months after lungs graft: Suracute voriconazole-induced periostitis and exostosis.

Tue, 12/05/2017 - 13:45
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Painful and swollen hands 3 months after lungs graft: Suracute voriconazole-induced periostitis and exostosis.

Joint Bone Spine. 2017 Jan;84(1):97-98

Authors: Metayer B, Bode-Milin C, Ansquer C, Haloun A, Maugars Y, Berthelot JM

PMID: 27117297 [PubMed - indexed for MEDLINE]

Intravenous Transplantation of Mesenchymal Progenitors Distribute Solely to the Lungs and Improve Outcomes in Cervical Spinal Cord Injury.

Tue, 12/05/2017 - 13:45
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Intravenous Transplantation of Mesenchymal Progenitors Distribute Solely to the Lungs and Improve Outcomes in Cervical Spinal Cord Injury.

Stem Cells. 2016 Jul;34(7):1812-25

Authors: White SV, Czisch CE, Han MH, Plant CD, Harvey AR, Plant GW

Abstract
Cellular transplantation strategies utilizing intraspinal injection of mesenchymal progenitor cells (MPCs) have been reported as beneficial for spinal cord injuries. However, intraspinal injection is not only technically challenging, but requires invasive surgical procedures for patients. Therefore, we investigated the feasibility and potential benefits of noninvasive intravenous injection of MPCs in two models of cervical spinal cord injury, unilateral C5 contusion and complete unilateral C5 hemisection. MPCs isolated from green fluorescence protein (GFP)-luciferase transgenic mice compact bone (1 × 10(6) cells), or vehicle Hank's Buffered Saline Solution (HBSS), were intravenously injected via the tail vein at D1, D3, D7, D10, or D14. Transplanted MPCs were tracked via bioluminescence imaging. Live in vivo imaging data showed that intravenously injected MPCs accumulate in the lungs, confirmed by postmortem bioluminescence signal-irrespective of the time of injection or injury model. The results showed a rapid, positive modulation of the inflammatory response providing protection to the injured spinal cord tissue. Histological processing of the lungs showed GFP(+) cells evenly distributed around the alveoli. We propose that injected cells can act as cellular target decoys to an immune system primed by injury, thereby lessening the inflammatory response at the injury site. We also propose that intravenous injected MPCs modulate the immune system via the lungs through secreted immune mediators or contact interaction with peripheral organs. In conclusion, the timing of intravenous injection of MPCs is key to the success for improving function and tissue preservation following cervical spinal cord injury. Stem Cells 2016;34:1812-1825.

PMID: 26989838 [PubMed - indexed for MEDLINE]

Phosphatase of regenerating liver-3 inhibits invasiveness and proliferation in non-small cell lung cancer by regulating the epithelial-mesenchymal transition.

Tue, 12/05/2017 - 13:45
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Phosphatase of regenerating liver-3 inhibits invasiveness and proliferation in non-small cell lung cancer by regulating the epithelial-mesenchymal transition.

Oncotarget. 2016 Apr 19;7(16):21799-811

Authors: Lin SY, Lee YX, Yu SL, Chang GC, Chen JJ

Abstract
Phosphatase of regenerating liver-3 (PRL-3) has been reported to be associated with colon and gastric cancer metastasis. However, the role and function of PRL-3 in human non-small cell lung cancer cells is unknown. Our studies showed that the expression of PRL-3mRNA and protein are higher in less invasive human lung adenocarcinoma cells than in highly invasive cell lines. Ectopic expression of PRL-3 reduced cell capacity for anchorage-dependent growth, anchorage-independent growth, migration, and invasion in vitro, as well as tumorigenesis in vivo. Conversely, catalytic (C104S) and prenylation-site (C170S) mutants enhanced cell invasion. Microarray profiling of PRL-3 transfectants revealed the pathways potentially involving PRL-3, including the epithelial-mesenchymal transition (EMT), extracellular matrix remodeling, and the WNT signaling pathway. Furthermore, we demonstrated that increased PRL-3 reduced Slug and enhanced E-cadherin gene expression through the AKT/GSK3β/β-catenin pathway. In conclusion, our data suggest that PRL-3 might play a tumor suppressor role in lung cancer, distinct from other cancers, by inhibiting EMT-related pathways.

PMID: 26967563 [PubMed - indexed for MEDLINE]

Hsa-miR-329 exerts tumor suppressor function through down-regulation of MET in non-small cell lung cancer.

Tue, 12/05/2017 - 13:45
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Hsa-miR-329 exerts tumor suppressor function through down-regulation of MET in non-small cell lung cancer.

Oncotarget. 2016 Apr 19;7(16):21510-26

Authors: Sun CC, Li SJ, Zhang F, Pan JY, Wang L, Yang CL, Xi YY, Li de J

Abstract
MicroRNAs (miRNAs) act as key regulators of multiple cancers. Hsa-miR-329 (miR-329) functions as a tumor suppressor in some malignancies. However, its role on lung cancer remains poorly understood. In this study, we investigated the role of miR-329 on the development of lung cancer. The results indicated that miR-329 was decreased in primary lung cancer tissues compared with matched adjacent normal lung tissues and very low levels were found in a non-small cell lung cancer (NSCLC) cell lines. Ectopic expression of miR-329 in lung cancer cell lines substantially repressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibiting cyclin D1, cyclin D2 and up-regulatiing p57(Kip2) and p21(WAF1/CIP1). In addition, miR-329 promoted NSCLC cell apoptosis, as indicated by up-regulation of key apoptosis gene cleaved caspase-3, and down-regulation of anti-apoptosis gene Bcl2. Moreover, miR-329 inhibited cellular migration and invasiveness through inhibiting matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene MET was revealed to be a putative target of miR-329, which was inversely correlated with miR-329 expression. Furthermore, down-regulation of MET by siRNA performed similar effects to over-expression of miR-329. Collectively, our results demonstrated that miR-329 played a pivotal role in lung cancer through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic MET.

PMID: 26909600 [PubMed - indexed for MEDLINE]

Mesenchymal Stem Cells Induce Suppressive Macrophages Through Phagocytosis in a Mouse Model of Asthma.

Tue, 12/05/2017 - 13:45
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Mesenchymal Stem Cells Induce Suppressive Macrophages Through Phagocytosis in a Mouse Model of Asthma.

Stem Cells. 2016 Jul;34(7):1836-45

Authors: Braza F, Dirou S, Forest V, Sauzeau V, Hassoun D, Chesné J, Cheminant-Muller MA, Sagan C, Magnan A, Lemarchand P

Abstract
Mesenchymal stem cell (MSC) immunosuppressive functions make them attractive candidates for anti-inflammatory therapy in allergic asthma. However, the mechanisms by which they ensure therapeutic effects remain to be elucidated. In an acute mouse model of house dust mite (Der f)-induced asthma, one i.v. MSC injection was sufficient to normalize and stabilize lung function in Der f-sensitized mice as compared to control mice. MSC injection decreased in vivo airway responsiveness and decreased ex vivo carbachol-induced bronchial contraction, maintaining bronchial expression of the inhibitory type 2 muscarinic receptor. To evaluate in vivo MSC survival, MSCs were labeled with PKH26 fluorescent marker prior to i.v. injection, and 1 to 10 days later total lungs were digested to obtain single-cell suspensions. 91.5 ± 2.3% and 86.6 ± 6.3% of the recovered PKH26(+) lung cells expressed specific macrophage markers in control and Der f mice, respectively, suggesting that macrophages had phagocyted in vivo the injected MSCs. Interestingly, only PKH26(+) macrophages expressed M2 phenotype, while the innate PKH26(-) macrophages expressed M1 phenotype. Finally, the remaining 0.5% PKH26(+) MSCs expressed 10- to 100-fold more COX-2 than before injection, suggesting in vivo MSC phenotype modification. Together, the results of this study indicate that MSCs attenuate asthma by being phagocyted by lung macrophages, which in turn acquire a M2 suppressive phenotype. Stem Cells 2016;34:1836-1845.

PMID: 26891455 [PubMed - indexed for MEDLINE]

Wnt3a, a Protein Secreted by Mesenchymal Stem Cells Is Neuroprotective and Promotes Neurocognitive Recovery Following Traumatic Brain Injury.

Tue, 12/05/2017 - 13:45
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Wnt3a, a Protein Secreted by Mesenchymal Stem Cells Is Neuroprotective and Promotes Neurocognitive Recovery Following Traumatic Brain Injury.

Stem Cells. 2016 May;34(5):1263-72

Authors: Zhao Y, Gibb SL, Zhao J, Moore AN, Hylin MJ, Menge T, Xue H, Baimukanova G, Potter D, Johnson EM, Holcomb JB, Cox CS, Dash PK, Pati S

Abstract
Intravenous administration of bone marrow derived mesenchymal stem cells (MSCs) has been shown to reduce blood brain barrier compromise and improve neurocognition following traumatic brain injury (TBI). These effects occur in the absence of engraftment and differentiation of these cells in the injured brain. Recent studies have shown that soluble factors produced by MSCs mediate a number of the therapeutic effects. In this study, we sought to determine if intravenous administration of MSCs (IV-MSCs) could enhance hippocampal neurogenesis following TBI. Our results demonstrate that IV-MSC treatment attenuates loss of neural stem cells and promotes hippocampal neurogenesis in TBI injured mice. As Wnt signaling has been implicated in neurogenesis, we measured circulating Wnt3a levels in serum following IV-MSC administration and found a significant increase in Wnt3a. Concurrent with this increase, we detected increased activation of the Wnt/β-catenin signaling pathway in hippocampal neurons. Furthermore, IV recombinant Wnt3a treatment provided neuroprotection, promoted neurogenesis, and improved neurocognitive function in TBI injured mice. Taken together, our results demonstrate a role for Wnt3a in the therapeutic potential of MSCs and identify Wnt3a as a potential stand-alone therapy or as part of a combination therapeutic strategy for the treatment of TBI. Stem Cells 2016;34:1263-1272.

PMID: 26840479 [PubMed - indexed for MEDLINE]

Long-term follow-up of ribavirin-free DAA-based treatment in HCV-recurrence after orthotopic liver transplantation.

Mon, 12/04/2017 - 22:47

Long-term follow-up of ribavirin-free DAA-based treatment in HCV-recurrence after orthotopic liver transplantation.

Liver Int. 2017 Dec 02;:

Authors: Beinhardt S, Al-Zoairy R, Kozbial K, Stättermayer AF, Maieron A, Stauber R, Strasser M, Zoller H, Graziadei I, Rasoul-Rockenschaub S, Trauner M, Ferenci P, Hofer H

Abstract
BACKGROUND & AIMS: Excellent efficacy and safety-profile of second generation DAA-combinations improved treatment of chronic hepatitis C (HCV) as well as in HCV-recurrence after orthothopic liver transplantation (OLT). The need of ribavirin-addition is under debate as anemia and decreased renal function are prevalent in transplant-cohorts. Aim of this study was thus to assess safety and long-term efficacy of RBV-free DAA-combinations in HCV-recurrent patients after OLT.
PATIENTS & METHODS: 62 OLT-recipients (male:50/81%; age:60.7±8.5 years [mean±SD]; GT-1: 48, GT-3: 9, GT-4: 5; cirrhosis:34/55% [7/21% decompensated], fibrosing cholestatic hepatitis:1/2%) received RBV-free treatment with second-generation DAA-combinations: sofosbuvir(SOF)/daclatasvir(DCV): 42/68%, SOF/simeprevir(SMV): 10/16%, SOF/ledipasvir(LDV): 6/10% and PrOD: 4/7%.
RESULTS: Data of at least 96 weeks of FUP after treatment cessation (mean:120; up to 167 weeks) were analyzed. All patients showed on-treatment response. By intention to treat (ITT) analysis SVR12 was 97% (60/62, GT-1a:11/11 (100%); 1b: 33/34 (97%), 1g:1/1 (100%), subtype not specified:2/2 (100%), GT3a:9/9 (100%); GT4:4/5 (80%)) compared to SVR96 of 89% (55/62). No late relapses occurred. In total 16 severe adverse events occurred, including 2 newly diagnosed carcinoma (lung cancer, hepatocellular carcinoma). Six patients died; one at treatment week24 (HCV-RNA undetectable), five during treatment-free FUP and after achieving SVR (SVR4: N=1, SVR12: N=3, after SVR96: N=1 respectively. Reasons for death were: multi organ failure (N=4), impaired graft function (N=1) and unknown (N=1).
CONCLUSION: RBV-free DAA-combinations for the treatment of HCV-recurrence after OLT are highly efficacious and well tolerated. Our long-term data show that viral eradication is durable but not necessarily translated into beneficial long-term clinical outcome. This article is protected by copyright. All rights reserved.

PMID: 29197145 [PubMed - as supplied by publisher]

Nafamostat mesilate negatively regulates the metastasis of triple-negative breast cancer cells.

Mon, 12/04/2017 - 22:47

Nafamostat mesilate negatively regulates the metastasis of triple-negative breast cancer cells.

Arch Pharm Res. 2017 Dec 01;:

Authors: Mander S, You DJ, Park S, Kim DH, Yong HJ, Kim DS, Ahn C, Kim YH, Seong JY, Hwang JI

Abstract
Triple-negative breast cancer (TNBC) lacking of oestrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2 is a highly malignant disease which results in a poor prognosis and rare treatment options. Despite the use of conventional chemotherapy for TNBC tumours, resistance and short duration responses limit the treatment efficacy. Therefore, a need exists to develop a new chemotherapy for TNBC. The aim of this study was to examine the anti-cancer effects of nafamostat mesilate (NM), a previously known serine protease inhibitor and highly safe drug on breast cancer cells. Here, we showed that NM significantly inhibits proliferation, migration, and invasion in MDA-MB231 cells, induces G2/M phase cell-cycle arrest, and inhibits the expression of cyclin-dependent kinase 1 (CDK1). Exposure of MDA-MB231 cells to NM also resulted in decreased transcription factor activities accompanied by the regulated phosphorylation of signalling molecules and a decrease in metalloproteinases, the principal modulators of the extracellular environment during cancer progression. Especially, inhibition of TGFβ-stimulated Smad2 phosphorylation and subsequent metastasis-related gene expression, and downregulation of ERK activity may be pivotal mechanisms underlying inhibitory effects of NM on NM inhibits lung metastasis of breast cancer cells and growth of colonized tumours in mice. Taken together, our data revealed that NM inhibits cell growth and metastasis of TNBC cells and indicated that NM is a multi-targeted drug that could be an adjunct therapy for TNBC treatment.

PMID: 29196918 [PubMed - as supplied by publisher]

Evolution of lung and kidney allograft function in patients receiving kidney after lung transplantation.

Sat, 12/02/2017 - 16:46

Evolution of lung and kidney allograft function in patients receiving kidney after lung transplantation.

Clin Transplant. 2017 Dec 01;:

Authors: Weber NT, Bonani M, Benden C, Schleich A, Fehr T, Mueller TF, Schuurmans MM

Abstract
Calcineurin inhibitor (CNI) toxicity leads to ESRD in almost half of long-term survivors after lung transplantation, some of them receiving kidney transplants. Little is known about the outcomes of kidney and lung allograft function following kidney after lung transplantation (KALTPL) in the modern era. We retrospectively analyzed a group of 13 consecutive patients who received a KALTPL with respect to their renal and pulmonary function and immunological evolution over 2 years. We documented a stable evolution of forced expiratory volume in one second (FEV1) after KALTPL in most patients as well as an excellent kidney graft during the 2-year follow-up period. In our small cohort, living donations showed a significantly higher estimated glomerular filtration rate (eGFR) compared to deceased donation (75.7 compared to 41.6 ml/min). Patients who received a preemptive KALTPL were more likely to improve their lung function after KALTPL. 4 patients developed de novo donor specific antibodies (DSA) against the kidney graft. There were no DSA against shared antigens from the lung allograft. De novo DSA did not lead to graft loss in any patient. All 13 patients survived the first 24 months after KALTPL. This article is protected by copyright. All rights reserved.

PMID: 29194767 [PubMed - as supplied by publisher]

Utility of transthoracic needle biopsy after lung transplantation.

Sat, 12/02/2017 - 16:46

Utility of transthoracic needle biopsy after lung transplantation.

Clin Transplant. 2017 Dec 01;:

Authors: Kavanagh J, Siemienowicz M, Keshavjee S, Rogalla P, Singer L, Kandel S

Abstract
The purpose of this study was to assess the diagnostic yield and complications of CT guided transthoracic needle biopsy (TTNB) after lung transplantation. A database search identified all TTNB performed in lung transplant patients over a 14-year period. 42 biopsies in transplant patients (transplant group) were identified and matched to the next biopsy performed in native lungs by the same operator (non-transplant group) as a control. Primary outcomes recorded were diagnosis, diagnostic yield, pneumothorax requiring intervention and symptomatic pulmonary hemorrhage. Biopsy outcomes were classified as diagnostic not specifically diagnostic and non-diagnostic. Patients in the transplant group were younger (p<0.002). Emphysema along the biopsy trajectory was more commonly seen in the non-transplant group (p<0.0006). Needle gauge, size of lesion, pleural punctures, lesion depth and number of passes was not significantly different. Diagnostic yield was 71% in the transplant group and 91% in the non-transplant group. There were 20/42 (48%) malignant nodules in the transplant group compared to 31/44 (70%) nodules in the non-transplant group (p=0.05). There were no complications in the transplant group. The non-transplant group had 2 pneumothoraces requiring intervention. TTNB after lung transplant is safe with a moderate diagnostic yield. Non-malignant lesions are more common after lung transplantation. This article is protected by copyright. All rights reserved.

PMID: 29194758 [PubMed - as supplied by publisher]

Technology Experience of Solid Organ Transplant Patients and Their Overall Willingness to Use Interactive Health Technology.

Sat, 12/02/2017 - 16:46

Technology Experience of Solid Organ Transplant Patients and Their Overall Willingness to Use Interactive Health Technology.

J Nurs Scholarsh. 2017 Nov 28;:

Authors: Vanhoof JMM, Vandenberghe B, Geerts D, Philippaerts P, De Mazière P, DeVito Dabbs A, De Geest S, Dobbels F, PICASSO-Tx Consortium

Abstract
BACKGROUND: The use of interactive health technology (IHT) is a promising pathway to tackle self-management problems experienced by many chronically ill patients, including solid organ transplant (Tx) patients. Yet, to ensure that the IHT is accepted and used, a human-centered design process is needed, actively involving end users in all steps of the development process. A first critical, predevelopment step involves understanding end users' characteristics. This study therefore aims to (a) select an IHT platform to deliver a self-management support intervention most closely related to Tx patients' current use of information and communication technologies (ICTs), (b) understand Tx patients' overall willingness to use IHT for self-management support, and investigate associations with relevant technology acceptance variables, and (c) explore Tx patients' views on potential IHT features.
DESIGN AND METHODS: We performed a cross-sectional, descriptive study between October and December 2013, enrolling a convenience sample of adult heart, lung, liver, and kidney Tx patients from the University Hospitals Leuven, Belgium. Broad inclusion criteria were applied to ensure a representative patient sample. We used a 35-item newly designed interview questionnaire to measure Tx patients' use of ICTs, their overall willingness to use IHT, and their views on potential IHT features, as well as relevant technology acceptance variables derived from the Unified Theory of Acceptance and Use of Technology and a literature review. Descriptive statistics were used as appropriate, and an ordinal logistic regression model was built to determine the association between Tx patients' overall willingness to use IHT, the selected technology acceptance variables, and patient characteristics.
FINDINGS: Out of 139 patients, 122 agreed to participate (32 heart, 30 lung, 30 liver, and 30 kidney Tx patients; participation rate: 88%). Most patients were male (57.4%), married or living together (68%), and had a mean age of 55.9 ± 13.4 years. Only 27.9% of Tx patients possessed a smartphone, yet 72.1% owned at least one desktop or laptop PC with wireless Internet at home. On a 10-point numeric scale, asking patients whether they think IHT development is important to support them personally in their self-management, patients gave a median score of 7 (25th percentile 5 points; 75th percentile 10 points). Patients who were single or married or living together were more likely to give a higher rating than divorced or widowed patients; patients who completed only secondary education gave a higher rating than higher educated patients; and patients with prior ICT use gave a higher rating than patients without prior ICT use. Tx patients also had clear preferences regarding IHT features, such as automatic data transfer, as much as possible, visual aids (e.g., graphs) over text messages, and personally deciding when to access the IHT.
CONCLUSIONS: By investigating Tx patients' possession and use of ICTs, we learned that computers and the Internet, and not smartphones, are the most suitable IHT platforms to deliver self-management interventions for our Tx patients. Moreover, Tx patients generally are open to using IHT, yet patient acceptance variables and their preferences for certain IHT features should be taken into account in the next steps of IHT development. Designers intending to develop or use existing IHTs should never overlook this critical first step in a human-centered design.
CLINICAL RELEVANCE: Before considering using eHealth technology in clinical practice, professionals should always check whether patients are familiar with using information and communication technology, and whether they are willing to use technology for health-related purposes.

PMID: 29193654 [PubMed - as supplied by publisher]

Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF.

Sat, 12/02/2017 - 16:46

Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF.

Eur J Heart Fail. 2017 Nov 30;:

Authors: Mogensen UM, Køber L, Jhund PS, Desai AS, Senni M, Kristensen SL, Dukát A, Chen CH, Ramires F, Lefkowitz MP, Prescott MF, Shi VC, Rouleau JL, Solomon SD, Swedberg K, Packer M, McMurray JJV, PARADIGM-HF Investigators and Committees

Abstract
AIMS: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF.
METHODS AND RESULTS: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1-Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (<5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m2 ), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09-1.50), P = 0.003], cardiovascular death [1.44 (1.11-1.77), P = 0.001], HF hospitalization [1.37 (1.11-1.70), P = 0.004], and all-cause mortality [1.36 (1.13-1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17-0.32) mg/dL over 12 months (P < 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration.
CONCLUSION: Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA.

PMID: 29193563 [PubMed - as supplied by publisher]

Stereological assessment of the blood-air barrier and the surfactant system after mesenchymal stem cell pretreatment in a porcine non-heart-beating donor model for lung transplantation.

Sat, 12/02/2017 - 16:46

Stereological assessment of the blood-air barrier and the surfactant system after mesenchymal stem cell pretreatment in a porcine non-heart-beating donor model for lung transplantation.

J Anat. 2017 Nov 28;:

Authors: Schnapper A, Christmann A, Knudsen L, Rahmanian P, Choi YH, Zeriouh M, Karavidic S, Neef K, Sterner-Kock A, Guschlbauer M, Hofmaier F, Maul AC, Wittwer T, Wahlers T, Mühlfeld C, Ochs M

Abstract
More frequent utilization of non-heart-beating donor (NHBD) organs for lung transplantation has the potential to relieve the shortage of donor organs. In particular with respect to uncontrolled NHBD, concerns exist regarding the risk of ischaemia/reperfusion (IR) injury-related graft damage or dysfunction. Due to their immunomodulating and tissue-remodelling properties, bone-marrow-derived mesenchymal stem cells (MSCs) have been suspected of playing a beneficial role regarding short- and long-term survival and function of the allograft. Thus, MSC administration might represent a promising pretreatment strategy for NHBD organs. To study the initial effects of warm ischaemia and MSC application, a large animal lung transplantation model was generated, and the structural organ composition of the transplanted lungs was analysed stereologically with particular respect to the blood-gas barrier and the surfactant system. In this study, porcine lungs (n = 5/group) were analysed. Group 1 was the sham-operated control group. In pigs of groups 2-4, cardiac arrest was induced, followed by a period of 3 h of ventilated ischaemia at room temperature. In groups 3 and 4, 50 × 106 MSCs were administered intravascularly via the pulmonary artery and endobronchially, respectively, during the last 10 min of ischaemia. The left lungs were transplanted, followed by a reperfusion period of 4 h. Then, lungs were perfusion-fixed and processed for light and electron microscopy. Samples were analysed stereologically for IR injury-related structural parameters, including volume densities and absolute volumes of parenchyma components, alveolar septum components, intra-alveolar oedema, and the intracellular and intra-alveolar surfactant pool. Additionally, the volume-weighted mean volume of lamellar bodies (lbs) and their profile size distribution were determined. Three hours of ventilated warm ischaemia was tolerated without eliciting histological or ultrastructural signs of IR injury, as revealed by qualitative and quantitative assessment. However, warm ischaemia influenced the surfactant system. The volume-weighted mean volume of lbs was reduced significantly (P = 0.024) in groups subjected to ischaemia (group medians of groups 2-4: 0.180-0.373 μm³) compared with the sham control group (median 0.814 μm³). This was due to a lower number of large lb profiles (size classes 5-15). In contrast, the intra-alveolar surfactant system was not altered significantly. No significant differences were encountered comparing ischaemia alone (group 2) or ischaemia plus application of MSCs (groups 3 and 4) in this short-term model.

PMID: 29193065 [PubMed - as supplied by publisher]

European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency.

Sat, 12/02/2017 - 16:46

European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency.

Eur Respir J. 2017 Nov;50(5):

Authors: Miravitlles M, Dirksen A, Ferrarotti I, Koblizek V, Lange P, Mahadeva R, McElvaney NG, Parr D, Piitulainen E, Roche N, Stolk J, Thabut G, Turner A, Vogelmeier C, Stockley RA

Abstract
α1-antitrypsin deficiency (AATD) is the most common hereditary disorder in adults. It is associated with an increased risk of developing pulmonary emphysema and liver disease. The pulmonary emphysema in AATD is strongly linked to smoking, but even a proportion of never-smokers develop progressive lung disease. A large proportion of individuals affected remain undiagnosed and therefore without access to appropriate care and treatment.The most recent international statement on AATD was published by the American Thoracic Society and the European Respiratory Society in 2003. Since then there has been a continuous development of novel, more accurate and less expensive genetic diagnostic methods. Furthermore, new outcome parameters have been developed and validated for use in clinical trials and a new series of observational and randomised clinical trials have provided more evidence concerning the efficacy and safety of augmentation therapy, the only specific treatment available for the pulmonary disease associated with AATD.As AATD is a rare disease, it is crucial to organise national and international registries and collect information prospectively about the natural history of the disease. Management of AATD patients must be supervised by national or regional expert centres and inequalities in access to therapies across Europe should be addressed.

PMID: 29191952 [PubMed - in process]

Inhibition of protein phosphatase 5 suppresses non-small cell lung cancer through AMP-activated kinase activation.

Sat, 12/02/2017 - 16:46

Inhibition of protein phosphatase 5 suppresses non-small cell lung cancer through AMP-activated kinase activation.

Lung Cancer. 2017 Oct;112:81-89

Authors: Hsieh FS, Hung MH, Wang CY, Chen YL, Hsiao YJ, Tsai MH, Li JR, Chen LJ, Shih CT, Chao TI, Chen KF

Abstract
OBJECTIVES: Non-small cell lung cancer (NSCLC) continues to be the top cause of cancer death. To improve the treatment of lung cancer, there is necessity to identify novel oncogenes and investigate their effects on lung carcinogenesis. Protein phosphatase 5 (PP5) has long been known to regulate stress-induced apoptosis and cell proliferation. Recently, PP5 has been found overexpressed and emerged as a viable therapeutic target in various human cancers, but its role in NSCLC remains elusive.
MATERIALS AND METHODS: The expression of PP5 in NSCLC cell lines (A549, H358, and H460) and human tumor samples were examined. Protein phosphatase inhibitors, cantharidin and norcantharidin, were used as proof-of-concept compounds to investigate the pathological function of PP5 in NSCLC. Apoptosis and cellular signaling were analyzed. In vivo efficacy was determined in nude mice with H460 xenograft.
RESULTS AND CONCLUSION: We found that PP5 was more highly expressed in human lung tumor samples than in adjacent normal tissues. Overexpression of PP5 promoted cell proliferation, colony formation, and sphere-forming ability of A549 cells. Inhibition of PP5 phosphatase activity by cantharidin induced significant apoptosis and upregulated AMP-activated protein kinase (AMPK) signaling. Importantly, we found that PP5-mediated dephosphorylation of AMPK determines the in vitro anti-NSCLC effects of cantharidin. Consistent with our in vitro data, PP5 inhibition suppressed H460 tumor growth and upregulated p-AMPK in tumor samples. Our results demonstrate that PP5 inhibition suppresses tumor growth via activating AMPK signaling. Targeting oncogenic PP5 represents an attractive therapeutic strategy for treating lung cancer.

PMID: 29191605 [PubMed - in process]

Changes in Outcomes of Cardiac Allograft Vasculopathy Over 30 Years Following Heart Transplantation.

Sat, 12/02/2017 - 16:46

Changes in Outcomes of Cardiac Allograft Vasculopathy Over 30 Years Following Heart Transplantation.

JACC Heart Fail. 2017 Dec;5(12):891-901

Authors: Tremblay-Gravel M, Racine N, de Denus S, Ducharme A, Pelletier GB, Giraldeau G, Liszkowski M, Parent MC, Carrier M, Fortier A, White M

Abstract
OBJECTIVES: This study investigated temporal changes in the demographics and the prognosis of cardiac allograft vasculopathy (CAV) over 30 years following heart transplantation (HTx).
BACKGROUND: Effects of the changing HTx demographics on CAV outcomes, based on International Society for Heart and Lung Transplantation (ISHLT) classification of CAV, have been incompletely investigated.
METHODS: Patients who underwent HTx at the Montreal Heart Institute were classified according to the severity of CAV (CAV 0 is no presence of CAV; CAV 1 is mild, CAV 2 to 3 is moderate to severe) and era of HTx (early: 1983 to 1998; recent: 1999 to 2011). We compared the risk of progression, survival, and independent predictors of outcomes among the groups.
RESULTS: A total of 298 patients were followed for 11.6 ± 6.6 years. Patients who received transplants in the early era exhibited a higher risk for progression from CAV 1 to a higher grade (adjusted odds ratio: 8.0; 95% confidence interval [CI]: 1.01 to 62.6). The presence of CAV was associated with a significantly increased risk for all-cause mortality in the early era (hazard ratio [HR]: 1.6; 95% CI: 1.1 to 2.5) but not in the recent era (HR: 1.1; 95% CI: 0.2 to 4.9). Regardless of the era, CAV classes 2 to 3 and CAV 1 were associated with a significantly increased risk for all-cause mortality compared to CAV 0 (HR: 6.5; 95% CI: 2.7 to 15.7; and HR: 1.750; 95% CI: 1.001 to 3.046, respectively).
CONCLUSIONS: The progression and prognosis of CAV have improved over 30 years. The ISHLT CAV classification accurately and independently predicts long-term outcome following HTx.

PMID: 29191295 [PubMed - in process]

Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelial-mesenchymal transition by inducing 14-3-3γ expression.

Sat, 12/02/2017 - 16:46
Related Articles

Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelial-mesenchymal transition by inducing 14-3-3γ expression.

Oncogene. 2017 Nov 16;36(46):6408-6419

Authors: Teo Z, Sng MK, Chan JSK, Lim MMK, Li Y, Li L, Phua T, Lee JYH, Tan ZW, Zhu P, Tan NS

Abstract
Metastatic cancer cells acquire energy-intensive processes including increased invasiveness and chemoresistance. However, how the energy demand is met and the molecular drivers that coordinate an increase in cellular metabolic activity to drive epithelial-mesenchymal transition (EMT), the first step of metastasis, remain unclear. Using different in vitro and in vivo EMT models with clinical patient's samples, we showed that EMT is an energy-demanding process fueled by glucose metabolism-derived adenosine triphosphate (ATP). We identified angiopoietin-like 4 (ANGPTL4) as a key player that coordinates an increase in cellular energy flux crucial for EMT via an ANGPTL4/14-3-3γ signaling axis. This augmented cellular metabolic activity enhanced metastasis. ANGPTL4 knockdown suppresses an adenylate energy charge elevation, delaying EMT. Using an in vivo dual-inducible EMT model, we found that ANGPTL4 deficiency reduces cancer metastasis to the lung and liver. Unbiased kinase inhibitor screens and Ingenuity Pathway Analysis revealed that ANGPTL4 regulates the expression of 14-3-3γ adaptor protein via the phosphatidylinositol-3-kinase/AKT and mitogen-activated protein kinase signaling pathways that culminate to activation of transcription factors, CREB, cFOS and STAT3. Using a different mode of action, as compared with protein kinases, the ANGPTL4/14-3-3γ signaling axis consolidated cellular bioenergetics and stabilized critical EMT proteins to coordinate energy demand and enhanced EMT competency and metastasis, through interaction with specific phosphorylation signals on target proteins.

PMID: 28745316 [PubMed - indexed for MEDLINE]

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