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A Case of Localized Pulmonary Calcification Presenting as a Persistent Mass Lesion in an Immunosuppressed Patient Following Treatment of a Pseudomonas Pneumonia.

Thu, 12/14/2017 - 13:45
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A Case of Localized Pulmonary Calcification Presenting as a Persistent Mass Lesion in an Immunosuppressed Patient Following Treatment of a Pseudomonas Pneumonia.

Cureus. 2017 Oct 11;9(10):e1765

Authors: Cecchini MJ, Shepherd DL, Shepherd JG

Abstract
We report a case of a persistent right upper lobe opacity following treatment for a Pseudomonas infection in an immunosuppressed patient with a recent renal transplantation. The patient underwent a surgical lung biopsy for definitive diagnosis of the mass. The lesion was composed of extensive calcifications deposited throughout the lung with associated fibrosis. The patient had a history of a remote parathyroidectomy for hyperparathyroidism; however, the parathyroid hormone (PTH) and the calcium levels were still mildly elevated. No other calcified lung lesions had developed in a follow-up after the initial resection. Pulmonary calcification has been classically associated with varicella pneumonia; no viral cytopathic changes were identified for varicella or other viruses in this case. The calcification appears to be secondary to the recent Pseudomonas pneumonia. To our knowledge, this is the first report of a Pseudomonas pneumonia resulting in extensive localized pulmonary calcification. This is an important diagnostic consideration as this benign entity should be considered in patients with persistent opacities following treatment for pneumonia.

PMID: 29234569 [PubMed]

Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.

Thu, 12/14/2017 - 13:45
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Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.

Blood. 2017 Dec 12;:

Authors: Hetzel M, Mucci A, Blank P, Nguyen AHH, Schiller J, Halle O, Kühnel MP, Billig S, Meineke R, Brand D, Herder V, Baumgärtner W, Bange FC, Goethe R, Jonigk D, Förster R, Gentner B, Casaova JL, Bustamante J, Schambach A, Kalinke U, Lachmann N

Abstract
Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare primary immunodeficiency, characterized by severe infections caused by weakly virulent mycobacteria. Bi-allelic null mutations in genes encoding interferon gamma (IFNγ) receptor 1 or -2 (IFNGR1, IFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant IFNγ therapy is inefficient and hematopoietic stem cell transplantation (HSCT) has a poor prognosis. Thus, we developed a HSC gene therapy approach using lentiviral vectors expressing Ifnγr1 either constitutively or myeloid-specifically. Transduction of mouse Ifnγr1-/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFNγ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored anti-mycobacterial activity against Mycobacterium avium and Mycobacterium bovis Bacillus-Calmette-Guérin (BCG) in vitro Transplantation of genetically corrected HSC into Ifnγr1-/- mice prior BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival of transplanted animals. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in the corresponding human patients.

PMID: 29233822 [PubMed - as supplied by publisher]

Gene editing & stem cells.

Thu, 12/14/2017 - 13:45
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Gene editing & stem cells.

J Cyst Fibros. 2017 Dec 09;:

Authors: Harrison PT, Hoppe N, Martin U

PMID: 29233638 [PubMed - as supplied by publisher]

Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer.

Thu, 12/14/2017 - 13:45
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Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer.

Cell Rep. 2017 01 17;18(3):601-610

Authors: Momcilovic M, Bailey ST, Lee JT, Fishbein MC, Magyar C, Braas D, Graeber T, Jackson NJ, Czernin J, Emberley E, Gross M, Janes J, Mackinnon A, Pan A, Rodriguez M, Works M, Zhang W, Parlati F, Demo S, Garon E, Krysan K, Walser TC, Dubinett SM, Sadeghi S, Christofk HR, Shackelford DB

Abstract
Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMP-activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with 18F-FDG and 11C-Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy.

PMID: 28099841 [PubMed - indexed for MEDLINE]

Pathologically decreased expression of miR-193a contributes to metastasis by targeting WT1-E-cadherin axis in non-small cell lung cancers.

Thu, 12/14/2017 - 13:45
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Pathologically decreased expression of miR-193a contributes to metastasis by targeting WT1-E-cadherin axis in non-small cell lung cancers.

J Exp Clin Cancer Res. 2016 Nov 07;35(1):173

Authors: Chen J, Gao S, Wang C, Wang Z, Zhang H, Huang K, Zhou B, Li H, Yu Z, Wu J, Chen C

Abstract
BACKGROUND: The metastatic cascade is a complex and multistep process with many potential barriers. Recently, miR-193a has been reported to be a suppressive miRNA in multiple types of cancers, but its underlying anti-oncogenic activity in non-small cell lung cancers (NSCLC) is not fully elucidated.
METHODS: The expressions of miR-193a (miR-193a-5p) in human lung cancer tissues and cell lines were detected by real-time PCR. Dual-luciferase reporter assay was used to identify the direct target of miR-193a. Cell proliferation, apoptosis, and metastasis were assessed by CCK-8, flow cytometry, and Transwell assay, respectively.
RESULTS: The expression of miR-193a in lung cancer tissues was decreased comparing to adjacent non-tumor tissues due to DNA hypermethylation in lung cancer tissues. Ectopic expression of miR-193a inhibited cell proliferation, colony formation, migration, and invasion in A549 and H1299 cells. Moreover, overexpression of miR-193a partially reversed tumor growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) in NSCLC cells. Mechanistically, miR-193a reduced the expression of WT1, which negatively regulated the protein level of E-cadherin, suggesting that miR-193a might prevent EMT via modulating WT1-E-cadherin axis. Importantly, knockdown of WT1 resembled the anti-cancer activity by miR-193a and overexpression of WT1 partially reversed miR-193a-induced anti-cancer activity, indicating that WT1 plays an important role in miR-193a-induced anti-cancer activity. Finally, overexpression of miR-193a decreased the growth of tumor xenografts in mice.
CONCLUSION: Collectively, our results have revealed an important role of miR-193a-WT1-E-cadherin axis in metastasis, demonstrated an important molecular cue for EMT, and suggested a therapeutic strategy of restoring miR-193a expression in NSCLC.

PMID: 27821145 [PubMed - indexed for MEDLINE]

MicroRNA-130b promotes lung cancer progression via PPARγ/VEGF-A/BCL-2-mediated suppression of apoptosis.

Thu, 12/14/2017 - 13:45
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MicroRNA-130b promotes lung cancer progression via PPARγ/VEGF-A/BCL-2-mediated suppression of apoptosis.

J Exp Clin Cancer Res. 2016 Jul 01;35(1):105

Authors: Tian J, Hu L, Li X, Geng J, Dai M, Bai X

Abstract
BACKGROUND: The prognosis of non-small-cell lung cancer (NSCLC) is poor yet mechanistic understanding and therapeutic options remain limited. We investigated the biological and clinical significance of microRNA-130b and its relationship with apoptosis in NSCLC.
METHODS: The level of microRNA-130b in relationship with the expression of PPARγ, VEGF-A, BCL-2 and apoptosis were analyzed in 91 lung cancer patient samples using immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay on tissue microarrays. Gain and loss-of-function studies were performed to investigate the effects of microRNA-130b, peroxisome proliferator-activated receptor γ (PPARγ) or vascular endothelial growth factor-A (VEGF-A) on biological functions of lung cancer cells using in vitro and in vivo approaches.
RESULTS: MicroRNA-130b up-regulation conferred unfavorable prognosis of lung cancer patients. Notably, microRNA-130b targeted PPARγ and inhibiting microRNA-130b markedly repressed proliferation, invasion and metastasis of lung cancer cells, leading to increased apoptosis. MicroRNA-130b-dependent biologic effects were due to suppression of PPARγ that in turn activated BCL-2, the key mediator of anti-apoptosis. Administration of microRNA-130b mimic to mouse xenografts promoted tumor growth. In vitro and in vivo, miR-130b enrichment associated with down-regulation of PPARγ, up-regulation of VEGF-A and BCL-2, and decreased apoptosis.
CONCLUSIONS: The present study demonstrates that microRNA-130b promotes lung cancer progression via PPARγ/VEGF-A/BCL-2-mediated suppression of apoptosis. Targeting microRNA-130b might have remarkable therapeutic potential for lung cancer therapy.

PMID: 27364335 [PubMed - indexed for MEDLINE]

Intratracheal instillation of alveolar type II cells enhances recovery from acute lung injury in rats.

Wed, 12/13/2017 - 13:45
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Intratracheal instillation of alveolar type II cells enhances recovery from acute lung injury in rats.

J Heart Lung Transplant. 2017 Nov 08;:

Authors: Guillamat-Prats R, Puig F, Camprubí-Rimblas M, Herrero R, Serrano-Mollar A, Gómez MN, Tijero J, Matthay MA, Blanch L, Artigas A

Abstract
BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by excess production of inflammatory factors. Alveolar type II (ATII) cells help repair damaged lung tissue, rapidly proliferating and differentiating into alveolar type I cells after epithelial cell injury. In ALI, the lack of viable ATII favors progression to more severe lung injury. ATII cells regulate the immune response by synthesizing surfactant and other anti-inflammatory proteins and lipids. Cross-talk between ATII and other cells such as macrophages may also be part of the ATII function. The aim of this study was to test the anti-inflammatory and reparative effects of ATII cells in an experimental model of ALI.
METHODS: In this study ATII cells (2.5 × 106 cells/animal) were intratracheally instilled in rats with HCl and lipopolysaccharide (LPS)-induced ALI and in healthy animals to check for side effects. The specific effect of ATII cells was compared with fibroblast transplantation.
RESULTS: ATII cell transplantation promoted recovery of lung function, decrease mortality and lung inflammation of the animals with ALI. The primary mechanisms for benefit were paracrine effects of prostaglandin E2 (PGE2) and surfactant protein A (SPA) released from ATII cells that modulate alveolar macrophages to an anti-inflammatory phenotype. To our knowledge, these data are the first to provide evidence that ATII cells secrete PGE2 and SPA, reducing pro-inflammatory macrophage activation and ALI.
CONCLUSION: ATII cells and their secreted molecules have shown an ability to resolve ALI, thereby highlighting a potential novel therapeutic target.

PMID: 29229270 [PubMed - as supplied by publisher]

The impact of screening method on HLA antibody detection before and after lung transplantation: A prospective pilot study.

Wed, 12/13/2017 - 13:45
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The impact of screening method on HLA antibody detection before and after lung transplantation: A prospective pilot study.

J Heart Lung Transplant. 2017 Nov 22;:

Authors: Cao S, Courtwright AM, Lamattina AM, Guleria I, Burkett P, El-Chemaly S, Goldberg HJ

PMID: 29229269 [PubMed - as supplied by publisher]

Pulmonary veno-occlusive disease: An important consideration in patients with pulmonary hypertension.

Wed, 12/13/2017 - 13:45
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Pulmonary veno-occlusive disease: An important consideration in patients with pulmonary hypertension.

Respir Med. 2017 Nov;132:203-209

Authors: Balko R, Edriss H, Nugent K, Test V

Abstract
Pulmonary veno-occlusive disease is a rare subcategory of pulmonary arterial hypertension (WHO Group 1). The disease is poorly understood and difficult to diagnose; it has no definitive cure to date. These patients present with nonspecific symptoms, including dyspnea, exercise intolerance, and weakness. Chest x-rays sometimes differ from idiopathic pulmonary arterial hypertension and may demonstrate alveolar infiltrates and pleural effusions. High resolution computed tomography scans reveal ground glass opacities, interlobular septal thickening, and lymphadenopathy. Echocardiography can estimate the level of pulmonary artery pressures; right heart catheterization is needed for complete hemodynamic characterization of these patients. Lung biopsies demonstrate remodeling of the venules and small veins with intimal and adventitial fibrosis. This can result in total venous occlusion and subsequent recanalization. Similar changes occur in the small arteries and arterioles but are less pronounced than the venous changes. There is no effective medical therapy for these patients, and treatment with the pulmonary arterial hypertension specific medications often causes acute deterioration with pulmonary edema. The recent discovery of the biallelic mutations of the EIF2AK4 gene as an etiology for heritable form of pulmonary veno-occlusive disease increases our understanding of the disease pathogenesis and potentially identifies a future approach to treatment. Without definitive treatment, the prognosis is very poor, and the life expectancy of these patients is much shorter than patients with pulmonary arterial hypertension. These patients need early referral to transplantation centers.

PMID: 29229098 [PubMed - in process]

Normalization of Elevated Tumor Marker CA27-29 after Bilateral Lung Transplantation in a patient with Breast Cancer and Idiopathic Pulmonary Fibrosis.

Wed, 12/13/2017 - 13:45
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Normalization of Elevated Tumor Marker CA27-29 after Bilateral Lung Transplantation in a patient with Breast Cancer and Idiopathic Pulmonary Fibrosis.

Oncol Res. 2017 Dec 11;:

Authors: Copur MS, Wurdeman JM, Nelson D, Ramaekers R, Gauchan D, Crockett D

Abstract
Solid tumors involving glandular organs express mucin glycoprotein which is eventually shed into the circulation. As aresult these proteins can easily be measured in the serum and be used as potential tumor markers. The most commonly used tumor markers for breast cancer are CA 27-29 and CA 15-3, which both measure the glycoprotein product of the mucin-1 (MUC1) gene. CA 27-29 has been approved by the US Food and Drug Administration for monitoring disease activity in breast cancer patients. Most oncology clinical practice guidelines do not recommend the use of tumor markers for routine surveillance of early stage disease but recognize their utility in the metastatic setting. Herein, we present a patient with stage III-A breast cancer and pre-existing hypersensitivity pneumonitis who is found to have an elevated serum tumor marker CA 27-29. After successful curative intent treatment of her early stage breast cancer, she developed gradual and progressive worsening of her lung disease with eventual development of severe pulmonary fibrosis requiring bilateral lung transplantation. As part of the pre-transplant evaluation, she was found to have an elevation of serum tumor marker CA 27-29. While the diagnostic evaluation, including imaging studies was negative for the presence of recurrent disease, the serial serum tumor marker CA 27-29 levels remained persistently elevated. The decision was made for her to undergo bilateral lung transplantation. Shortly after surgery her CA27-29 tumor marker level returned to normal range, and it has continued to remain in the normal range with no evidence of breast cancer recurrence.

PMID: 29229020 [PubMed - as supplied by publisher]

Multimedia Education Reduces Anxiety in Lung Transplant Patients.

Wed, 12/13/2017 - 13:45
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Multimedia Education Reduces Anxiety in Lung Transplant Patients.

Prog Transplant. 2017 Jan 01;:1526924817746910

Authors: Gerity SL, Silva SG, Reynolds JM, Hoffman B, Oermann MH

Abstract
CONTEXT: A significant contribution to the success of lung transplantation is the recipient's ability to self-manage a multidrug regimen and follow complex instructions. Effective education has always been an integral component of the process of preparing patients to care for themselves post lung transplant. Impaired cognition, anxiety, and psychological distress, however, can decrease the retention of posttransplant care information provided during education sessions.
OBJECTIVE: This quality improvement project evaluated whether a multimedia education method compared to standard education method improves posttransplant care knowledge, anxiety, and satisfaction with the education experience in lung transplant patients and their caregivers.
METHODS: Two education methods groups, comprised of transplant patients and their primary caregivers, were compared: (1) historic control group who received the standard education (n = 19 dyads) and (2) multimedia group who received the new multimedia education (n = 18 dyads). Knowledge of posttransplant care was evaluated in both groups before and after receiving the education. A satisfaction survey was administered at the end of the education program.
RESULTS: A significantly higher percentage of patients receiving the multimedia method reported gains in posttransplant care knowledge ( P = .05), less anxiety about the transplant surgery ( P = .02), and satisfaction with the education method ( P = .02) when compared to those receiving the standard method. Caregivers and transplant team member also indicated that the multimedia method was more effective than the standard method.
CONCLUSION: Multimedia methods decrease anxiety and increase satisfaction with the education experience when preparing patients for lung transplantation.

PMID: 29228864 [PubMed - as supplied by publisher]

Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma.

Wed, 12/13/2017 - 13:45
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Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma.

Oncotarget. 2017 Nov 17;8(58):98280-98297

Authors: Yin M, Tissari M, Tamminen J, Ylivinkka I, Rönty M, von Nandelstadh P, Lehti K, Hyytiäinen M, Myllärniemi M, Koli K

Abstract
Malignant mesothelioma originates from mesothelial cells and is a cancer type that aggressively invades into the surrounding tissue, has poor prognosis and no effective treatment. Gremlin-1 is a cysteine knot protein that functions by inhibiting BMP-pathway activity during development. BMP-independent functions have also been described for gremlin-1. We have previously shown high gremlin-1 expression in mesothelioma tumor tissue. Here, we investigated the functions of gremlin-1 in mesothelioma cell migration and invasive growth. Gremlin-1 promoted mesothelioma cell sprouting and invasion into three dimensional collagen and Matrigel matrices. The expression level of gremlin-1 was linked to changes in the expression of SNAI2, integrins, matrix metalloproteinases (MMP) and TGF-β family signaling - all previously associated with a mesenchymal invasive phenotype. Small molecule inhibitors of MMPs completely blocked mesothelioma cell invasive growth. In addition, inhibitors of TGF-β receptors significantly reduced invasive growth. This was associated with reduced expression of MMP2 but not SNAI2, indicating that gremlin-1 has both TGF-β pathway dependent and independent mechanisms of action. Results of in vivo mesothelioma xenograft experiments indicated that gremlin-1 overexpressing tumors were more vascular and had a tendency to send metastases. This suggests that by inducing a mesenchymal invasive cell phenotype together with enhanced tumor vascularization, gremlin-1 drives mesothelioma invasion and metastasis. These data identify gremlin-1 as a potential therapeutic target in mesothelioma.

PMID: 29228689 [PubMed]

Clinical mutational profiling of 1006 lung cancers by next generation sequencing.

Wed, 12/13/2017 - 13:45
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Clinical mutational profiling of 1006 lung cancers by next generation sequencing.

Oncotarget. 2017 Nov 14;8(57):96684-96696

Authors: Illei PB, Belchis D, Tseng LH, Nguyen D, De Marchi F, Haley L, Riel S, Beierl K, Zheng G, Brahmer JR, Askin FB, Gocke CD, Eshleman JR, Forde PM, Lin MT

Abstract
Analysis of lung adenocarcinomas for actionable mutations has become standard of care. Here, we report our experience using next generation sequencing (NGS) to examine AKT1, BRAF, EGFR, ERBB2, KRAS, NRAS, and PIK3CA genes in 1006 non-small cell lung cancers in a clinical diagnostic setting. NGS demonstrated high sensitivity. Among 760 mutations detected, the variant allele frequency (VAF) was 2-5% in 33 (4.3%) mutations and 2-10% in 101 (13%) mutations. A single bioinformatics pipeline using Torrent Variant Caller, however, missed a variety of EGFR mutations. Mutations were detected in KRAS (36% of tumors), EGFR (19%) including 8 (0.8%) within the extracellular domain (4 at codons 108 and 4 at codon 289), BRAF (6.3%), and PIK3CA (3.7%). With a broader reportable range, exon 19 deletion and p.L858R accounted for only 36% and 26% of EGFR mutations and p.V600E accounted for only 24% of BRAF mutations. NGS provided accurate sequencing of complex mutations seen in 19% of EGFR exon 19 deletion mutations. Doublet (compound) EGFR mutations were observed in 29 (16%) of 187 EGFR-mutated tumors, including 69% with two non-p.L858R missense mutations and 24% with p.L858 and non-p.L858R missense mutations. Concordant VAFs suggests doublet EGFR mutations were present in a dominant clone and cooperated in oncogenesis. Mutants with predicted impaired kinase, observed in 25% of BRAF-mutated tumors, were associated with a higher incidence of concomitant activating KRAS mutations. NGS demonstrates high analytic sensitivity, broad reportable range, quantitative VAF measurement, single molecule sequencing to resolve complex deletion mutations, and simultaneous detection of concomitant mutations.

PMID: 29228562 [PubMed]

ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

Wed, 12/13/2017 - 13:45
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ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

Cancer Res. 2017 Nov 15;77(22):6267-6281

Authors: Shukla V, Rao M, Zhang H, Beers J, Wangsa D, Wangsa D, Buishand FO, Wang Y, Yu Z, Stevenson HS, Reardon ES, McLoughlin KC, Kaufman AS, Payabyab EC, Hong JA, Zhang M, Davis S, Edelman D, Chen G, Miettinen MM, Restifo NP, Ried T, Meltzer PA, Schrump DS

Abstract
In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSCs (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAECs. Of particular novelty, we identified the PRC2-associated protein, ASXL3, which was markedly upregulated in Lu-iPSCs and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSCs, and diminished clonogenicity and malignant growth of SCLC cells in vivo Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and highlight ASXL3 as a novel candidate target for SCLC therapy. Cancer Res; 77(22); 6267-81. ©2017 AACR.

PMID: 28935813 [PubMed - indexed for MEDLINE]

Favourable long-term outcome after coronary artery bypass grafting in a nationwide cohort.

Wed, 12/13/2017 - 13:45
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Favourable long-term outcome after coronary artery bypass grafting in a nationwide cohort.

Scand Cardiovasc J. 2017 Dec;51(6):327-333

Authors: Johannesdottir H, Arnadottir LO, Adalsteinsson JA, Axelsson TA, Sigurdsson MI, Helgadottir S, Helgason D, Gardarsdottir HR, Marteinsson SA, Geirsson A, Thorgeirsson G, Gudbjartsson T

Abstract
OBJECTIVES: In a nationwide cohort, we analyzed long-term outcome following coronary artery bypass grafting, using the combined strategy of left internal mammary artery to the left anterior descending artery and saphenous vein as secondary graft to other coronary targets.
METHODS: 1,507 consecutive patients that underwent myocardial revascularization during 2001-2012 in Iceland. Mean follow-up was 6.8 years. Major adverse cardiac and cerebrovascular events were depicted using the Kaplan-Meier method. Cox-regression was used to define risk factors. Relative survival was estimated by comparing overall survival to the survival of Icelanders of the same age and gender.
RESULTS: Mean age was 66 years, 83% were males, mean EuroSCOREst was 4.5, and 23% of the procedures were performed off-pump. At 5 years, 19.7% had suffered a major adverse cardiac or cerebrovascular event, 4.5% a stroke, 2.2% myocardial infarction, and 6.2% needed repeat revascularization. Overall 5-year survival was 89.9%, with a relative survival of 0.990. Independent predictors of major adverse cardiac and cerebrovascular events were left ventricular ejection fraction ≤30%, a previous history of percutaneous coronary intervention, chronic obstructive lung disease, chronic kidney disease, diabetes, and old age. The same variables and an earlier year of operation were predictors of long-term mortality.
CONCLUSIONS: The long-term outcome following myocardial revascularization, using the left internal mammary artery and the great saphenous vein as conduits, is favourable and improving. This is reflected by the 5-year survival of 89.9%, deviating minimally from the survival rate of the general Icelandic population, together with a freedom from major adverse cardiac and cerebrovascular events of 80.3%.

PMID: 28805102 [PubMed - indexed for MEDLINE]

Malignant Pleural Mesothelioma: State of the art and advanced cell therapy.

Wed, 12/13/2017 - 13:45
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Malignant Pleural Mesothelioma: State of the art and advanced cell therapy.

Eur J Med Chem. 2017 Dec 15;142:266-270

Authors: Facchetti G, Petrella F, Spaggiari L, Rimoldi I

Abstract
Malignant Pleural Mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy, with a response rate of 20% of patients and for this reason an efficient treatment is still a challenge. Platinum-based chemotherapy in association with a third-generation antifolate is the front-line standard of care whereas any second-line treatment was approved for MPM thus making it a pathology that evokes the need for new therapeutic agents. Different platinum-drugs were synthesised and tested as an option for patients who are not candidates to cisplatin-based therapy. Among these, monofunctional cationic antineoplastic platinum compounds received a special attention in the last decade. Alternative strategies to the commonly used combination-therapy resulted from the use of Mesenchymal Stromal Cells (MSC) widely used in the field of regenerative medicine and recently proposed as natural carriers for a selective delivery of chemotherapeutic agents and from the use of immune checkpoint and kinase inhibitors. The present short review shed light on the recent state of art and the future perspectives relative to MPM therapy.

PMID: 28800871 [PubMed - indexed for MEDLINE]

Are De Novo DQ Donor-Specific Antibodies the Key to Chronic Lung Allograft Dysfunction?

Wed, 12/13/2017 - 13:45
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Are De Novo DQ Donor-Specific Antibodies the Key to Chronic Lung Allograft Dysfunction?

Am J Respir Crit Care Med. 2016 09 01;194(5):534-5

Authors: Shenoy KV

PMID: 27585379 [PubMed - indexed for MEDLINE]

Human amniotic fluid stem cells labeled with up-conversion nanoparticles for imaging-monitored repairing of acute lung injury.

Wed, 12/13/2017 - 13:45
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Human amniotic fluid stem cells labeled with up-conversion nanoparticles for imaging-monitored repairing of acute lung injury.

Biomaterials. 2016 Sep;100:91-100

Authors: Xu Y, Xiang J, Zhao H, Liang H, Huang J, Li Y, Pan J, Zhou H, Zhang X, Wang JH, Liu Z, Wang J

Abstract
Human amniotic fluid stem (hAFS) cells have generated a great deal of excitement in cell-based therapies and regenerative medicine. Here, we examined the effect of hAFS cells labeled with dual-polymer-coated UCNP-PEG-PEI nanoparticles in a murine model of acute lung injury (ALI). We observed hAFS cells migration to the lung using highly sensitive in vivo upconversion luminescence (UCL) imaging. We demonstrated that hAFS cells remained viable and retained their ability to differentiate even after UCNP-PEG-PEI labeling. More importantly, hAFS cells displayed remarkable positive effects on ALI-damaged lung tissue repair compared with mouse bone marrow mesenchymal stem cells (mBMSCs), which include recovery of the integrity of alveolar-capillary membrane, attenuation of transepithelial leukocyte and neutrophil migration, and down-regulation of proinflammatory cytokine and chemokine expression. Our work highlights a promising role for imaging-guided hAFS cell-based therapy in ALI.

PMID: 27244692 [PubMed - indexed for MEDLINE]

Temporal Changes of Inflammatory Cytokine Profiles in Epithelial Lining Fluid in a Canine Lung Transplant Model.

Tue, 12/12/2017 - 16:48

Temporal Changes of Inflammatory Cytokine Profiles in Epithelial Lining Fluid in a Canine Lung Transplant Model.

Tokai J Exp Clin Med. 2017 Dec 20;42(4):165-175

Authors: Wada A, Kohno M, Oiwa K, Hashimoto R, Koizumi T, Nakamura Y, Nakagawa T, Masuda R, Kaga K, Iwazaki M

Abstract
OBJECTIVES: Ischemia-reperfusion injury resulting in post-transplant lung dysfunction involves a complicated network of cytokines that has yet to be fully investigated. We analyzed temporal changes in cytokine levels in epithelial lining fluid (ELF) from the distal airways of a canine lung transplantation model.
METHODS: Ischemic time was set to 18 hours to enhance lung injury in a left single-lung transplantation model. ELF was collected via bronchoscopic microsampling, a minimally-invasive technique allowing repeated sampling, hourly up to 5 hours after reperfusion started. We compared levels of pro-inflammatory cytokines in ELF with those at baseline (time zero), and with a sham-operated control group.
RESULTS: Concentrations of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) significantly increased immediately after the start of lung reperfusion in the transplant group relative to the sham group (P < 0.005 and P < 0.05, respectively); both were sustained through the 5 hours. Interferon gamma (IFN-γ levels were significantly reduced 3 h after reperfusion started (P < 0.05).
CONCLUSIONS: We found time- and cytokine-dependent changes in TNF-α, IL-6, and IFN-γ in ELF from the lung transplantation model. These specific changes in the cytokine profile may relate to the mechanism underlying post-transplant lung dysfunction.

PMID: 29228414 [PubMed - in process]

Myeloid Neoplasms Following Solid Organ Transplantation: Clinicopathologic Studies of 23 Cases.

Tue, 12/12/2017 - 16:48

Myeloid Neoplasms Following Solid Organ Transplantation: Clinicopathologic Studies of 23 Cases.

Am J Clin Pathol. 2017 Dec 07;:

Authors: Wu B, Ingersoll K, Jug R, Yang LH, Luedke C, Lo A, Su P, Liu X, Rehder C, Gong J, Lu CM, Wang E

Abstract
Objectives: Myeloid neoplasms (MNs) after solid organ transplant are rare, and their clinicopathologic features have not been well characterized.
Methods: We retrospectively analyzed 23 such cases.
Results: The ages ranged from 2 to 76 years, with a median of 59 years at the diagnosis. The median interval between the transplant and diagnosis was 56 months (range, 8-384 months). The transplanted organs included liver in five, kidney in six, lung in five, heart in six, and heart/lung in one case(s). The types of MN included acute myeloid leukemia (AML) in 12, myelodysplastic syndrome (MDS) in five, chronic myelogenous leukemia (CML) in four, and myeloproliferative neoplasms (MPNs) in two cases. Cytogenetics demonstrated clonal abnormalities in 18 (78.3%) cases, including unbalanced changes in 10 (55.6%), Philadelphia chromosome in four (22.2%), and other balanced aberrations in four (22.2%) cases. Thirteen (56.5%) patients died, with an estimated median survival of 9 months. With disease stratification, AML and MDS have short median survivals (3.5 and 7 months, respectively), with an initial precipitous decline of the survival curve.
Conclusions: Posttransplant MNs have a latency period between that seen in AML/MDS related to alkylators and that associated with topoisomerase II inhibitors. The cytogenetic profile suggests a mutagenic effect on leukemogenesis. The clinical outcome for AML/MDS is dismal, with death occurring at an early phase of treatment.

PMID: 29228125 [PubMed - as supplied by publisher]

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