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Applications of Ventilation-Perfusion Scintigraphy in Surgical Management of Chronic Obstructive Lung Disease and Cancer.

Wed, 10/04/2017 - 12:45

Applications of Ventilation-Perfusion Scintigraphy in Surgical Management of Chronic Obstructive Lung Disease and Cancer.

Semin Nucl Med. 2017 Nov;47(6):671-679

Authors: Tulchinsky M, Fotos JS, Wechalekar K, Dadparvar S

Abstract
Ventilation-perfusion scintigraphy (VPS) depicts the two main physiological processes that are fundamental to oxygen-dependent life. The test has affirmed its critical place in the evaluation of patients with lung cancer preparing for lung resection. The results of the study can differentiate patients who are very likely to survive surgery and the subsequent pulmonary function loss from those who are not. This review presents validated and evolving testing techniques for this critical indication. VPS has long been an integral part of the preoperative evaluation of lung transplant candidates, guiding the single lung grafts to the side with the worst function. New applications are emerging in the rapidly developing surgical and interventional management of severe chronic obstructive lung diseases. Enhanced by the advancements in hybrid imaging and computer processing, the VPS examination continues to be reinvented and updated to keep pace with the needs of modern medicine.

PMID: 28969765 [PubMed - in process]

Preoperative Pulmonary Rehabilitation for Lung Transplant: Effects on Pulmonary Function, Exercise Capacity, and Quality of Life; First Results in Turkey.

Wed, 10/04/2017 - 12:45

Preoperative Pulmonary Rehabilitation for Lung Transplant: Effects on Pulmonary Function, Exercise Capacity, and Quality of Life; First Results in Turkey.

Exp Clin Transplant. 2017 Sep 30;:

Authors: Pehlivan E, Balcı A, Kılıç L, Kadakal F

Abstract
OBJECTIVES: The frequency and success rates of lung transplant in patients with end-stage lung disease are increasing. In our study, we investigated the effects of preoperative pulmonary rehabilitation on pulmonary function, exercise capacity, and quality of life in patients who are candidates for lung transplant.
MATERIALS AND METHODS: This prospective study included 39 consecutive patients who were candidates for lung transplant. All patients underwent preoperative pulmonary rehabilitation for at least 3 weeks.
RESULTS: Our patient group included 25 male and 14 female patients with a mean age of 36 years (range, 15 -68 y). Although no significant improvement was shown in the forced expiratory volume in 1 second after pulmonary rehabilitation, significant improvements were observed in the Modified Medical Research Council dyspnea scores (P = .001) and 6-minute walk distance (P = .001). We also observed statistically significant improvements in the Short-Form 36 Quality of Life Questionnaire's physical function (P = .01) and emotional role (P = .02) subparameters. We also found a significant improvement in the Beck Depression Inventory score (P = .004). There was no correlation between Beck Depression Inventory scores before and after rehabilitation and 6-minute walk distance, Short-Form 36, and Modified Medical Research Council dyspnea scores.
CONCLUSIONS: Our results suggest that preoperative pulmonary rehabilitation improves exercise capacity, reduces the sensation of dyspnea and muscle strength loss, and has a positive effect on the psychologic state of patients who are candidates for lung transplant.

PMID: 28969527 [PubMed - as supplied by publisher]

Polymorphisms in Genes Related to Epithelial-Mesenchymal Transition and Risk of Non-Small Cell Lung Cancer.

Tue, 10/03/2017 - 12:45

Polymorphisms in Genes Related to Epithelial-Mesenchymal Transition and Risk of Non-Small Cell Lung Cancer.

Carcinogenesis. 2017 Aug 04;:

Authors: Xie K, Ye Y, Zeng Y, Gu J, Yang H, Wu X

Abstract
The epithelial-mesenchymal transition (EMT) process is a crucial step for tumor invasion and metastasis. Previous research investigating EMT has mostly focused on its role in cancer progression. Recent studies showed that EMT and EMT-driving transcription factor expression are early events in lung cancer pathogenesis, implying a potential association between EMT and lung cancer risk. In this study, we examined whether genetic variants in EMT-related genes are associated with risk of non-small cell lung cancer (NSCLC). We used data from a genome-wide association study (GWAS) of 1482 NSCLC cases and 1544 healthy controls as the discovery phase, in which we analyzed 1602 single nucleotide polymorphisms (SNPs) within 159 EMT-related genes. We then validated the significant SNPs in another 5699 cases and 5815 controls from the NCI lung cancer GWAS. Cumulative effects were evaluated for validated SNPs, and a gene-based test was performed to explore gene-level association with disease risk. In the discovery phase, 174 SNPs demonstrated significant associations with NSCLC risk. In the validation phase, seven SNPs mapped to EGFR, NOTCH3, ADGRF1 and SMAD3 were confirmed. Cumulative effects analysis of the significant SNPs demonstrated increasing risk with the number of unfavorable genotypes in the discovery and validation datasets. Gene-based analysis implicated ADGRF1, NOTCH3 and CDH1 as significant for NSCLC risk. Functional prediction revealed several potential mechanisms underlying these associations. Our results suggest that EMT-related gene variants may be involved in susceptibility to NSCLC; if confirmed, they might help identify higher-risk individuals.

PMID: 28968839 [PubMed - as supplied by publisher]

Disseminated toxoplasmosis in a heart transplant patient despite co-trimoxazole prophylaxis: A case report.

Tue, 10/03/2017 - 12:45

Disseminated toxoplasmosis in a heart transplant patient despite co-trimoxazole prophylaxis: A case report.

Biomedica. 2017 Sep 01;37(3):303-307

Authors: Dávila V, Roncancio-Villamil G, Correa LA, Restrepo C, Madrid CA, González JM

Abstract
We report the case of a 61 year-old male who underwent heart transplantation eight months before developing a systemic condition with central nervous system, lung, kidney, colonic, cutaneous, and hematologic involvement, found to be secondary to a systemic toxoplasmosis despite co-trimoxazole prophylaxis in a previous-to-transplant seronegative patient receiving a heart from a seropositive donor. A review of prophylactic options in our environment is discussed.

PMID: 28968006 [PubMed - in process]

Pulmonary Pathologic Manifestations of Anti-Alanyl-tRNA Synthetase (Anti-PL-12)-Related Inflammatory Myopathy.

Tue, 10/03/2017 - 12:45

Pulmonary Pathologic Manifestations of Anti-Alanyl-tRNA Synthetase (Anti-PL-12)-Related Inflammatory Myopathy.

Arch Pathol Lab Med. 2017 Oct 02;:

Authors: Schneider F, Yousem SA, Oddis CV, Aggarwal R

Abstract
CONTEXT: - Patients with anti-aminoacyl-tRNA synthetase syndrome (ARS), a subset of idiopathic inflammatory myopathy, have a high prevalence of lung involvement. Autoantibodies directed against alanyl-tRNA synthetase (anti-PL-12 Abs) represent 1 of the 8 autoantibodies currently described under the rubric of ARS.
OBJECTIVE: - To describe the clinical, radiographic, and pulmonary histopathologic findings in patients possessing anti-PL-12 autoantibodies.
DESIGN: - Patients with anti-PL-12 ARS were identified in the University of Pittsburgh Idiopathic Inflammatory Myopathy registry. Lung biopsies from 10 patients and lung explants from 2 patients with anti-PL-12 ARS were reviewed, together with chest computed tomography and clinical records.
RESULTS: - Patients primarily presented with dyspnea and variable combinations of cough, fever, mechanic's hands, Raynaud phenomenon, and skin and muscle involvement. Chest computed tomography most commonly showed lower lung zone-predominant reticular infiltrates and traction bronchiectasis, with or without honeycomb change. Surgical lung biopsies and pneumonectomies for lung transplantation revealed usual interstitial pneumonia in 8 of 12 cases (67%), nonspecific interstitial pneumonia in 2 of 12 cases (17%), and organizing pneumonia in 2 of 12 cases (17%). Lymphoplasmacytic interstitial inflammation with lymphoid aggregates was common.
CONCLUSIONS: - Lung disease is often the first manifestation of anti-PL-12 ARS. There are no pathognomonic histopathologic features to distinguish anti-PL-12 ARS-related lung disease from idiopathic variants of diffuse interstitial lung disease. Increased inflammation, lymphoid aggregates, and nonspecific interstitial pneumonia-like areas in a biopsy, as well as clinical features of mechanic's hands, Raynaud phenomenon, arthritis, and fever, should prompt pathologists to suggest involvement by ARS.

PMID: 28967806 [PubMed - as supplied by publisher]

Kang G, Ha R, Banerjee D. Pulmonary Artery Pulsatility Index Predicts Right Ventricular Failure After Left Ventricular Assist Device Implantation. J Heart Lung Transplant 2016;35(1):67-73.

Tue, 10/03/2017 - 12:45

Kang G, Ha R, Banerjee D. Pulmonary Artery Pulsatility Index Predicts Right Ventricular Failure After Left Ventricular Assist Device Implantation. J Heart Lung Transplant 2016;35(1):67-73.

J Heart Lung Transplant. 2017 Sep 26;:

Authors:

PMID: 28967483 [PubMed - as supplied by publisher]

Just a number? The impact of age on lung transplantation.

Tue, 10/03/2017 - 12:45

Just a number? The impact of age on lung transplantation.

J Thorac Cardiovasc Surg. 2017 Aug 26;:

Authors: van Berkel V

PMID: 28967428 [PubMed - as supplied by publisher]

Overhydration, underhydration, and total body sodium: A tricky "ménage a trois" in dialysis patients.

Tue, 10/03/2017 - 12:45

Overhydration, underhydration, and total body sodium: A tricky "ménage a trois" in dialysis patients.

Semin Dial. 2017 Oct 01;:

Authors: Voroneanu L, Gavrilovici C, Covic A

Abstract
Overhydration is a frequent complication in dialysis patients. It has been linked with hypertension, left ventricular hypertrophy, arterial stiffness, atherosclerosis uremic cardiomyopathy, and all-cause mortality or cardiovascular morbidity. In addition, predialysis underhydration is also associated with increased risk of death in ESRD patients. In this context, the optimal evaluation of hydration status is a must. However, this mission is not easy or accurate. In the last 10 years, several new methods have been tested in dialysis patients, particularly bioimpedance and lung ultrasonography. The precise clinical value of these techniques in the daily care of hemodialysis patients is not obvious yet. Sodium is also an important piece of this puzzle. Salt intake and/or removal of sodium during dialysis are essential determinants of optimal hydration status. Recent studies have revealed that salt and water homeostasis is also dependent of tissue sodium storage-increased in hemodialysis patients. However, the significance of increased sodium tissue storage as a cardiovascular risk factor and the relationship between tissue sodium content and hard CV endpoint have not yet been elucidated yet.

PMID: 28967233 [PubMed - as supplied by publisher]

Late recurrence of hepatocellular carcinoma after liver transplantation.

Tue, 10/03/2017 - 12:45

Late recurrence of hepatocellular carcinoma after liver transplantation.

Hepatoma Res. 2017;3:58-66

Authors: Zhang JA, Kwee SA, Wong LL

Abstract
AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and liver transplant (LT) prolongs survival. However, 15-20% will experience recurrent HCC, most occurring within 2 years of LT. HCC patients with late recurrences (>5 years after LT) may have distinctive clinical/biological characteristics.
METHODS: A retrospective review was conducted of 88 patients who underwent LT for HCC between 1993-2015, analyzing demographics, clinical factors, explant pathology, and outcome.
RESULTS: Median follow-up was 6.4 years. HCC recurred in 15 (17.0%) patients with mean time to recurrence of 3.96 +/- 3.99 years. Five patients recurred >5 years post-LT. All late recurrences involved males in their 50s, recurring at 8.5 years on average. Recurrences occurred in chest wall (2), liver (2), lung (2), bone (1) and pelvis (1), with multifocal involvement in 2 patients. Four patients died within 18 months of late recurrence. The fifth patient is alive after ablation of liver recurrence and treatment with sorafenib and everolimus.
CONCLUSIONS: One-third of post-LT patients with recurrent HCC experienced late recurrence. Although the sample size makes it difficult to identify significant risk factors, this study highlights the importance of long-term follow up and need for biomarkers to identify patients at risk for late recurrences.

PMID: 28966983 [PubMed]

Transfusion-associated hypoxemia in pediatric patients with solid tumors after autologous peripheral blood stem cell transplantation.

Tue, 10/03/2017 - 12:45

Transfusion-associated hypoxemia in pediatric patients with solid tumors after autologous peripheral blood stem cell transplantation.

Transfus Apher Sci. 2017 Sep 20;:

Authors: Yanagisawa R, Abe S, Fujihara I, Komori K, Kondo Y, Sakashita K, Nakamura T

Abstract
BACKGROUND: Although several types of transfusion-related adverse reactions (TRARs) have been reported, one of the most important involves respiratory features during and after blood transfusion. Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are the most severe adverse events following blood transfusion, whereas transfusion-associated dyspnea (TAD) is a less severe respiratory distress. However, there exists little evidence of these factors in pediatric populations.
CASE REPORT: Here, two cases of atypical TRARs with respiratory features, in pediatric patients with solid tumors, appearing after transfusion of platelet concentrate following autologous peripheral blood stem cell transplantation are reported. Both patients developed mild hypoxemia during PC transfusion, which continued for approximately 2 weeks. Chest radiography in either patient did not reveal any abnormalities that are included in the criteria of either TRALI or TACO. Both patients recovered following oxygen administration.
CONCLUSION: This complication of TRARs with respiratory features may occur more frequently in pediatric populations than realized because it may be under-recognized or under-reported. Accumulation of additional cases, including non-typical cases, is necessary to fully understand the pathology of TRARs, correctly classify these reactions, and improve care of patients receiving blood transfusions.

PMID: 28965826 [PubMed - as supplied by publisher]

Second annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) report: Pre-implant characteristics and outcomes.

Tue, 10/03/2017 - 12:45

Second annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) report: Pre-implant characteristics and outcomes.

J Heart Lung Transplant. 2017 Jul 04;:

Authors: Blume ED, VanderPluym C, Lorts A, Baldwin JT, Rossano JW, Morales DLS, Cantor RS, Miller MA, St Louis JD, Koehl D, Sutcliffe DL, Eghtesady P, Kirklin JK, Rosenthal DN, Pedimacs Investigators

Abstract
BACKGROUND: Expanded use of pediatric ventricular assist devices (VADs) has decreased mortality in children awaiting heart transplantation. Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs), a National Heart, Lung, and Blood Institute-sponsored North American database, provides a platform to understand this emerging population.
METHODS: Between September 2012 and September 2016, patients aged younger than 19 years who underwent VAD implantation were enrolled in Pedimacs. FDA approved durable devices as well as temporary support devices were included. The second annual report updates the current Pedimacs data. Patients implanted with temporary devices are included in Pedimacs and this analysis includes this group of paracorporeal continuous flow VADs.
RESULTS: Over the 4 years, 42 hospitals implanted 432 devices in 364 patients less than 19 yrs of age. Diagnoses included cardiomyopathy in 223 (61%), myocarditis in 41 (11%), and congenital heart disease in 77 (21%), of which 48 had single-ventricle physiology. At implant, 87% were at Intermacs patient profile 1 or 2. The age distribution of children (59% male) supported on VAD included 69 (19%) aged younger than 1 year, 66 (18%) aged 1 to 6 years, 56 (15%) aged 6 to 10 years, and 173 (48%) aged 11 to 19 years. Median follow-up was 2.2 months (range, 1 day to 41.5 months). Median (interquartile) age at implant was 1.7 (0.3-10.0) years for paracorporeal continuous-flow pumps (n = 60), 1.7 (0.4-5.3) years for paracorporeal pulsatile pumps (n = 105), and 15.0 (11.3-16.9) years for implantable continuous-flow pumps (n = 174). Support strategies included LVAD in 293 (80%), biventricular device in 55 (15%), and total artificial heart in 8 (2%). Nearly 50% of patients underwent transplantation within 6 months, with overall mortality of 19%. Adverse event burden continues to be high.
CONCLUSIONS: Pedimacs constitutes the largest longitudinal pediatric VAD registry. Preimplant data across centers will be helpful at creating shared protocols with which to improve outcomes. Adverse events continue to be the major challenge, especially among the young critically ill children with complex congenital disease.

PMID: 28965736 [PubMed - as supplied by publisher]

Endostatin sensitizes p53-deficient non-small-cell lung cancer to genotoxic chemotherapy by targeting DNA-dependent protein kinase catalytic subunit.

Tue, 10/03/2017 - 12:45
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Endostatin sensitizes p53-deficient non-small-cell lung cancer to genotoxic chemotherapy by targeting DNA-dependent protein kinase catalytic subunit.

J Pathol. 2017 Oct;243(2):255-266

Authors: Jia L, Lu XA, Liu G, Wang S, Xu M, Tian Y, Zhang S, Fu Y, Luo Y

Abstract
Endostatin was discovered as an endogenous angiogenesis inhibitor with broad-spectrum antitumour activities. Although clinical efficacy was observed when endostatin was combined with standard chemotherapy for non-small cell lung cancer (NSCLC), as well as other cancer types, the specific mechanisms underlying the benefit of endostatin are not completely understood. Extensive investigations suggest that endostatin is a multifunctional protein possessing more than anti-angiogenic activity. Here, we found that endostatin exerts a direct chemosensitizing effect on p53-deficient tumour cells. Concomitant treatment with endostatin and genotoxic drugs resulted in therapeutic synergy in both cellular and animal models of p53-deficient NSCLC. Mechanistically, endostatin specifically interacts with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in tumour cells and suppresses its DNA repair activity. Using isogenic NSCLC cells with different p53 statuses, we discovered that p53-deficient tumour cells show chemoresistance to genotoxic drugs, creating a synthetic dependence on DNA-PKcs-mediated DNA repair. In this setting, endostatin exerted inhibitory effects on DNA-PKcs activity, leading to accumulation of DNA lesions and promotion of the therapeutic effect of genotoxic chemotherapy. In contrast, p53-proficient tumour cells were more sensitive to genotoxic drugs so that DNA-PKcs could be cleaved by drug-activated caspase-3, making DNA-PKcs inhibition less effective during this ongoing apoptotic process. Therefore, our data demonstrate a novel mechanism for endostatin as a DNA-PKcs suppressor, and indicate that combination therapy of endostatin with genotoxic drugs could be a promising treatment strategy for cancer patients with p53-deficient tumours. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PMID: 28771739 [PubMed - indexed for MEDLINE]

In- and ex-vivo molecular imaging of apoptosis to assess sensitivity of non-small cell lung cancer to EGFR inhibitors using probe-based confocal laser endomicroscopy.

Tue, 10/03/2017 - 12:45
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In- and ex-vivo molecular imaging of apoptosis to assess sensitivity of non-small cell lung cancer to EGFR inhibitors using probe-based confocal laser endomicroscopy.

PLoS One. 2017;12(7):e0180576

Authors: Guisier F, Bohn P, Patout M, Piton N, Farah I, Vera P, Thiberville L, Salaün M

Abstract
BACKGROUND: Prediction of treatment outcome of non-small cell lung cancer (NSCLC) with EGFR inhibitors on the basis of the genetic analysis of the tumor can be incorrect in case of rare or complex mutations, bypass molecular activation pathways, or pharmacodynamic variations. The aim of this study was to develop an ex vivo and in vivo real-time quantitative imaging test for EGFR inhibitors sensitivity assessment.
METHODS: Erlotinib resistant (A549, H460, H1975), insensitive (H1650) and hypersensitive (HCC827) cell lines were injected subcutaneously in Nude mice. Tumor xenografts from mice treated with Erlotinib were imaged ex vivo and in vivo using probe-based confocal laser endomicroscopy (pCLE) and NucView 488 Caspase 3 substrate, a fluorescent probe specific for the activated caspase 3.
RESULTS: Assessment of apoptosis at 24h post treatment, both ex vivo in explanted tumor xenografts and in vivo, showed a significant difference between resistant cell lines (A549, H460 and H1975) and insensitive (H1650) or hypersensitive (HCC827) ones (p<0.05 for ex vivo imaging, p≤0.02 for in vivo imaging). There was also a significant difference between insensitive and hypersensitive cell lines, both ex vivo (p<0.05) and in vivo (p = 0.01).
CONCLUSION: Real-time in vivo and ex vivo assessment of apoptosis using pCLE differentiates resistant from sensitive NSCLC xenografts to Erlotinib.

PMID: 28671975 [PubMed - indexed for MEDLINE]

Mesenchymal stem cells improves survival in LPS-induced acute lung injury acting through inhibition of NETs formation.

Tue, 10/03/2017 - 12:45
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Mesenchymal stem cells improves survival in LPS-induced acute lung injury acting through inhibition of NETs formation.

J Cell Physiol. 2017 12;232(12):3552-3564

Authors: Pedrazza L, Cunha AA, Luft C, Nunes NK, Schimitz F, Gassen RB, Breda RV, Donadio MV, de Souza Wyse AT, Pitrez PMC, Rosa JL, de Oliveira JR

Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are syndromes of acute hypoxemic respiratory failure resulting from a variety of direct and indirect injuries to the gas exchange parenchyma of the lungs. During the ALI, we have an increase release of proinflammatory cytokines and high reactive oxygen species (ROS) formation. These factors are responsible for the release and activation of neutrophil-derived proteases and the formation of neutrophil extracellular traps (NETs). The excessive increase in the release of NETs cause damage to lung tissue. Recent studies have studies involving the administration of mesenchymal stem cells (MSCs) for the treatment of experimental ALI has shown promising results. In this way, the objective of our study is to evaluate the ability of MSCs, in a lipopolysaccharide (LPS)-induced ALI model, to reduce inflammation, oxidative damage, and consequently decrease the release of NETs. Mice were submitted lung injury induced by intratracheal instillation of LPS and subsequently treated or not with MSCs. Treatment with MSCs was able to modulate pulmonary inflammation, decrease oxidative damage, and reduce the release of NETs. These benefits from treatment are evident when we observe a significant increase in the survival curve in the treated animals. Our results demonstrate that MSCs treatment is effective for the treatment of ALI. For the first time, it is described that MSCs can reduce the formation of NETs and an experimental model of ALI. This finding is directly related to these cells modulate the inflammatory response and oxidative damage in the course of the pathology.

PMID: 28112391 [PubMed - indexed for MEDLINE]

TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction.

Tue, 10/03/2017 - 12:45
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TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction.

Cardiovasc Res. 2017 Jan;113(1):15-29

Authors: Rogers NM, Sharifi-Sanjani M, Yao M, Ghimire K, Bienes-Martinez R, Mutchler SM, Knupp HE, Baust J, Novelli EM, Ross M, St Croix C, Kutten JC, Czajka CA, Sembrat JC, Rojas M, Labrousse-Arias D, Bachman TN, Vanderpool RR, Zuckerbraun BS, Champion HC, Mora AL, Straub AC, Bilonick RA, Calzada MJ, Isenberg JS

Abstract
AIMS: Thrombospondin-1 (TSP1) is a ligand for CD47 and TSP1(-/-) mice are protected from pulmonary hypertension (PH). We hypothesized the TSP1-CD47 axis is upregulated in human PH and promotes pulmonary arterial vasculopathy.
METHODS AND RESULTS: We analyzed the molecular signature and functional response of lung tissue and distal pulmonary arteries (PAs) from individuals with (n = 23) and without (n = 16) PH. Compared with controls, lungs and distal PAs from PH patients showed induction of TSP1-CD47 and endothelin-1/endothelin A receptor (ET-1/ETA) protein and mRNA. In control PAs, treatment with exogenous TSP1 inhibited vasodilation and potentiated vasoconstriction to ET-1. Treatment of diseased PAs from PH patients with a CD47 blocking antibody improved sensitivity to vasodilators. Hypoxic wild type (WT) mice developed PH and displayed upregulation of pulmonary TSP1, CD47, and ET-1/ETA concurrent with down regulation of the transcription factor cell homolog of the v-myc oncogene (cMyc). In contrast, PH was attenuated in hypoxic CD47(-/-) mice while pulmonary TSP1 and ET-1/ETA were unchanged and cMyc was overexpressed. In CD47(-/-) pulmonary endothelial cells cMyc was increased and ET-1 decreased. In CD47(+/+ )cells, forced induction of cMyc suppressed ET-1 transcript, whereas suppression of cMyc increased ET-1 signaling. Furthermore, disrupting TSP1-CD47 signaling in pulmonary smooth muscle cells abrogated ET-1-stimulated hypertrophy. Finally, a CD47 antibody given 2 weeks after monocrotaline challenge in rats upregulated pulmonary cMyc and improved aberrations in PH-associated cardiopulmonary parameters.
CONCLUSIONS: In pre-clinical models of PH CD47 targets cMyc to increase ET-1 signaling. In clinical PH TSP1-CD47 is upregulated, and in both, contributes to pulmonary arterial vasculopathy and dysfunction.

PMID: 27742621 [PubMed - indexed for MEDLINE]

Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators.

Tue, 10/03/2017 - 12:45
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Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators.

BMC Cancer. 2016 Aug 11;16:623

Authors: Wu J, Jordan M, Waxman DJ

Abstract
BACKGROUND: Cyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). In contrast, we find that two other syngeneic B6 mouse tumors, LLC lung carcinoma and B16F10 melanoma, do not exhibit these drug-induced immune responses despite their intrinsic sensitivity to CPA cytotoxicity.
METHODS: To elucidate underlying mechanisms, we investigated gene expression and molecular pathway changes associated with the disparate immune responsiveness of these tumors to CPA/6d treatment.
RESULTS: Global transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong CPA/6d activation of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment is shown to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) - which results in a strong but transient natural killer cell response followed by early tumor growth rebound - induced fewer cytokines and increased expression of drug metabolism genes.
CONCLUSIONS: These findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules.

PMID: 27515027 [PubMed - indexed for MEDLINE]

Phenotypic Clusters Predict Outcomes in a Longitudinal Interstitial Lung Disease Cohort.

Mon, 10/02/2017 - 12:45

Phenotypic Clusters Predict Outcomes in a Longitudinal Interstitial Lung Disease Cohort.

Chest. 2017 Sep 27;:

Authors: Adegunsoye A, Oldham JM, Chung JH, Montner SM, Lee C, Witt LJ, Stahlbaum D, Bermea RS, Chen LW, Hsu S, Husain AN, Noth I, Vij R, Strek ME, Churpek M

Abstract
BACKGROUND: The current interstitial lung disease (ILD) classification has overlapping clinical presentations and outcomes. Cluster analysis modeling is a valuable tool in identifying distinct clinical phenotypes in heterogeneous diseases. However, this approach has yet to be implemented in ILD.
METHODS: Using cluster analysis, we identified novel ILD phenotypes among subjects from a longitudinal ILD cohort and stratified outcomes by phenotypic clusters compared to subgroups by current American Thoracic Society (ATS)/European Respiratory Society (ERS) ILD classification criteria.
RESULTS: Among subjects with complete data for baseline variables (n=770), four clusters were identified. Cluster 1: "younger Caucasian obese females" had the highest baseline forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO). Cluster 2: "younger African-American females with elevated antinuclear antibody titers" had the lowest baseline FVC. Cluster 3: "elderly Caucasian male smokers with coexistent emphysema" had intermediate FVC and DLCO. Cluster 4: "elderly Caucasian male smokers with severe honeycombing" had the lowest baseline DLCO. Compared to classification by ILD subgroup, stratification by phenotypic clusters was associated with significant differences in monthly FVC decline (Cluster 4, -0.30% vs Cluster 2, +0.01%; P<0.0001). Stratification by clusters also independently predicted progression-free survival (P<0.001), and transplant-free survival (P<0.001).
CONCLUSIONS: Among adults with diverse chronic ILDs, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might better predict meaningful clinical outcomes than current ILD diagnostic criteria.

PMID: 28964798 [PubMed - as supplied by publisher]

Controversy regarding amiodarone use before heart transplantation.

Mon, 10/02/2017 - 12:45

Controversy regarding amiodarone use before heart transplantation.

J Heart Lung Transplant. 2017 Sep 13;:

Authors: Spartalis M, Tzatzaki E, Nikiteas NI, Spartalis E

PMID: 28964646 [PubMed - as supplied by publisher]

Proteinuria in left ventricular assist device candidates: An emerging risk factor for renal failure and mortality.

Mon, 10/02/2017 - 12:45

Proteinuria in left ventricular assist device candidates: An emerging risk factor for renal failure and mortality.

J Heart Lung Transplant. 2017 Sep 14;:

Authors: Topkara VK, Colombo PC

PMID: 28964645 [PubMed - as supplied by publisher]

Should induction therapy be the standard protocol in pediatric heart transplant recipients?

Mon, 10/02/2017 - 12:45

Should induction therapy be the standard protocol in pediatric heart transplant recipients?

J Heart Lung Transplant. 2017 Sep 13;:

Authors: Darragh R

PMID: 28964644 [PubMed - as supplied by publisher]

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