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Identification of miRNAs Potentially Involved in Bronchiolitis Obliterans Syndrome: A Computational Study.

Wed, 08/09/2017 - 12:45
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Identification of miRNAs Potentially Involved in Bronchiolitis Obliterans Syndrome: A Computational Study.

PLoS One. 2016;11(8):e0161771

Authors: Di Carlo S, Rossi E, Politano G, Inghilleri S, Morbini P, Calabrese F, Benso A, Savino A, Cova E, Zampieri D, Meloni F

Abstract
The pathogenesis of Bronchiolitis Obliterans Syndrome (BOS), the main clinical phenotype of chronic lung allograft dysfunction, is poorly understood. Recent studies suggest that epigenetic regulation of microRNAs might play a role in its development. In this paper we present the application of a complex computational pipeline to perform enrichment analysis of miRNAs in pathways applied to the study of BOS. The analysis considered the full set of miRNAs annotated in miRBase (version 21), and applied a sequence of filtering approaches and statistical analyses to reduce this set and to score the candidate miRNAs according to their potential involvement in BOS development. Dysregulation of two of the selected candidate miRNAs-miR-34a and miR-21 -was clearly shown in in-situ hybridization (ISH) on five explanted human BOS lungs and on a rat model of acute and chronic lung rejection, thus definitely identifying miR-34a and miR-21 as pathogenic factors in BOS and confirming the effectiveness of the computational pipeline.

PMID: 27564214 [PubMed - indexed for MEDLINE]

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma.

Wed, 08/09/2017 - 12:45
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Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma.

Mol Cancer Res. 2016 May;14(5):448-57

Authors: Zhou X, Guo J, Ji Y, Pan G, Liu T, Zhu H, Zhao J

Abstract
UNLABELLED: The epidermal growth factor receptor (EGFR) activates downstream mTOR phosphorylation to promote the progression of many different tumor types, thus making it a prime therapeutic target. However, the role of DEP domain-containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, remains unclear in this process. Here, it is reported that EGFR expression is significantly increased in tumors of lung adenocarcinoma patients and is negatively correlated with the expression of DEPTOR. Activation of EGFR signaling, by EGF, in A549 lung adenocarcinoma cells (overexpressing EGFR) significantly enhanced the function of the mTOR autoamplification loop, consisting of S6K, mTOR, CK1α, and βTrCP1, which resulted in downregulation of DEPTOR expression. Gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of the mTOR autoamplification loop. Furthermore, a series of assays conducted in DEPTOR knockout or ectopic expression in A549 cells confirmed that DEPTOR inhibited proliferation, migration, and invasion as well as the in vivo tumor growth of lung adenocarcinoma. Importantly, tumor progression mediated by EGFR ectopic expression was diminished by transfection with DEPTOR. This study uncovers the important inhibitory role of DEPTOR in lung adenocarcinoma progression and reveals a novel mechanism that EGFR downregulates DEPTOR expression to facilitate tumor growth.
IMPLICATIONS: DEPTOR acts as a tumor suppressor by limiting EGFR-driven lung adenocarcinoma progression. Mol Cancer Res; 14(5); 448-57. ©2016 AACR.

PMID: 26896556 [PubMed - indexed for MEDLINE]

Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment.

Tue, 08/08/2017 - 15:46
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Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment.

Sci Immunol. 2016 Dec 16;1(6):

Authors: Heidkamp GF, Sander J, Lehmann CHK, Heger L, Eissing N, Baranska A, Lühr JJ, Hoffmann A, Reimer KC, Lux A, Söder S, Hartmann A, Zenk J, Ulas T, McGovern N, Alexiou C, Spriewald B, Mackensen A, Schuler G, Schauf B, Forster A, Repp R, Fasching PA, Purbojo A, Cesnjevar R, Ullrich E, Ginhoux F, Schlitzer A, Nimmerjahn F, Schultze JL, Dudziak D

Abstract
In mice, conventional and plasmacytoid dendritic cells (DCs) derive from separate hematopoietic precursors before they migrate to peripheral tissues. Moreover, two classes of conventional DCs (cDC1 and cDC2 DCs) and one class of plasmacytoid DCs (pDCs) have been shown to be transcriptionally and functionally distinct entities. In humans, these three DC subtypes can be identified using the cell surface markers CD1c (cDC2), CD141 (cDC1), and CD303 (pDCs), albeit it remains elusive whether DC functionality is mainly determined by ontogeny or the tissue microenvironment. By phenotypic and transcriptional profiling of these three DC subtypes in different human tissues derived from a large number of human individuals, we demonstrate that DC subpopulations in organs of the lymphohematopoietic system (spleen, thymus, and blood) are strongly defined by ontogeny rather than by signals from the microenvironment. In contrast, DC subsets derived from human lung or skin differed substantially, strongly arguing that DCs react toward modulatory signals from tissue microenvironments. Collectively, the data obtained in this study may serve as a major resource to guide further studies into human DC biology during homeostasis and inflammation.

PMID: 28783692 [PubMed]

A TSLP-complement axis mediates neutrophil killing of methicillin-resistant Staphylococcus aureus.

Tue, 08/08/2017 - 15:46
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A TSLP-complement axis mediates neutrophil killing of methicillin-resistant Staphylococcus aureus.

Sci Immunol. 2016 Nov 18;1(5):

Authors: West EE, Spolski R, Kazemian M, Yu ZX, Kemper C, Leonard WJ

Abstract
Community-acquired Staphylococcus aureus infections often present as serious skin infections in otherwise healthy individuals and have become a worldwide epidemic problem fueled by the emergence of strains with antibiotic resistance, such as methicillin-resistant S. aureus (MRSA). The cytokine thymic stromal lymphopoietin (TSLP) is highly expressed in the skin and in other barrier surfaces and plays a deleterious role by promoting T helper cell type 2 (TH2) responses during allergic diseases; however, its role in host defense against bacterial infections has not been well elucidated. We describe a previously unrecognized non-TH2 role for TSLP in enhancing neutrophil killing of MRSA during an in vivo skin infection. Specifically, we demonstrate that TSLP acts directly on both mouse and human neutrophils to augment control of MRSA. Additionally, we show that TSLP also enhances killing of Streptococcus pyogenes, another clinically important cause of human skin infections. Unexpectedly, TSLP mechanistically mediates its antibacterial effect by directly engaging the complement C5 system to modulate production of reactive oxygen species by neutrophils. Thus, TSLP increases MRSA killing in a neutrophil- and complement-dependent manner, revealing a key connection between TSLP and the innate complement system, with potentially important therapeutic implications for control of MRSA infection.

PMID: 28783679 [PubMed]

Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts.

Tue, 08/08/2017 - 15:46
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Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts.

Sci Immunol. 2017 Jun 23;2(12):

Authors: Dai H, Friday AJ, Abou-Daya KI, Williams AL, Mortin-Toth S, Nicotra ML, Rothstein DM, Shlomchik WD, Matozaki T, Isenberg JS, Oberbarnscheidt MH, Danska JS, Lakkis FG

Abstract
Mice devoid of T, B, and natural killer (NK) cells distinguish between self and allogeneic nonself despite the absence of an adaptive immune system. When challenged with an allograft, they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce interleukin-12 and present antigen to T cells. However, the molecular mechanisms by which the innate immune system detects allogeneic nonself to generate these DCs are not known. To address this question, we studied the innate response of Rag2(-/-) γc(-/-) mice, which lack T, B, and NK cells, to grafts from allogeneic donors. By positional cloning, we identified that donor polymorphism in the gene encoding signal regulatory protein α (SIRPα) is a key modulator of the recipient's innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. The response was mediated by binding of donor SIRPα to recipient CD47 and was modulated by the strength of the SIRPα-CD47 interaction. Therefore, sensing SIRPα polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic nonself independently of T, B, and NK cells.

PMID: 28783664 [PubMed]

Response to anti-programmed cell death protein-1 antibodies in men treated for platinum refractory germ cell cancer relapsed after high-dose chemotherapy and stem cell transplantation.

Tue, 08/08/2017 - 15:46
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Response to anti-programmed cell death protein-1 antibodies in men treated for platinum refractory germ cell cancer relapsed after high-dose chemotherapy and stem cell transplantation.

Eur J Cancer. 2017 May;76:1-7

Authors: Zschäbitz S, Lasitschka F, Hadaschik B, Hofheinz RD, Jentsch-Ullrich K, Grüner M, Jäger D, Grüllich C

Abstract
INTRODUCTION: Treatment options for patients with platinum refractory metastatic germ cell tumours (GCT) relapsing after high-dose chemotherapy and autologous stem cell transplantation are limited and survival is poor. Antibodies directed against programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) are currently assessed within clinical trials. We present updated data on our experience with checkpoint inhibitors as a compassionate use off-label treatment attempt for highly-pretreated patients with GCT and provide an overview of the current literature on PD-L1 expression in this rare tumour entity.
PATIENTS AND METHODS: We analysed all patients with platinum refractory GCT treated with checkpoint inhibitors at our institutions between 2015 and 2017. Data were retrieved retrospectively from the patient charts.
RESULTS: Seven patients were treated with nivolumab or pembrolizumab. Four patients received single-dose treatment and died shortly afterwards due to tumour progression; the remaining three patients received treatment for at least 6 months. No significant treatment toxicity was observed. Long-term tumour response was achieved in two of the three patients, both of them highly positive for PD-L1 staining.
INTERPRETATION: We consider checkpoint inhibition to be efficient in carefully selected patients with platinum refractory GCT. However, predictive markers associated with tumour response are not yet known and larger prospective clinical trials are warranted.

PMID: 28262583 [PubMed - indexed for MEDLINE]

Experience with miltefosine for persistent or relapsing visceral leishmaniasis in solid organ transplant recipients: A case series from Spain.

Tue, 08/08/2017 - 15:46
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Experience with miltefosine for persistent or relapsing visceral leishmaniasis in solid organ transplant recipients: A case series from Spain.

Transpl Infect Dis. 2017 Feb;19(1):

Authors: Pérez-Jacoiste Asín MA, Carrasco-Antón N, Fernández-Ruiz M, San Juan R, Alonso-Moralejo R, González E, Andrés A, López-Medrano F, Aguado JM

Abstract
The incidence of visceral leishmaniasis (VL) after solid organ transplantation (SOT) is increasing. The optimal therapy for post-transplant VL remains unclear, as relapses after liposomal amphotericin B (L-AmB) are common. Miltefosine has been shown to be effective for treating VL in immunocompetent patients, although data in the specific population of SOT recipients are lacking. In the setting of an outbreak of leishmaniasis occurring in Southwest Madrid, we reviewed our experience in 6 SOT recipients with persistent or relapsing VL who received a 28-day course of miltefosine (2.5 mg/kg/day) as salvage therapy. All patients had been treated previously with L-AmB as first-line therapy. The incident episode of VL occurred at a median of 14 months after transplantation. Two patients experienced persistent infection and the remaining 4 had a relapse after a median interval of 168 days since the completion of the course of L-AmB. All the patients had an apparent initial clinical improvement with miltefosine. However, VL relapsed in 3 of them (after a median interval of 46 days), which required retreatment with L-AmB-based regimens. Miltefosine therapy was followed by a prolonged secondary prophylaxis with L-AmB in the only 2 cases with sustained clinical response and ongoing immunosuppression. No adverse effects associated with miltefosine were observed. Albeit limited, our experience suggests that miltefosine monotherapy likely has a limited utility to obtain a long-lasting clinical response in complicated (persistent or relapsing) forms of post-transplant VL, although its role in association with L-AmB-based secondary prophylaxis may merit further investigation.

PMID: 27768239 [PubMed - indexed for MEDLINE]

The administration of drugs inhibiting cholesterol/oxysterol synthesis is safe and increases the efficacy of immunotherapeutic regimens in tumor-bearing mice.

Tue, 08/08/2017 - 15:46
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The administration of drugs inhibiting cholesterol/oxysterol synthesis is safe and increases the efficacy of immunotherapeutic regimens in tumor-bearing mice.

Cancer Immunol Immunother. 2016 Nov;65(11):1303-1315

Authors: Lanterna C, Musumeci A, Raccosta L, Corna G, Moresco M, Maggioni D, Fontana R, Doglioni C, Bordignon C, Traversari C, Russo V

Abstract
Tumor-derived metabolites dampen tumor-infiltrating immune cells and antitumor immune responses. Among the various metabolites produced by tumors, we recently showed that cholesterol oxidized products, namely oxysterols, favor tumor growth through the inhibition of DC migration toward lymphoid organs and by promoting the recruitment of pro-tumor neutrophils within the tumor microenvironment. Here, we tested different drugs capable of blocking cholesterol/oxysterol formation. In particular, we tested efficacy and safety of different administration schedules, and of immunotherapy-based combination of a class of compounds, namely zaragozic acids, which inhibit cholesterol pathway downstream of mevalonate formation, thus leaving intact the formation of the isoprenoids, which are required for the maturation of proteins involved in the immune cell function. We show that zaragozic acids inhibit the in vivo growth of the RMA lymphoma and the Lewis lung carcinoma (LLC) without inducing side effects. Tumor growth inhibition requires an intact immune system, as immunodeficient tumor-bearing mice do not respond to zaragozic acid treatment. Of note, the effect of zaragozic acids is accompanied by a marked reduction in the LXR target genes Abcg1, Mertk, Scd1 and Srebp-1c in the tumor microenvironment. On the other hand, zoledronate, which blocks also isoprenoid formation, did not control the LLC tumor growth. Finally, we show that zaragozic acids potentiate the antitumor effects of active and adoptive immunotherapy, significantly prolonging the overall survival of tumor-bearing mice treated with the combo zaragozic acids and TAA-loaded DCs. This study identifies zaragozic acids as new antitumor compounds exploitable for the treatment of cancer patients.

PMID: 27520505 [PubMed - indexed for MEDLINE]

Uncontrolled donation after circulatory death: European practices and recommendations for the development and optimization of an effective programme.

Tue, 08/08/2017 - 15:46
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Uncontrolled donation after circulatory death: European practices and recommendations for the development and optimization of an effective programme.

Transpl Int. 2016 Aug;29(8):842-59

Authors: Domínguez-Gil B, Duranteau J, Mateos A, Núñez JR, Cheisson G, Corral E, De Jongh W, Del Río F, Valero R, Coll E, Thuong M, Akhtar MZ, Matesanz R

Abstract
The shortage of organs remains one of the biggest challenges in transplantation. To address this, we are increasingly turning to donation after circulatory death (DCD) donors and now in some countries to uncontrolled DCD donors. We consolidate the knowledge on uncontrolled DCD in Europe and provide recommendations and guidance for the development and optimization of effective uncontrolled DCD programmes.

PMID: 26706366 [PubMed - indexed for MEDLINE]

Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1α.

Mon, 08/07/2017 - 18:48
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Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1α.

Stem Cell Reports. 2017 Jul 24;:

Authors: Tsang KM, Hyun JS, Cheng KT, Vargas M, Mehta D, Ushio-Fukai M, Zou L, Pajcini KV, Rehman J, Malik AB

Abstract
The generation of functional arterial endothelial cells (aECs) from embryonic stem cells (ESCs) holds great promise for vascular tissue engineering. However, the mechanisms underlying their generation and the potential of aECs in revascularizing ischemic tissue are not fully understood. Here, we observed that hypoxia exposure of mouse ESCs induced an initial phase of HIF1α-mediated upregulation of the transcription factor Etv2, which in turn induced the commitment to the EC fate. However, sustained activation of HIF1α in these EC progenitors thereafter induced NOTCH1 signaling that promoted the transition to aEC fate. We observed that transplantation of aECs mediated arteriogenesis in the mouse hindlimb ischemia model. Furthermore, transplantation of aECs in mice showed engraftment in ischemic myocardium and restored cardiac function in contrast to ECs derived under normoxia. Thus, HIF1α activation of Etv2 in ESCs followed by NOTCH1 signaling is required for the generation aECs that are capable of arteriogenesis and revascularization of ischemic tissue.

PMID: 28781077 [PubMed - as supplied by publisher]

Early aspirin use and the development of cardiac allograft vasculopathy.

Mon, 08/07/2017 - 18:48
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Early aspirin use and the development of cardiac allograft vasculopathy.

J Heart Lung Transplant. 2017 Jul 03;:

Authors: Kim M, Bergmark BA, Zelniker TA, Mehra MR, Stewart GC, Page DS, Woodcome EL, Smallwood JA, Gabardi S, Givertz MM

Abstract
BACKGROUND: Cardiac allograft vasculopathy (CAV) remains a leading cause of morbidity and mortality after orthotopic heart transplantation (OHT). Little is known about the influence of aspirin on clinical expression of CAV.
METHODS: We followed 120 patients with OHT at a single center for a median of 7 years and categorized them by the presence or absence of early aspirin therapy post-transplant (aspirin treatment ≥6 months in the first year). The association between aspirin use and time to the primary end-point of angiographic moderate or severe CAV (International Society for Heart and Lung Transplantation grade ≥2) was investigated. Propensity scores for aspirin treatment were estimated using boosting models and applied by inverse probability of treatment weighting (IPTW).
RESULTS: Despite a preponderance of risk factors for CAV among patients receiving aspirin (male sex, ischemic heart disease as the etiology of heart failure, and smoking), aspirin therapy was associated with a lower rate of moderate or severe CAV at 5 years. Event-free survival was 95.9% for patients exposed to aspirin compared with 79.6% for patients without aspirin exposure (log-rank p = 0.005). IPTW-weighted Cox regression revealed a powerful inverse association between aspirin use and moderate to severe CAV (adjusted hazard ratio 0.13; 95% confidence interval 0.03-0.59), which was directionally consistent for CAV of any severity (adjusted hazard ratio 0.50; 95% confidence interval 0.23-1.08).
CONCLUSIONS: This propensity score-based comparative observational analysis suggests that early aspirin exposure may be associated with a reduced risk of development of moderate to severe CAV. These findings warrant prospective validation in controlled investigations.

PMID: 28781013 [PubMed - as supplied by publisher]

Registry of the International Society for Heart and Lung Transplantation: Twentieth Pediatric Lung and Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time.

Mon, 08/07/2017 - 18:48
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Registry of the International Society for Heart and Lung Transplantation: Twentieth Pediatric Lung and Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time.

J Heart Lung Transplant. 2017 Jul 19;:

Authors: Goldfarb SB, Levvey BJ, Cherikh WS, Chambers DC, Khush K, Kucheryavaya AY, Lund LH, Meiser B, Rossano JW, Yusen RD, Stehlik J, International Society for Heart and Lung Transplantation

PMID: 28781012 [PubMed - as supplied by publisher]

Pre-operative proteinuria in left ventricular assist devices and clinical outcome.

Mon, 08/07/2017 - 18:48
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Pre-operative proteinuria in left ventricular assist devices and clinical outcome.

J Heart Lung Transplant. 2017 Jul 15;:

Authors: Muslem R, Caliskan K, Akin S, Sharma K, Gilotra NA, Brugts JJ, Houston B, Whitman G, Tedford RJ, Hesselink DA, Bogers AJJC, Manintveld OC, Russell SD

Abstract
BACKGROUND: This study evaluated the association of pre-operative proteinuria before continuous flow left ventricular assist device (CF-LVAD) implantation in relation to mortality and the need for renal replacement therapy (RRT) during the first year of follow-up.
METHODS: This retrospective, multicenter cohort study evaluated all patients (n = 241) who underwent CF-LVAD implantation in the 2 participating tertiary referral centers. Patients were included if a urine dipstick was performed within 7 days before CF-LVAD implantation. Proteinuria was defined as trace or higher.
RESULTS: In total, 173 patients (72%) were included (78% men; mean age, 52.3 ± 13.3; mean estimated glomerular filtration rate, 60.1 ± 25.9 mL/min/1.73 m(2)), and 42 patients (24%) had pre-operative proteinuria. The observed survival in patients with proteinuria vs without proteinuria was 57% vs 86% at 3 months and 52% vs 78% at 1 year (log-rank p < 0.001), respectively. In addition, during the first year after implantation, 32% of the patients with proteinuria and 15% of the patients without proteinuria required RRT (log-rank p = 0.02). Multivariate Cox regression analysis confirmed that pre-operative proteinuria was an independent predictor for mortality (adjusted hazard ratio, 2.09; 95% confidence interval, 1.10-3.80, p = 0.02) and for the need of RRT during the first year (adjusted hazard ratio, 2.23; 95% confidence interval, 1.13-4.84; p = 0.02).
CONCLUSIONS: Proteinuria, which was present in 25% of all tested LVAD patients, predicts worse outcome in all-cause mortality and need of RRT in patients with a CF-LVAD. This warrants the use of proteinuria in risk stratification when selecting patients for CF-LVAD therapy.

PMID: 28781011 [PubMed - as supplied by publisher]

An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection.

Mon, 08/07/2017 - 18:48
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An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection.

J Heart Lung Transplant. 2017 Jun 23;:

Authors: Kusne S, Mooney M, Danziger-Isakov L, Kaan A, Lund LH, Lyster H, Wieselthaler G, Aslam S, Cagliostro B, Chen J, Combs P, Cochrane A, Conway J, Cowger J, Frigerio M, Gellatly R, Grossi P, Gustafsson F, Hannan M, Lorts A, Martin S, Pinney S, Silveira FP, Schubert S, Schueler S, Strueber M, Uriel N, Wrightson N, Zabner R, Huprikar S

PMID: 28781010 [PubMed - as supplied by publisher]

The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: Allograft ischemic time.

Mon, 08/07/2017 - 18:48
Related Articles

The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: Allograft ischemic time.

J Heart Lung Transplant. 2017 Jul 20;:

Authors: Lund LH, Khush KK, Cherikh WS, Goldfarb S, Kucheryavaya AY, Levvey BJ, Meiser B, Rossano JW, Chambers DC, Yusen RD, Stehlik J, International Society for Heart and Lung Transplantation

PMID: 28779893 [PubMed - as supplied by publisher]

The Registry of the International Society for Heart and Lung Transplantation: Twentieth Pediatric Heart Transplantation Report-2017; Focus Theme: Allograft Ischemic Time.

Mon, 08/07/2017 - 18:48
Related Articles

The Registry of the International Society for Heart and Lung Transplantation: Twentieth Pediatric Heart Transplantation Report-2017; Focus Theme: Allograft Ischemic Time.

J Heart Lung Transplant. 2017 Jul 20;:

Authors: Rossano JW, Cherikh WS, Chambers DC, Goldfarb S, Khush K, Kucheryavaya AY, Levvey BJ, Lund LH, Meiser B, Yusen RD, Stehlik J, International Society for Heart and Lung Transplantation

PMID: 28779892 [PubMed - as supplied by publisher]

Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis.

Sun, 08/06/2017 - 12:45
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Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis.

Inflammopharmacology. 2017 Aug 04;:

Authors: Grabarz F, Aguiar CF, Correa-Costa M, Braga TT, Hyane MI, Andrade-Oliveira V, de Almeida Landgraf M, Câmara NOS

Abstract
Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (Jα18(-/-)) were subjected to the protocol of bleomycin-induced pulmonary fibrosis with or without treatment with NKT cell agonists α-galactosylceramide and sulfatide. The participation of different cell populations, collagen deposition, and protein levels of different cytokines involved in inflammation and fibrosis was evaluated. The results indicate a benign role of NKT cells in Jα18(-/-) mice and in wild-type α-galactosylceramide-sulfatide-treated groups. These animals presented lower levels of collagen deposition, fibrogenic molecules such as TGF-β and vimentin and improved survival rates. In contrast, WT mice developed a Th2-driven response augmenting IL-4, 5, and 13 protein synthesis and increased collagen deposition. Furthermore, the arginase-1 metabolic pathway was downregulated in wild-type NKT-activated and knockout mice indicating lower activity of M2 macrophages in lung tissue. Hence, our data suggest that NKT cells play a protective role in this experimental model by down modulating the Th2 milieu, inhibiting M2 polarization and finally preventing fibrosis.

PMID: 28779430 [PubMed - as supplied by publisher]

Lung cancer in lung transplantation: incidence and outcome.

Sun, 08/06/2017 - 12:45
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Lung cancer in lung transplantation: incidence and outcome.

Postgrad Med J. 2017 Aug 04;:

Authors: Pã Rez-Callejo D, Torrente MA, Parejo C, Laporta R, Ussetti P, Provencio M

Abstract
INTRODUCTION: Malignancies are one of the causes of mortality after lung transplantation. However, little is known about lung cancer outcome after lung transplantation.
METHODS: We performed a retrospective search of the lung transplantation database at our institution to identify patients diagnosed with lung cancer after lung transplantation.
RESULTS: Out of 633 lung transplant patients, lung cancer was detected in 23 of them (3.63%). The most common causes for transplantation were idiopathic pulmonary fibrosis (47.8%) and emphysema (43.4%). A total of 18 patients were diagnosed during follow-up, 12 cases in the native lung (52.2%) and 6 cases in the donor lung (26.1%). The diagnosis was evidenced in the explanted lung in five patients (21.7%). The median of time from transplantation to cancer diagnosis was 39.7 months (24.3â€"56.6). Lung cancer was the cause of death in 16 patients. Survival rate at 1 year from diagnosis of lung cancer was 45.64% (95% CI 0.2431 to 0.6473).
CONCLUSIONS: Lung transplant recipients constitute a high-risk group for developing lung cancer. Among our patients, lung cancer was predominantly diagnosed in the native lung and at an advanced stage. The primary tumour was the main cause of death in most of these patients.

PMID: 28778949 [PubMed - as supplied by publisher]

Early assessment of dosimetric and biological differences of total marrow irradiation versus total body irradiation in rodents.

Sun, 08/06/2017 - 12:45
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Early assessment of dosimetric and biological differences of total marrow irradiation versus total body irradiation in rodents.

Radiother Oncol. 2017 Aug 01;:

Authors: Hui S, Takahashi Y, Holtan SG, Azimi R, Seelig D, Yagi M, Ingvalson J, Alaei P, Sharkey L, Kodal B, Peterson N, Meyer C, Godin L, Ehrhardt M, Storme G, Zhou D, Panoskaltsis-Mortari A

Abstract
PURPOSE: To develop a murine total marrow irradiation (TMI) model in comparison with the total body irradiation (TBI) model.
MATERIALS AND METHODS: Myeloablative TMI and TBI were administered in mice using a custom jig, and the dosimetric differences between TBI and TMI were evaluated. The early effects of TBI/TMI on bone marrow (BM) and organs were evaluated using histology, FDG-PET, and cytokine production. TMI and TBI with and without cyclophosphamide (Cy) were evaluated for donor cell engraftment and tissue damage early after allogeneic hematopoietic cell transplantation (HCT). Stromal derived factor-1 (SDF-1) expression was evaluated.
RESULTS: TMI resulted in similar dose exposure to bone and 50% reduction in dose to bystander organs. BM histology was similar between the groups. In the non-HCT model, TMI mice had significantly less acute intestinal and lung injury compared to TBI. In the HCT model, recipients of TMI had significantly less acute intestinal injury and spleen GVHD, but increased early donor cell engraftment and BM:organ SDF-1 ratio compared to TBI recipients.
CONCLUSIONS: The expected BM damage was similar in both models, but the damage to other normal tissues was reduced by TMI. However, BM engraftment was improved in the TMI group compared to TBI, which may be due to enhanced production of SDF-1 in BM relative to other organs after TMI.

PMID: 28778346 [PubMed - as supplied by publisher]

Mesenchymal Stem Cells in Fibrotic Disease.

Sat, 08/05/2017 - 12:45
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Mesenchymal Stem Cells in Fibrotic Disease.

Cell Stem Cell. 2017 Aug 03;21(2):166-177

Authors: El Agha E, Kramann R, Schneider RK, Li X, Seeger W, Humphreys BD, Bellusci S

Abstract
Fibrosis is associated with organ failure and high mortality and is commonly characterized by aberrant myofibroblast accumulation. Investigating the cellular origin of myofibroblasts in various diseases is thus a promising strategy for developing targeted anti-fibrotic treatments. Recent studies using genetic lineage tracing technology have implicated diverse organ-resident perivascular mesenchymal stem cell (MSC)-like cells and bone marrow-MSCs in myofibroblast generation during fibrosis development. In this Review, we give an overview of the emerging role of MSCs and MSC-like cells in myofibroblast-mediated fibrotic disease in the kidney, lung, heart, liver, skin, and bone marrow.

PMID: 28777943 [PubMed - in process]

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