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Two novel direct SPIO labels and in vivo MRI detection of labeled cells after acute myocardial infarct.

Thu, 08/17/2017 - 15:47
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Two novel direct SPIO labels and in vivo MRI detection of labeled cells after acute myocardial infarct.

Acta Radiol Open. 2017 Aug;6(8):2058460117718407

Authors: Korpi RM, Alestalo K, Ruuska T, Lammentausta E, Borra R, Yannopoulos F, Lehtonen S, Korpi JT, Lappi-Blanco E, Anttila V, Lehenkari P, Juvonen T, Blanco Sequieros R

Abstract
BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. Cellular decay due hypoxia requires rapid and validated methods for possible therapeutic cell transplantation.
PURPOSE: To develop direct and rapid superparamagnetic iron oxide (SPIO) cell label for a large-animal model and to assess in vivo cell targeting by magnetic resonance imaging (MRI) in an experimental AMI model.
MATERIAL AND METHODS: Bone marrow mononuclear cells (BMMNCs) were labeled with SPIO particles using two novel direct labeling methods (rotating incubation method and electroporation). Labeling, iron incorporation in cells and label distribution, cellular viability, and proliferation were validated in vitro. An AMI porcine model was used to evaluate the direct labeling method (rotating incubation method) by examining targeting of labeled BMMNCs using MRI and histology.
RESULTS: Labeling (1 h) did not alter either cellular differentiation potential or viability of cells in vitro. Cellular relaxation values at 9.4 T correlated with label concentration and MRI at 1.5 T showing 89 ± 4% signal reduction compared with non-labeled cells in vitro. In vivo, a high spatial correlation between MRI and histology was observed. The extent of macroscopic pathological myocardial changes (hemorrhage) correlated with altered function detected on MRI.
CONCLUSION: We demonstrated two novel direct SPIO labeling methods and demonstrated the feasibility of clinical MRI for monitoring targeting of the labeled cells in animal models of AMI.

PMID: 28811932 [PubMed]

Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Thu, 08/17/2017 - 15:47
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Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Transplant Rev (Orlando). 2017 Jul 26;:

Authors: Aguado JM, Silva JT, Fernández-Ruiz M, Cordero E, Fortún J, Gudiol C, Martínez-Martínez L, Vidal E, Almenar L, Almirante B, Cantón R, Carratalá J, Caston JJ, Cercenado E, Cervera C, Cisneros JM, Crespo-Leiro MG, Cuervas-Mons V, Elizalde-Fernández J, Fariñas MC, Gavaldà J, Goyanes MJ, Gutiérrez-Gutiérrez B, Hernández D, Len O, López-Andujar R, López-Medrano F, Martín-Dávila P, Montejo M, Moreno A, Oliver A, Pascual A, Pérez-Nadales E, Román-Broto A, San-Juan R, Serón D, Solé-Jover A, Valerio M, Muñoz P, Torre-Cisneros J, Spanish Society of Transplantation (SET), Group for Study of Infection in Transplantation of the Spanish Society of Infectious Diseases and Clinical Microbiology (GESITRA-SEIMC), Spanish Network for Research in Infectious Diseases (REIPI) (RD16/0016)

Abstract
Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate's phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection.

PMID: 28811074 [PubMed - as supplied by publisher]

Regulatory T-Cell Levels in the Longest Surviving Asian Patient After Heart-Lung Transplant.

Thu, 08/17/2017 - 15:47
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Regulatory T-Cell Levels in the Longest Surviving Asian Patient After Heart-Lung Transplant.

Exp Clin Transplant. 2017 Aug 13;:

Authors: Huang L, Ji M, Yi S, Zhou X

Abstract
Heart-lung transplant is the most effective therapy for patients with end-stage cardiopulmonary disease. Here, we report an initial assessment of a 31-year-old man who had survived more than 11 years after heart-lung transplant, which represents the longest survival time in this procedure in Asian studies. At his 11th anniversary after transplant, extensive tests were carried out, especially to detect regulatory T-cell levels for the first time in a surviving heart-lung transplant recipient. Preliminarily data revealed the status of his immunologic function in relation to chronic allograft rejection. All data indicated that the patient was in good condition. This is the first study detecting regulatory T-cell levels in a heart-lung transplant patient.

PMID: 28810825 [PubMed - as supplied by publisher]

[The function of NLRP1 in noninfectious pulmonary injury following allogeneic hematopoietic stem cell transplantation].

Thu, 08/17/2017 - 15:47
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[The function of NLRP1 in noninfectious pulmonary injury following allogeneic hematopoietic stem cell transplantation].

Zhonghua Xue Ye Xue Za Zhi. 2017 Jul 14;38(7):607-611

Authors: Li MF, Li W, Ding L, Wu YL, Liu L, Ju W, Qiao JL, Xu KL, Zeng LY

Abstract
Objective: To explore the function of NLRP1 in noninfectious pulmonary injury (nonIPI) after allogeneic stem cell transplantation (allo-HSCT) . Methods: In this study, we established the model of allo-HSCT with C57BL/6 and NLRP(-/-) mouse as recipients. Chimera rate was measured by flow cytometry. The HE staining was used to observe the pathology changes in the lungs. NLRP1 and relevant inflammatory proteins were measured by Western Blot. Results: On the day 14 after allo-HSCT, the chimera rate was more than 96%, HSCs of donors had been successfully transplanted into recipients. HE staining showed that nonIPI occurred after allo-HSCT. The degrees of injuries reached the peak on day 21. In addition, the expressions of MPO, NLRP1, p20, Mature-IL-1β and Mature-IL-18 had same tends with the degrees of nonIPI. When we knocked out NLRP1 gene of recipients, the degrees of nonIPI reduced and the expressions of MPO, p20, Mature-IL-1β and Mature-IL-18 were less than in non-knockout group. Conclusion: allo-HSCT could cause nonIPI and high expressions of MPO, p20, IL-1β, IL-18, NLRP1. Knocking out NLRP1 gene could alleviate the degrees of nonIPI and reduce the expressions of relevant inflammatory proteins, indicating that NLRP1 might be one of factors contributed to nonIPI after allo-HSCT.

PMID: 28810330 [PubMed - in process]

[Adult peripheral primary neuroectodermal tumor: a case report and literature review].

Thu, 08/17/2017 - 15:47
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[Adult peripheral primary neuroectodermal tumor: a case report and literature review].

Zhonghua Jie He He Hu Xi Za Zhi. 2017 Aug 12;40(8):611-615

Authors: Hu MH, Long F, Jiang SJ

Abstract
Objective: To analyze the clinical features, diagnosis and differential diagnosis of peripheral primary neuroectodermal tumor(pPNET). Methods: The clinical data and diagnosis of a patient with rapid progressive pPNET in Shandong Provincial Hospital affiliated to Shandong University in January 2016 was reported and the related literatures were reviewed.The literature reviews were carried out respectively in CNKI, Wanfang and PubMed by July 2016 with "primitive neurotodermal tumour" and "PNET" being the search term from March 1994 to July 2016, including 13 articles. Results: A 41 year-old male patient was admitted to the hospital because of shortness of breath and occasional chest tightness, accompanied by general asthenia of about 15 d. Positron emission and transmission-CT of total trunk showed a mass in the right femoral osteoperiosteal mass, and multiple nodules in the left lung, lumps and nodules in the right lung, and right pleural thickening and effusion. Thoracoscopy was performed and pathology study confirmed the diagnosis of peripheral primary neuroectodermal tumor. The patient was given 2 courses of chemotherapy, but had rapid progressive worsening and died 1 month after PNET diagnosis. A total of 13 literatures of PNET were retrieved, all of which were case reports, and a total of 15 cases were reported.There were 9 male and 7 female patients, with a median age of 26 years.The symptoms had no specificity and most of them were solid masses in chest images, with or without pleural effusion. Eight cases were diagnosed by imaging guided percutaneous biopsy, 7 by operation and pathology, and 1 by medical thoracoscopy. Four cases underwent chemotherapy, and the survival time was less than 6 months. Twelve cases got surgical resection: 2 with surgical treatment, 7 with postoperative chemotherapy, 2 with postoperative radiotherapy and chemotherapy, 1 with postoperative chemotherapy and autologous bone marrow transplantation treatment, among which 11 patients completed follow-up. During follow-up, 3 cases died, and the survival time was 10 months, 3 years and 7 years, respectively. Conclusions: PNET is rare.Due to the lack of specificity of clinical manifestations, clinical diagnosis depends on biopsy. Early diagnosis and surgical resection are especially important for prognosis and quality of life.

PMID: 28810315 [PubMed - in process]

The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

Thu, 08/17/2017 - 15:47
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The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

Biophys Rev. 2017 Aug 14;:

Authors: Dos Remedios CG, Lal SP, Li A, McNamara J, Keogh A, Macdonald PS, Cooke R, Ehler E, Knöll R, Marston SB, Stelzer J, Granzier H, Bezzina C, van Dijk S, De Man F, Stienen GJM, Odeberg J, Pontén F, Linke W, van der Velden J

Abstract
The Sydney Heart Bank (SHB) is one of the largest human heart tissue banks in existence. Its mission is to provide high-quality human heart tissue for research into the molecular basis of human heart failure by working collaboratively with experts in this field. We argue that, by comparing tissues from failing human hearts with age-matched non-failing healthy donor hearts, the results will be more relevant than research using animal models, particularly if their physiology is very different from humans. Tissue from heart surgery must generally be used soon after collection or it significantly deteriorates. Freezing is an option but it raises concerns that freezing causes substantial damage at the cellular and molecular level. The SHB contains failing samples from heart transplant patients and others who provided informed consent for the use of their tissue for research. All samples are cryopreserved in liquid nitrogen within 40 min of their removal from the patient, and in less than 5-10 min in the case of coronary arteries and left ventricle samples. To date, the SHB has collected tissue from about 450 failing hearts (>15,000 samples) from patients with a wide range of etiologies as well as increasing numbers of cardiomyectomy samples from patients with hypertrophic cardiomyopathy. The Bank also has hearts from over 120 healthy organ donors whose hearts, for a variety of reasons (mainly tissue-type incompatibility with waiting heart transplant recipients), could not be used for transplantation. Donor hearts were collected by the St Vincent's Hospital Heart and Lung transplantation team from local hospitals or within a 4-h jet flight from Sydney. They were flushed with chilled cardioplegic solution and transported to Sydney where they were quickly cryopreserved in small samples. Failing and/or donor samples have been used by more than 60 research teams around the world, and have resulted in more than 100 research papers. The tissues most commonly requested are from donor left ventricles, but right ventricles, atria, interventricular system, and coronary arteries vessels have also been reported. All tissues are stored for long-term use in liquid N or vapor (170-180 °C), and are shipped under nitrogen vapor to avoid degradation of sensitive molecules such as RNAs and giant proteins. We present evidence that the availability of these human heart samples has contributed to a reduction in the use of animal models of human heart failure.

PMID: 28808947 [PubMed - as supplied by publisher]

Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value.

Thu, 08/17/2017 - 15:47
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Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):266-273

Authors: Laffey JG, Matthay MA

Abstract
On the basis of several preclinical studies, cell-based therapy has emerged as a potential new therapeutic for acute respiratory distress syndrome (ARDS). Of the various cell-based therapy options, mesenchymal stem/stromal cells (MSCs) from bone marrow, adipose tissue, and umbilical cord have the most experimental data to support their potential efficacy for lung injury from both infectious and noninfectious causes. Mechanistically, MSCs exert their beneficial effects by release of paracrine factors, microvesicles, and transfer of mitochondria, all of which have antiinflammatory and pro-resolving effects on injured lung endothelium and alveolar epithelium, including enhancing the resolution of pulmonary edema by up-regulating sodium-dependent alveolar fluid clearance. MSCs also have antimicrobial effects mediated by release of antimicrobial factors and by up-regulating monocyte/macrophage phagocytosis. Phase 2a clinical trials to establish safety in ARDS are in progress, and two phase 1 trials did not report any serious adverse events. Several issues need further study, including: determining the optimal methods for large-scale production, reconstitution of cryopreserved cells for clinical use, defining cell potency assays, and determining the therapeutic potential of conditioned media derived from MSCs. Because ARDS is a heterogeneous syndrome, targeting MSCs to patients with ARDS with a more hyperinflammatory endotype may further enhance their potential for efficacy.

PMID: 28306336 [PubMed - indexed for MEDLINE]

Glomerular filtration rate affects interpretation of pulmonary function test in a Korean general population: results from the Korea National Health and Nutrition Examination Survey 2010 to 2012.

Thu, 08/17/2017 - 15:47
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Glomerular filtration rate affects interpretation of pulmonary function test in a Korean general population: results from the Korea National Health and Nutrition Examination Survey 2010 to 2012.

Korean J Intern Med. 2016 Nov;31(6):1101-1109

Authors: Kim YS, Kim HY, Ahn HS, Sohn TS, Song JY, Lee YB, Lee DH, Lee JI, Lee TK, Jeong SC, Hong M, Chae HS, Han K, Yeo CD

Abstract
BACKGROUND/AIMS: The pulmonary abnormalities (principally restrictive abnormalities) are characteristic of renal transplant recipients or those with end-stage renal disease. Our aim was to explore whether the prevalence of spirometric abnormalities was influenced by the estimated glomerular filtration rates (GFRs) in a Korean general population.
METHODS: We used data obtained during the 2010 to 2012 Korean National Health and Nutrition Examination Survey, a national cross-sectional survey. We analyzed data from subjects for whom spirometric assays and estimated GFRs were of acceptable quality.
RESULTS: A total of 8,809 subjects (3,868 male and 4,941 female) was included. In both males and females with GFR values < 60 mL/min/1.73 m(2), the linear trends toward the presence of obstructive and restrictive patterns were significant. However, the percent predicted forced vital capacity (FVC) decreased with a decline in the estimated GFR, but only in males (p for trend < 0.0031). Multivariate linear regression analysis showed a decline in the estimated GFR was independently associated with falls in the percent predicted FVC and the forced expiratory volume in 1 second/FVC ratio in both males and females. However, the percent predicted FVC was independently predictive only in males (p = 0.002).
CONCLUSIONS: Impaired pulmonary function was associated with a decline in the estimated GFR. The percent predicted FVC decrease paralleled the decline in estimated GFR in male only. Careful interpretation of pulmonary function test data is required in patients with decreased GFRs or impaired renal function, especially males.

PMID: 26996347 [PubMed - indexed for MEDLINE]

Hepatocyte growth factor-modified mesenchymal stem cells improve ischemia/reperfusion-induced acute lung injury in rats.

Thu, 08/17/2017 - 15:47
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Hepatocyte growth factor-modified mesenchymal stem cells improve ischemia/reperfusion-induced acute lung injury in rats.

Gene Ther. 2017 Jan;24(1):3-11

Authors: Chen S, Chen X, Wu X, Wei S, Han W, Lin J, Kang M, Chen L

Abstract
Accumulative evidence demonstrated that mesenchymal stem cell (MSC) engraftment could protect tissue injury from ischemia/reperfusion (I/R). Hepatocyte growth factor (HGF) has important roles in the cell and tissue repairment and regeneration. Here we investigated the enhanced effects of HGF-modified MSCs on I/R-induced acute lung injury. Rat bone marrow-derived MSCs were successfully transfected to express HGF. HGF modification did not affect the characteristics of MSCs, and increased MSC viability, and inhibit the proinflammatory phenotype of MSCs in the inflammatory condition. In the rat model of I/R-induced lung injury, MSC-HGF engraftment attenuated lung wet-to-dry weight ratio, enhanced PaO2 level and improved lung pathological injury, compared with MSC treatment. Moreover, the decreased acitivity of malondialdehyde, myeloperoxidase and tumor necrosis factor-α and increased superoxide dismutase content and interleukin-10 level were also observed in the MSC-HGF treatment, compared with the MSC group. Importantly, we found that HGF contributed to the survival of engrafted MSCs in the lung tissue through upregulation of Bcl-2 level and reduction of Caspase 3 activation. Thus our data show for the first time a clear beneficial effect of HGF gene modification on the survival of MSCs and enhanced improvement for I/R-induced lung injury.

PMID: 27556817 [PubMed - indexed for MEDLINE]

Misinformed users: improving informed decision-making on social media.

Thu, 08/17/2017 - 15:47
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Misinformed users: improving informed decision-making on social media.

Transpl Int. 2016 Jun;29(6):740-1

Authors: Peña AM

PMID: 27295970 [PubMed - indexed for MEDLINE]

Incidence and outcomes of primary central nervous system lymphoma in solid organ transplant recipients.

Tue, 08/15/2017 - 12:45

Incidence and outcomes of primary central nervous system lymphoma in solid organ transplant recipients.

Am J Transplant. 2017 Aug 14;:

Authors: Mahale P, Shiels MS, Lynch CF, Engels EA

Abstract
Primary central nervous system lymphoma (PCNSL) risk is greatly increased in immunosuppressed HIV-infected people. Using data from the United States transplant registry linked with 17 cancer registries (1987-2014), we studied PCNSL and systemic non-Hodgkin lymphoma (NHL) in 288,029 solid organ transplant recipients. Transplant recipients had elevated incidence for PCNSL compared with the general population (standardized incidence ratio=65.1; N=168), and this elevation was stronger than for systemic NHL (standardized incidence ratio=11.5; N=2,043). Compared to kidney recipients, PCNSL incidence was lower in liver recipients (adjusted incidence rate ratio [aIRR]=0.52), similar in heart and/or lung recipients, and higher in other/multiple organ recipients (aIRR=2.45). PCNSL incidence was higher in Asians/Pacific Islanders than non-Hispanic whites (aIRR=2.09); after induction immunosuppression with alemtuzumab (aIRR=3.12), monoclonal antibodies (aIRR=1.83), or polyclonal antibodies (aIRR=2.03); in recipients who were Epstein-Barr virus-seronegative at the time of transplant and at risk of primary infection (aIRR=1.95); and within the first 1.5 years after transplant (aIRR>2.00). Compared to other recipients, those with PCNSL had increased risk of death (adjusted hazard ratio [aHR]=11.79) or graft failure/retransplantation (aHR=3.24). Recipients with PCNSL also had higher mortality than those with systemic NHL (aHR=1.48). In conclusion, PCNSL risk is highly elevated among transplant recipients, and it carries a poor prognosis. This article is protected by copyright. All rights reserved.

PMID: 28805292 [PubMed - as supplied by publisher]

Conditioning neoadjuvant therapies for improved immunotherapy of cancer.

Tue, 08/15/2017 - 12:45
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Conditioning neoadjuvant therapies for improved immunotherapy of cancer.

Biochem Pharmacol. 2017 Aug 10;:

Authors: Benson Z, Manjili SH, Habibi M, Guruli G, Toor AA, Payne KK, Manjili MH

Abstract
Recent advances in the treatment of melanoma and non-small cell lung cancer (NSCLC) by combining conventional therapies with anti-PD1/PD-L1 immunotherapies, have renewed interests in immunotherapy of cancer. The emerging concept of conventional cancer therapies combined with immunotherapy differs from the classical concept in that it is not simply taking advantage of their additive anti-tumor effects, but it is to use certain therapeutic regimens to condition the tumor microenvironment for optimal response to immunotherapy. To this end, low dose immunogenic chemotherapies, epigenetic modulators and inhibitors of cell cycle progression are potential candidates for rendering tumors highly responsive to immunotherapy. Next generation immunotherapeutics are therefore predicted to be highly effective against cancer, when they are used following appropriate immune modulatory compounds or targeted delivery of tumor cell cycle inhibitors using nanotechnology.

PMID: 28803721 [PubMed - as supplied by publisher]

Effect of positive perioperative donor and recipient respiratory bacterial cultures on early post-transplant outcomes in lung transplant recipients.

Tue, 08/15/2017 - 12:45
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Effect of positive perioperative donor and recipient respiratory bacterial cultures on early post-transplant outcomes in lung transplant recipients.

Transpl Infect Dis. 2017 Aug 13;:

Authors: Howell CK, Paciullo CA, Lyon MG, Neujahr D, Lyu P, Cotsonis G, Hurtik M

Abstract
BACKGROUND: It is standard practice to administer prophylactic antibiotics post lung transplantation. However, no studies have evaluated the impact of culture positivity. The purpose of this study was to evaluate early post-transplant outcomes of culture-positive and culture-negative lung transplant (LT) recipients and the appropriateness of the empiric regimens used.
METHODS: Adult patients who received an LT at Emory University Hospital between January 1, 2010 and August 31, 2015 were reviewed and stratified into three groups: (i) culture-positive appropriate empiric treatment, (ii) culture-positive inappropriate empiric treatment, and (iii) culture-negative. Antibiotics were defined as appropriate if bacteria were sensitive to the empiric regimen. The primary endpoint was 30-day mortality. Secondary endpoints included hospital length of stay (LOS), intensive care unit (ICU) LOS, percent neutrophil count in a bronchoalveolar lavage (BAL), presence of airway ischemia, and appropriateness of the empiric antibiotic regimen.
RESULTS: Respectively nine, zero, and four patients died within 30 days in the culture-positive appropriate (n=113), culture-positive inappropriate (n=5), and culture-negative groups (n=29) (P=.564). The median hospital LOS was 19, 16, and 15 days respectively. Median ICU LOS was 6, 5, and 7 respectively. The respective percent neutrophil counts in the BAL fluid were 79, 83, and 65. The presence of airway ischemia was only documented in eight patients, all in the culture-positive appropriate group.
CONCLUSION: We did not identify an association between antibiotic appropriateness and 30-day mortality, hospital LOS or ICU LOS in post-LT recipients. This article is protected by copyright. All rights reserved.

PMID: 28803455 [PubMed - as supplied by publisher]

Recombinant Human Elafin Promotes Alveologenesis in Newborn Mice Exposed to Chronic Hyperoxia.

Tue, 08/15/2017 - 12:45
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Recombinant Human Elafin Promotes Alveologenesis in Newborn Mice Exposed to Chronic Hyperoxia.

Int J Biochem Cell Biol. 2017 Aug 09;:

Authors: Han W, Li X, Zhang H, Yu B, Guo C, Deng C

Abstract
BACKGROUND/AIMS: Elastase inhibitors reverse elastin degradation and abnormal alveologenesis and attenuate the lung structural abnormalities induced by mechanical ventilation with O2-rich gas. The potential of these molecules to improve endothelial function and to ameliorate severe bronchopulmonary dysplasia (BPD) during lung development is not yet understood. We sought to determine whether the intratracheal treatment of newborn mice with the elastase inhibitor elafin would prevent hyperoxia-induced lung elastin degradation and the cascade of events that cause abnormal alveologenesis.
METHODS: Newborn mice were exposed to 85% O2 for 3, 7, 14 or 21 days. Recombinant human elafin was administered administered by intratracheal instillation from the first day every two days for 20 days. We next used morphometric analyses, quantitative RT-PCR, immunostaining, Western blotting, and ELISA methods to assess the key variables involved in elastogenesis disruption and the potential signaling pathways noted below in recombinant human elafin-treated mouse pups that had been exposed to 85% O2.
RESULTS: We found that impaired alveolar development and aberrant elastin production were associated with elevations in whole lung elastase levels in 85% O2-exposed lungs. Elafin attenuated the structural disintegration that developed in the hyperoxia-damaged lungs. Furthermore, elafin prevented the elastin degradation, neutrophil influx, activation of TGF-β1 and apoptosis caused by 85% O2 exposure.
CONCLUSIONS: Pulmonary elastase plays an important role in disrupting elastogenesis during O2-induced damage, which is the result of a pulmonary inflammatory response. Elafin prevents these changes by inhibiting elastase and the TGF-β1 signalling cascade and may be a new therapeutic target for preventing O2-induced lung injury in neonates.

PMID: 28802561 [PubMed - as supplied by publisher]

Report of the International Society for Heart and Lung Transplantation Working Group on Primary Lung Graft Dysfunction, part II: Epidemiology, risk factors, and outcomes-A 2016 Consensus Group statement of the International Society for Heart and Lung...

Tue, 08/15/2017 - 12:45
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Report of the International Society for Heart and Lung Transplantation Working Group on Primary Lung Graft Dysfunction, part II: Epidemiology, risk factors, and outcomes-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.

J Heart Lung Transplant. 2017 Jul 26;:

Authors: Diamond JM, Arcasoy S, Kennedy CC, Eberlein M, Singer JP, Patterson GM, Edelman JD, Dhillon G, Pena T, Kawut SM, Lee JC, Girgis R, Dark J, Thabut G

PMID: 28802530 [PubMed - as supplied by publisher]

Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells.

Tue, 08/15/2017 - 12:45
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Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells.

Cancer Lett. 2017 May 01;393:52-59

Authors: Klampatsa A, Achkova DY, Davies DM, Parente-Pereira AC, Woodman N, Rosekilly J, Osborne G, Thayaparan T, Bille A, Sheaf M, Spicer JF, King J, Maher J

Abstract
Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4(+) T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma.

PMID: 28223167 [PubMed - indexed for MEDLINE]

Generation of patient-derived xenografts from fine needle aspirates or core needle biopsy.

Tue, 08/15/2017 - 12:45
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Generation of patient-derived xenografts from fine needle aspirates or core needle biopsy.

Surgery. 2017 May;161(5):1246-1254

Authors: Roife D, Kang Y, Wang L, Fang B, Swisher SG, Gershenwald JE, Pretzsch S, Dinney CP, Katz MHG, Fleming JB

Abstract
BACKGROUND: Patient-derived xenografts have recently become a powerful tool for cancer research and may be used to guide personalized therapy. Thus far, patient-derived xenografts have been grown from tumor tissue obtained after operative resection; however, many cancer patients never undergo operative intervention for a variety of reasons. We hypothesized that xenograft tumors could be grown from smaller volumes of patient tissue, such as those obtained during diagnostic biopsies.
METHODS: Surgical specimens were obtained after resection of primary or metastatic lesions of the following cancers: pancreatic carcinoma, non-small cell lung cancer, bladder (urothelial) carcinoma, and melanoma. At least 10 cases of each cancer were included in this study. To mimic clinical biopsies, small fragments of the surgical specimens were biopsied with a 22-gauge needle, and the needle contents were injected subcutaneously in immunocompromised mice. The tumor fragment from which the biopsy was taken was also implanted subcutaneously in the contralateral side of the same mouse as a control.
RESULTS: Success rates of the traditional method of xenograft implantation ranged from 27.3%-70%. Success rates of the fine needle aspirate technique ranged from 0%-36.4%. An attempt to engraft a percutaneous core needle liver biopsy of a metastatic pancreatic adenocarcinoma also was successful.
CONCLUSION: We have found that it is possible to engraft fine needle aspirates and core biopsies of solid tumors in order to generate patient-derived xenografts. This may open up xenografting to a wider cancer patient population than previously possible.

PMID: 28081955 [PubMed - indexed for MEDLINE]

Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial.

Tue, 08/15/2017 - 12:45
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Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial.

Chest. 2017 May;151(5):971-981

Authors: Glassberg MK, Minkiewicz J, Toonkel RL, Simonet ES, Rubio GA, DiFede D, Shafazand S, Khan A, Pujol MV, LaRussa VF, Lancaster LH, Rosen GD, Fishman J, Mageto YN, Mendizabal A, Hare JM

Abstract
BACKGROUND: Despite Food and Drug Administration approval of 2 new drugs for idiopathic pulmonary fibrosis (IPF), curative therapies remain elusive and mortality remains high. Preclinical and clinical data support the safety of human mesenchymal stem cells as a potential novel therapy for this fatal condition. The Allogeneic Human Cells (hMSC) in patients with Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER) trial was the first study designed to evaluate the safety of a single infusion of bone marrow-derived mesenchymal stem cells in patients with idiopathic pulmonary fibrosis.
METHODS: Nine patients with mild to moderate IPF were sequentially assigned to 1 of 3 cohorts and dosed with a single IV infusion of 20, 100, or 200 × 10(6) human bone marrow-derived mesenchymal stem cells per infusion from young, unrelated, men. All baseline patient data were reviewed by a multidisciplinary study team to ensure accurate diagnosis. The primary end point was the incidence (at week 4 postinfusion) of treatment-emergent serious adverse events, defined as the composite of death, nonfatal pulmonary embolism, stroke, hospitalization for worsening dyspnea, and clinically significant laboratory test abnormalities. Safety was assessed until week 60 and additionally 28 days thereafter. Secondary efficacy end points were exploratory and measured disease progression.
RESULTS: No treatment-emergent serious adverse events were reported. Two nontreatment-related deaths occurred because of progression of IPF (disease worsening and/or acute exacerbation). By 60 weeks postinfusion, there was a 3.0% mean decline in % predicted FVC and 5.4% mean decline in % predicted diffusing capacity of the lungs for carbon monoxide.
CONCLUSIONS: Data from this trial support the safety of a single infusion of human mesenchymal stem cells in patients with mild-moderate IPF.
TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02013700; URL: www.clinicaltrials.gov.

PMID: 27890713 [PubMed - indexed for MEDLINE]

Prophylaxis with enoxaparin for prevention of venous thromboembolism after lung transplantation: A retrospective study.

Sun, 08/13/2017 - 12:45
Related Articles

Prophylaxis with enoxaparin for prevention of venous thromboembolism after lung transplantation: A retrospective study.

Transpl Int. 2017 Aug 12;:

Authors: Sáez-Giménez B, Berastegui C, Sintes H, Perez J, Figueredo A, López Meseguer M, Monforte V, Bravo C, Santamaría A, Ramon MA, Gómez S, Roman A

Abstract
BACKGROUND: Venous thromboembolism (VTE) is a frequent complication after solid organ transplantation (SOT) and, specifically, after lung transplantation (LT). The objectives of this study were to evaluate prophylaxis with enoxaparin and to describe risk factors for VTE after LT.
METHODS: We retrospectively reviewed the clinical records of 333 patients who underwent LT in our institution between 2009 and 2014. We compared 2 consecutive cohorts, one that received enoxaparin only during post-transplant hospital admissions and a second cohort that received 90-day extended prophylaxis with enoxaparin. Cumulative incidence function for competing risk analysis was used to determine incidence of VTE during the first year after transplantation. Risk factors were analyzed using a Cox proportional hazards regression model.
RESULTS: The cumulative incidence of VTE was 15.3% (95% CI: 11.6-19.4). Median time from transplant to the event was 40 (p25-p75, 14-112) days. Ninety-day extended prophylaxis did not reduce the incidence of VTE. In the present study, the risk factors associated with VTE were male gender and interstitial lung disease.
CONCLUSIONS: VTE is a major complication after LT, and 90-day extended prophylaxis was not able to prevent it. Large, multicenter, randomized clinical trials should be performed to define the best strategy for preventing VTE. This article is protected by copyright. All rights reserved.

PMID: 28801922 [PubMed - as supplied by publisher]

Rational Heart Transplant From Hepatitis C Donor: New Antiviral Weapons Conquer the Trojan.

Sun, 08/13/2017 - 12:45
Related Articles

Rational Heart Transplant From Hepatitis C Donor: New Antiviral Weapons Conquer the Trojan.

J Card Fail. 2017 Aug 08;:

Authors: Gottlieb RL, Sam T, Wada SY, Trotter JF, Asrani SK, Lima B, Joseph SM, Gonzalez-Stawinski G, Hall SA

Abstract
BACKGROUND: Donors with hepatitis C (HCV) viremia are rarely utilized for orthotopic heart transplantation (OHTx) due to post-transplant risks. New, highly effective HCV antivirals may alter the landscape.
METHODS: An adult patient unsuitable for bridging mechanical support therapy accepted a heart transplant offer from a donor with HCV viremia. Upon daily logarithmic rise in HCV viral load and adequate titers to ensure successful genotyping, once daily sofosbuvir 400 mg / velpatasvir 100 mg (Epclusa) was initiated empirically pending HCV genotype (genotype 3a confirmed after initiation of therapy).
RESULTS: We report the kinetics of acute Hepatitis C viremia and therapeutic response to treatment with a new pangenotypic antiviral agent after donor-derived acute HCV infection transmitted incidental to successful cardiac transplant into a HCV negative OHTx recipient. Prompt resolution of viremia was noted by the first week of a 12 week course of antiviral therapy. Sustained virologic remission continues beyond 12 weeks after completion of HCV therapy (SVR-12).
CONCLUSIONS: The availability of effective pangenotypic therapy for HCV may expand donor availability. The feasibility of early versus late treatment of HCV remains to be determined through formalized protocols. We hypothesize pharmacoeconomics to be the greatest limitation to widespread availability of this promising tool.

PMID: 28801074 [PubMed - as supplied by publisher]

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