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Racial differences in the development of de-novo donor-specific antibodies and treated antibody-mediated rejection after heart transplantation.

Tue, 12/05/2017 - 13:45

Racial differences in the development of de-novo donor-specific antibodies and treated antibody-mediated rejection after heart transplantation.

J Heart Lung Transplant. 2017 Nov 04;:

Authors: Cole RT, Gandhi J, Bray RA, Gebel HM, Yin M, Shekiladze N, Young A, Grant A, Mahoney I, Laskar SR, Gupta D, Bhatt K, Book W, Smith A, Nguyen D, Vega JD, Morris AA

Abstract
BACKGROUND: Despite improvements in outcomes after heart transplantation, black recipients have worse survival compared with non-black recipients. The source of such disparate outcomes remains largely unknown. We hypothesize that a propensity to generate de-novo donor-specific antibodies (dnDSA) and subsequent antibody-mediated rejection (AMR) may account for racial differences in sub-optimal outcomes after heart transplant. In this study we aimed to determine the role of dnDSA and AMR in racial disparities in post-transplant outcomes.
METHODS: This study was a single-center, retrospective analysis of 137 heart transplant recipients (81% male, 48% black) discharged from Emory University Hospital. Patients were classified as black vs non-black for the purpose of our analysis. Kaplan-Meier and Cox regression analyses were used to evaluate the association between race and selected outcomes. The primary outcome was the development of dnDSA. Secondary outcomes included treated AMR and a composite of all-cause graft dysfunction or death.
RESULTS: After 3.7 years of follow-up, 39 (28.5%) patients developed dnDSA and 19 (13.8%) were treated for AMR. In multivariable models, black race was associated with a higher risk of developing dnDSA (hazard ratio [HR] 3.65, 95% confidence interval [CI] 1.54 to 8.65, p = 0.003) and a higher risk of treated AMR (HR 4.86, 95% CI 1.26 to 18.72, p = 0.021) compared with non-black race. Black race was also associated with a higher risk of all-cause graft dysfunction or death in univariate analyses (HR 2.10, 95% CI 1.02 to 4.30, p = 0.044). However, in a multivariable model incorporating dnDSA, black race was no longer a significant risk factor. Only dnDSA development was significantly associated with all-cause graft dysfunction or death (HR 4.85, 95% CI 1.89 to 12.44, p = 0.001).
CONCLUSION: Black transplant recipients are at higher risk for the development of dnDSA and treated AMR, which may account for racial disparities in outcomes after heart transplantation.

PMID: 29198929 [PubMed - as supplied by publisher]

Lung autoantibodies: Ready for prime time?

Tue, 12/05/2017 - 13:45

Lung autoantibodies: Ready for prime time?

J Heart Lung Transplant. 2017 Nov 08;:

Authors: Milross L, Hachem R, Levine D, Glanville AR

Abstract
Despite advances in our understanding of the immunology of lung allograft tolerance and a reduction in the rate of acute allograft rejection using contemporary immunosuppressive protocols, the rate of chronic lung allograft dysfunction (CLAD), both obstructive and restrictive, remains unacceptably high. CLAD, particularly the restrictive phenotype, is a harbinger of a foreshortened survival. The development of a consensus approach to the diagnosis of antibody-mediated rejection by the International Society for Heart and Lung Transplantation has highlighted the need for a uniform approach toward the investigation, diagnosis, implications and management of both human leukocyte antigen (HLA) and non-HLA-related antibody formation. This Perspective summarizes the current information that underpins the way forward in recognizing the potential importance of non-HLA-related antibody formation with respect to allograft injury and outcomes.

PMID: 29198928 [PubMed - as supplied by publisher]

Morphologic and immunohistochemical features of pulmonary vasculopathy in end-stage left ventricular systolic failure.

Tue, 12/05/2017 - 13:45

Morphologic and immunohistochemical features of pulmonary vasculopathy in end-stage left ventricular systolic failure.

J Heart Lung Transplant. 2017 Nov 15;:

Authors: Ribeiro de Campos PT, Lopes AA, Issa VS, Aiello VD

PMID: 29198927 [PubMed - as supplied by publisher]

Targeting resolution of pulmonary edema in primary graft dysfunction after lung transplantation: Is inhaled AP301 the answer?

Tue, 12/05/2017 - 13:45

Targeting resolution of pulmonary edema in primary graft dysfunction after lung transplantation: Is inhaled AP301 the answer?

J Heart Lung Transplant. 2017 Nov 16;:

Authors: Ware LB

PMID: 29198870 [PubMed - as supplied by publisher]

The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation.

Tue, 12/05/2017 - 13:45

The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation.

J Heart Lung Transplant. 2017 Oct 22;:

Authors: Choi DH, Chmura SA, Ramachandran V, Dionis-Petersen KY, Kobayashi Y, Nishi T, Luikart H, Dimbil S, Kobashigawa J, Khush K, Lewis DB, Fearon WF

Abstract
BACKGROUND: The aim of this study was to determine the value of the ratio of the percentage of circulating regulatory cluster of differentiation 4 T cells (%Tregs) to the percentage of endothelial progenitor cells (%EPCs; Treg/EPC ratio) for predicting clinically significant acute rejection.
METHODS: Peripheral blood %Tregs and %EPCs were quantified in 91 cardiac transplant recipients using flow cytometry at a mean of 42 ± 13 days after transplant. The primary end point was clinically significant acute rejection, defined as an event that led to an acute augmentation of immunosuppression in conjunction with an International Society for Heart and Lung Transplantation grade ≥ 2R in a right ventricular endomyocardial biopsy specimen or non-cellular rejection (specimen-negative rejection) with hemodynamic compromise (decrease in left ventricular ejection fraction by > 25%).
RESULTS: Significant rejection occurred in 27 recipients (29.7%) during a median of 49.4 months (interquartile range, 37.0-62.0 months). The mean %Tregs and %EPCs were not significantly different between those with and without an episode of significant rejection, but the mean Treg/EPC ratio was significantly lower in recipients with significant rejection (44.9 vs 106.7, p = 0.001). Receiver operating characteristic curve analysis showed an area under the curve value for significant rejection for a Treg/EPC ratio of 0.712. The best cutoff value of the Treg/EPC ratio that distinguished between those with or without significant rejection was ≤ 18 by receiver operating characteristic curve analysis. Kaplan-Meier analysis revealed that patients with a Treg/EPC ratio of ≤ 18 had a significantly higher rate of rejection than those with a Treg/EPC ratio > 18 (61.5% vs 16.9%, log-rank p < 0.0001). A low Treg/EPC ratio was an independent predictor of significant rejection.
CONCLUSIONS: A low Treg/EPC ratio measured soon after heart transplantation is an independent predictor of acute rejection. The Treg/EPC ratio has potential as an early biomarker after heart transplantation for predicting acute rejection.

PMID: 29198869 [PubMed - as supplied by publisher]

An Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of hospitalization, functional status, and mortality after mechanical circulatory support in adults with congenital heart disease.

Tue, 12/05/2017 - 13:45

An Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of hospitalization, functional status, and mortality after mechanical circulatory support in adults with congenital heart disease.

J Heart Lung Transplant. 2017 Nov 17;:

Authors: Cedars A, Vanderpluym C, Koehl D, Cantor R, Kutty S, Kirklin JK

Abstract
BACKGROUND: Adult congenital heart disease (ACHD) prevalence is increasing worldwide, with advanced heart failure (HF) as a leading cause of death. Limited data are available on durable mechanical circulatory support (MCS) in ACHD patients.
METHODS: ACHD patients from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database were identified and propensity matched with non-ACHD patients using risk factors from the INTERMACS Seventh Annual Report. We compared these groups for the primary outcome of post-MCS mortality. We also investigated adverse event rates, functional status, and health-related quality of life.
RESULTS: ACHD (n = 128) and non-ACHD (n = 512) patients were appropriately matched by baseline characteristics. ACHD patients had a longer length of stay at MCS implant (24 vs 19 days, p = 0.006) but similar rates of post-MCS adverse events and hospitalization. There were similar improvements in functional status and health related quality of life post-MCS in both groups. ACHD patients had significantly higher mortality post-MCS exclusively during the first 5 months after implant (p = 0.003) and a lower probability of receiving a transplant (p = 0.003). Risk factors for early mortality were biventricular or total artificial heart device implant and age > 50 years.
CONCLUSIONS: ACHD patients experience a higher early mortality after MCS but have similar adverse event rates and similar improvements in functional capacity and quality of life compared with non-ACHD patients. These data support expansion of MCS use in selected ACHD patients.

PMID: 29198868 [PubMed - as supplied by publisher]

Extracorporeal Membrane Oxygenation: An Expanding Role in Cardiovascular Care.

Tue, 12/05/2017 - 13:45

Extracorporeal Membrane Oxygenation: An Expanding Role in Cardiovascular Care.

Heart Lung Circ. 2018 Jan;27(1):3-5

Authors: Buscher H, Hayward C

PMID: 29198832 [PubMed - in process]

Toronto bridges to successful lung transplantation.

Tue, 12/05/2017 - 13:45

Toronto bridges to successful lung transplantation.

J Thorac Cardiovasc Surg. 2017 Nov 07;:

Authors: Van Raemdonck D, Neyrinck A, Vos R, Verleden GM

PMID: 29198806 [PubMed - as supplied by publisher]

Yesterday's heroic measure is now standard procedure: Extracorporeal membrane oxygenation as a bridge to lung transplant.

Tue, 12/05/2017 - 13:45

Yesterday's heroic measure is now standard procedure: Extracorporeal membrane oxygenation as a bridge to lung transplant.

J Thorac Cardiovasc Surg. 2017 Nov 07;:

Authors: van Berkel V

PMID: 29198789 [PubMed - as supplied by publisher]

Preexisting Cerebral Aspergillosis Successfully Treated After Liver Transplantation: A Case Report.

Tue, 12/05/2017 - 13:45

Preexisting Cerebral Aspergillosis Successfully Treated After Liver Transplantation: A Case Report.

Transplant Proc. 2017 Dec;49(10):2402-2405

Authors: Lee JS, Kim SH, Kwon JH, Yoon YC

Abstract
BACKGROUND: Invasive aspergillosis (IA) is a rare condition that generally affects immunosuppressed patients. The mortality of IA is known to be >90% in liver transplantation (LT) recipients; the lung is the most commonly affected organ, followed by the brain. There have been reports in the literature of cerebral aspergillosis (CA) in LT recipients. In all previous reports, CA developed after LT. We present the first case (to the best of our knowledge) of preexisting CA diagnosed and successfully treated after LT.
CASE REPORT: A 59-year-old male patient underwent emergency deceased-donor LT for alcoholic liver cirrhosis. Preoperative imaging showed multiple lesions in both cerebral hemispheres, indicative of brain abscess or metastases. Before definitive diagnosis of the brain lesion, the deceased-donor LT was performed. On postoperative day 15, the patient developed a fever of 38.0°C and drowsy mental status. Magnetic resonance imaging showed increased number and size of brain abscesses. Stereotactic brain abscess aspiration was performed, and pathologic findings revealed aspergillosis. Voriconazole was started immediately. The patient improved steadily and was discharged 1 month after initiation of voriconazole treatment.
CONCLUSIONS: This case is the first report of preexisting CA treated successfully after LT. Voriconazole is a potent therapeutic agent of CA. When LT is performed with an undiagnosed brain lesion, aggressive diagnostic measures are necessary postoperatively. If CA is diagnosed, successful treatment may be possible with voriconazole.

PMID: 29198690 [PubMed - in process]

Syndrome of Inappropriate Antidiuretic Hormone Secretion Complicating Systemic Nocardiosis in a Renal Transplant Recipient: A Case Report.

Tue, 12/05/2017 - 13:45

Syndrome of Inappropriate Antidiuretic Hormone Secretion Complicating Systemic Nocardiosis in a Renal Transplant Recipient: A Case Report.

Transplant Proc. 2017 Dec;49(10):2368-2371

Authors: Melexopoulou C, Pavlopoulou ID, Zormpala A, Daikos GL, Boletis JN, Marinaki S

Abstract
BACKGROUND: Infection by Nocardia species is an uncommon cause of severe clinical syndromes, particularly in immunocompromised patients, and solid-organ transplantation is the most common underlying condition. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been described thus far in lung and stem cell transplants with systemic nocardiosis.
CASE REPORT: We report the first case of SIADH in a female elderly renal transplant recipient diagnosed with systemic nocardiosis 2 years after transplantation. The SIADH was managed appropriately, and her immunosuppressive regimen remained unchanged but was adjusted at a lower level. The systemic Nocardia infection was successfully treated with intravenous administration of trimethoprim-sulfamethoxazole and imipenem for 2 weeks followed by oral trimethoprim-sulfamethoxazole for a total of 12 months.
CONCLUSIONS: The SIADH syndrome is a recognizable complication of Nocardia infection in renal transplant recipients. Prompt identification along with proper management and prolonged antimicrobial treatment are essential to improve patients' outcome.

PMID: 29198680 [PubMed - in process]

Epidemiology and Risk Factors for Cancer After Lung Transplantation.

Tue, 12/05/2017 - 13:45

Epidemiology and Risk Factors for Cancer After Lung Transplantation.

Transplant Proc. 2017 Dec;49(10):2285-2291

Authors: Berastegui C, LaPorta R, López-Meseguer M, Romero L, Gómez-Ollés S, Riera J, Monforte V, Sáez B, Bravo C, Roman A, Ussetti P

Abstract
Cancer is the third most common cause of death among lung transplant (LT) recipients who survive for more than 1 year. The purpose of this study was to analyze the incidence and risk factors for cancer after LT in a Spanish cohort. The epidemiology and risk factors for cancer were retrospectively analyzed in LT recipients from 2 cities in Spain, Madrid and Barcelona. Of the 1353 LT patients initially included in the study, 125 (9.2%) developed cancer after a mean of 3.7 years. This frequency was 5-fold higher than in the general population. The most prevalent tumors were skin cancer (32%), lymphoproliferative disease (18%), and lung cancer (16.5%). In 4 patients, lung cancer was diagnosed on the day of the operation. The risk of cancer increased with age >55 year (hazard ratio [HR] 2.89 [1.64-5.09]; P < .001), in men (HR 2.8 [1.4-5.6]; P = .004), and in heavy smokers (>20 pack-years) (HR 2.94 [1.64-5.27]; P < .001). Other factors such as sun exposure were not found to be risk factors. In conclusion, prevalence of cancer is high in LT recipients in a Mediterranean country. Skin tumors, lymphoproliferative disease, and lung cancer are the most prevalent cancers. Age, male sex, and smoking were the main risk factors for cancer in this population.

PMID: 29198662 [PubMed - in process]

Analytic Morphomics Predict Outcomes After Lung Transplantation.

Tue, 12/05/2017 - 13:45

Analytic Morphomics Predict Outcomes After Lung Transplantation.

Ann Thorac Surg. 2017 Dec 01;:

Authors: Pienta MJ, Zhang P, Derstine BA, Enchakalody B, Weir WB, Grenda T, Goulson R, Reddy RM, Chang AC, Wang SC, Lin J

Abstract
BACKGROUND: The purpose of this study was to identify morphomic factors on standard, pretransplantation computed tomography (CT) scans associated with outcomes after lung transplantation.
METHODS: A retrospective review of 200 patients undergoing lung transplantation at a single institution from 2003 to 2014 was performed. CT scans obtained within 1 year before transplantation underwent morphomic analysis. Morphomic characteristics included lung, dorsal muscle group, bone, and subcutaneous and visceral fat area and density. Patient data were gathered from institutional and United Network for Organ Sharing databases. Outcomes, including initial ventilator support greater than 48 hours, length of stay, and survival, were evaluated using univariate and multivariable analyses.
RESULTS: On multivariable Cox regression, subcutaneous fat/total body area (hazard ratio [HR] 0.60, p = 0.001), lung density 3 volume (HR 0.67, p = 0.013), and creatinine (HR 4.37, p = 0.010) were independent predictors of survival. Initial ventilator support more than 48 hours was associated with decreased vertebral body to linea alba distance (odds ratio [OR] 0.49, p = 0.002) and Zubrod score 4 (OR 14.0, p < 0.001). Increased bone mineral density (p < 0.001) and increased cross-sectional body area (p < 0.001) were associated with decreased length of stay, whereas supplemental oxygen (p < 0.001), bilateral transplantation (p = 0.002), cardiopulmonary bypass (p < 0.001), and Zubrod score 3 (p < 0.001) or 4 (p = 0.040) were associated with increased length of stay.
CONCLUSIONS: Morphomic factors associated with lower metabolic reserve and frailty, including decreased subcutaneous fat, bone density, and body dimensions were independent predictors of survival, prolonged ventilation, and increased length of stay. Analytic morphomics using pretransplantation CT scans may improve recipient selection and risk stratification.

PMID: 29198627 [PubMed - as supplied by publisher]

Infants with Atypical Presentations of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins Who Underwent Bilateral Lung Transplantation.

Tue, 12/05/2017 - 13:45

Infants with Atypical Presentations of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins Who Underwent Bilateral Lung Transplantation.

J Pediatr. 2017 Nov 30;:

Authors: Towe CT, White FV, Grady RM, Sweet SC, Eghtesady P, Wegner DJ, Sen P, Szafranski P, Stankiewicz P, Hamvas A, Cole FS, Wambach JA

Abstract
OBJECTIVE: To describe disease course, histopathology, and outcomes for infants with atypical presentations of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) who underwent bilateral lung transplantation.
STUDY DESIGN: We reviewed clinical history, diagnostic studies, explant histology, genetic sequence results, and post-transplant course for 6 infants with atypical ACDMPV who underwent bilateral lung transplantation at St. Louis Children's Hospital. We compared their histology with infants with classic ACDMPV and compared their outcomes with infants transplanted for other indications.
RESULTS: In contrast with neonates with classic ACDPMV who present with severe hypoxemia and refractory pulmonary hypertension within hours of birth, none of the infants with atypical ACDMPV presented with progressive neonatal respiratory failure. Three infants had mild neonatal respiratory distress and received nasal cannula oxygen. Three other infants had no respiratory symptoms at birth and presented with hypoxemia and pulmonary hypertension at 2-3 months of age. Bilateral lung transplantation was performed at 4-20 months of age. Unlike in classic ACDMPV, histopathologic findings were not distributed uniformly and were not diffuse. Three subjects had apparent nonmosaic genetic defects involving FOXF1. Two infants had extrapulmonary anomalies (posterior urethral valves, inguinal hernia). Three transplanted children are alive at 5-16 years of age, similar to outcomes for infants transplanted for other indications. Lung explants from infants with atypical ACDMPV demonstrated diagnostic but nonuniform histopathologic findings.
CONCLUSIONS: The 1- and 5-year survival rates for infants with atypical ACDMPV are similar to infants transplanted for other indications. Given the clinical and histopathologic spectra, ACDMPV should be considered in infants with hypoxemia and pulmonary hypertension, even beyond the newborn period.

PMID: 29198536 [PubMed - as supplied by publisher]

First-in-Man Fully Percutaneous Complete Bypass of Heart and Lung.

Tue, 12/05/2017 - 13:45

First-in-Man Fully Percutaneous Complete Bypass of Heart and Lung.

JACC Cardiovasc Interv. 2017 Nov 18;:

Authors: Napp LC, Vogel-Claussen J, Schäfer A, Haverich A, Bauersachs J, Kühn C, Tongers J

PMID: 29198456 [PubMed - as supplied by publisher]

Fractures frequently occur in older cancer patients: the MD Anderson Cancer Center experience.

Tue, 12/05/2017 - 13:45

Fractures frequently occur in older cancer patients: the MD Anderson Cancer Center experience.

Support Care Cancer. 2017 Dec 02;:

Authors: Edwards BJ, Sun M, Zhang X, Holmes HM, Song J, Khalil P, Karuturi M, Shah JB, Dinney CP, Gagel RF, Valero V, Champlin RE, Tripathy D, Murphy WA

Abstract
PURPOSE AND INTRODUCTION: A growing number of cancer patients are older adults aged 65 years and older. Patients with cancer are at increased risk for developing osteoporosis, falls, and fractures. We sought to identify the incidence of fractures in older adults who underwent cancer care between January 2013 and December 2015.
METHODS: A comprehensive geriatric assessment was performed, and bone densitometry was measured at baseline, with a 2-year follow-up.
RESULTS: In this study, among 304 patients with gastrointestinal, urologic, breast, lung, and gynecologic cancers we evaluated, and who completed the bone density testing (n = 199), 80% had osteoporosis or low bone mass (osteopenia). There was a higher prevalence of osteoporosis in cancer patients (40 vs. 16%, p = 0.05) than in population studies. Vitamin D insufficiency (< 30 ng/ml) was identified in 49% of tested cases (n = 245). Risk factors for low bone mass or osteoporosis were advanced age (p = 0.05), malnutrition (p = 0.04), and frailty (p = 0.01). Over the following 2 years (median follow-up 18 months), there was an incidence of fractures of 110 per 1000 person-years, or 2.8 times higher than reported in individuals without cancer. Risk factors for fractures included advanced age (70-79 vs. 60-69 years, p = 0.05) and frailty (p = 0.03).
CONCLUSION: Most older cancer patients studied have osteoporosis or low bone mass, resulting in an almost 3-fold increase in fracture risk as compared to epidemiologic studies. Bone health issues are commonly seen in older cancer patients, we recommend universal bone density testing. The initiation of antiresorptive treatment when findings are of osteopenia or osteoporosis will reduce the risk of fractures.

PMID: 29197959 [PubMed - as supplied by publisher]

Distinct Biomarker Profiles in Ex-Vivo T Cell Depletion Graft Manipulation Strategies: CD34+ Selection vs CD3+/19+ Depletion in Matched Sibling Allogeneic Peripheral Blood Stem Cell Transplantation.

Tue, 12/05/2017 - 13:45

Distinct Biomarker Profiles in Ex-Vivo T Cell Depletion Graft Manipulation Strategies: CD34+ Selection vs CD3+/19+ Depletion in Matched Sibling Allogeneic Peripheral Blood Stem Cell Transplantation.

Biol Blood Marrow Transplant. 2017 Nov 29;:

Authors: Cantilena CR, Ito S, Tian X, Jain P, Chinian F, Anandi P, Keyvanfar K, Draper D, Koklanaris E, Hauffe S, Superata J, Stroncek D, Muranski P, Barrett AJ, Battiwalla M

Abstract
Various approaches have been developed for ex vivo T cell depletion in allogeneic stem cell transplantation to prevent graft versus host disease (GVHD). However, direct comparisons between T-cell depletion strategies have not been well studied. We evaluated cellular and plasma biomarkers in two different graft manipulation strategies: CD3+CD19+ cell depletion (CD3/19D) versus CD34+ selection (CD34S) and their association with clinical outcomes. Identical conditions including the myeloablative preparative regimen, HLA-identical sibling donor, GVHD prophylaxis, and graft source were used for each cohort. Major clinical outcomes were similar between the two groups in terms of overall survival, non-relapse mortality, and cumulative incidence of relapse, however, the cumulative incidence of acute GVHD trended to be higher in CD3/19D compared to CD34S. A distinct biomarker profile was noted in the CD3/19D cohort: higher levels of ST2, impaired Helios- FoxP3+Tregs reconstitution, and rapid reconstitution of naïve, Th2, and Th17 CD4 cells in the early post-transplant period. In vitro graft replication studies confirmed that CD3/19D disproportionately depleted Tregs and other CD4 subset repertoires in the graft. This study confirmed the utility of biomarker monitoring which can be directly correlated to biological consequences and possible future therapeutic indications.

PMID: 29197677 [PubMed - as supplied by publisher]

A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.

Tue, 12/05/2017 - 13:45
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A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.

Nat Immunol. 2017 Dec;18(12):1310-1320

Authors: Machiels B, Dourcy M, Xiao X, Javaux J, Mesnil C, Sabatel C, Desmecht D, Lallemand F, Martinive P, Hammad H, Guilliams M, Dewals B, Vanderplasschen A, Lambrecht BN, Bureau F, Gillet L

Abstract
The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the TH2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.

PMID: 29035391 [PubMed - indexed for MEDLINE]

SIRT7 antagonizes TGF-β signaling and inhibits breast cancer metastasis.

Tue, 12/05/2017 - 13:45
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SIRT7 antagonizes TGF-β signaling and inhibits breast cancer metastasis.

Nat Commun. 2017 08 22;8(1):318

Authors: Tang X, Shi L, Xie N, Liu Z, Qian M, Meng F, Xu Q, Zhou M, Cao X, Zhu WG, Liu B

Abstract
Distant metastasis is the main cause of breast cancer-related death; however, effective therapeutic strategies targeting metastasis are still scarce. This is largely attributable to the spatiotemporal intratumor heterogeneity during metastasis. Here we show that protein deacetylase SIRT7 is significantly downregulated in breast cancer lung metastases in human and mice, and predicts metastasis-free survival. SIRT7 deficiency promotes breast cancer cell metastasis, while temporal expression of Sirt7 inhibits metastasis in polyomavirus middle T antigen breast cancer model. Mechanistically, SIRT7 deacetylates and promotes SMAD4 degradation mediated by β-TrCP1, and SIRT7 deficiency activates transforming growth factor-β signaling and enhances epithelial-to-mesenchymal transition. Significantly, resveratrol activates SIRT7 deacetylase activity, inhibits breast cancer lung metastases, and increases survival. Our data highlight SIRT7 as a modulator of transforming growth factor-β signaling and suppressor of breast cancer metastasis, meanwhile providing an effective anti-metastatic therapeutic strategy.Metastatic disease is the major reason for breast cancer-related deaths; therefore, a better understanding of this process and its players is needed. Here the authors report the role of SIRT7 in inhibiting SMAD4-mediated breast cancer metastasis providing a possible therapeutic avenue.

PMID: 28827661 [PubMed - indexed for MEDLINE]

Lasp2 enhances tumor invasion via facilitating phosphorylation of FAK and predicts poor overall survival of non-small cell lung cancer patients.

Tue, 12/05/2017 - 13:45
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Lasp2 enhances tumor invasion via facilitating phosphorylation of FAK and predicts poor overall survival of non-small cell lung cancer patients.

Mol Carcinog. 2017 Dec;56(12):2558-2565

Authors: Zhang X, Cai L, Zhou H, Liu Y, Fan C, Wang L, Li A, Miao Y, Li Q, Qiu X, Wang E

Abstract
Lasp2, as well as Lasp1, is a member of the LIM-protein subfamily of the nebulin group characterized by the combined presence of LIM and SH3 domains. Lasp1 and Lasp2 are highly conserved in their LIM, nebulin-like, and SH3 domains but differ significantly at their linker regions. Lasp1 had been described as an oncogenic protein that was highly expressed in diverse cancer types and facilitated tumor proliferation, invasion, and metastasis process. However, unlike Lasp1, little is known about the functions of Lasp2. In the present study, using immunohistochemistry, we found that Lasp2 expression was significantly correlated with histological type (P = 0.012), advanced TNM stage (P = 0.024), positive regional lymph node metastasis (P = 0.035), and poor overall survival (P = 0.001). Would healing assay and transwell assay results indicated that Lasp2 promoted tumor migration and invasion in NSCLC cells. Furthermore, Lasp2 facilitated Snail expression and inhibited Zo-1. The levels of phosphorylated FAK (Tyr397 and Tyr925) were obviously increased after overexpressing Lasp2 and were downregulated by transfecting Lasp2-siRNA. FAK inhibitor counteracted upregulating Snail expression and downregulating of Zo-1 expression induced by Lasp2 overexpression. Taken together, Lasp2 may facilitate tumor migration and invasion of NSCLCs through FAK-Snail/Zo-1 signaling pathway. Lasp2 may be a potential prognostic predictor of NSCLC patients.

PMID: 28667800 [PubMed - indexed for MEDLINE]

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