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Three-dimensional image in lung transplantation.

Thu, 10/19/2017 - 12:45
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Three-dimensional image in lung transplantation.

Gen Thorac Cardiovasc Surg. 2017 Oct 16;:

Authors: Chen-Yoshikawa TF, Date H

Abstract
Three-dimensional computed tomography (3D-CT) technologies have been developed and, recently, high-speed and high-quality 3D-CT technologies have been introduced to the field of thoracic surgery. The purpose of this manuscript is to demonstrate the clinical application of 3D-CT technologies in lung transplantation. In Japan, because of the severe donor shortage, living-donor lobar lung transplantation (LDLLT) is essential, in addition to cadaveric lung transplantation. In LDLLT, size matching is a grave issue, since ideal size matching between donor and recipient is usually difficult because of the limited population of potential donor. Size matching using pulmonary function test results has been widely used as a gold standard, but anatomical size matching using 3D-CT volumetry data has also been utilized in LDLLT. In donor lobectomy, 3D-CT images provided a variety of information regarding anatomical variation of pulmonary vessels and bronchial trees preoperatively. These images ensure surgical quality and safety, and they also affect surgical procedures for the recipient. 3D-CT images are also utilized in various aspects of postoperative care, such as detection of chronic lung allograft dysfunction and clarification of its subtypes. Furthermore, preoperative 3D-CT simulation is useful in developing and performing a special surgical procedure, such as right-to-left inverted LDLLT. In conclusion, following the introduction of 3D-CT to the field of thoracic surgery, various 3D-CT images and their application to preoperative simulations have been introduced in lung transplantation. In the near future, this technique will become more prevalent, and frequent use by thoracic surgeons will be seen worldwide in daily practice.

PMID: 29039137 [PubMed - as supplied by publisher]

TRIM29 promotes DNA virus infections by inhibiting innate immune response.

Thu, 10/19/2017 - 12:45
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TRIM29 promotes DNA virus infections by inhibiting innate immune response.

Nat Commun. 2017 Oct 16;8(1):945

Authors: Xing J, Zhang A, Zhang H, Wang J, Li XC, Zeng MS, Zhang Z

Abstract
Many double-stranded DNA viruses, such as Epstein-Barr virus, can establish persistent infection, but the underlying virus-host interactions remain poorly understood. Here we report that in human airway epithelial cells Epstein-Barr virus induces TRIM29, a member of the TRIM family of proteins, to inhibit innate immune activation. Knockdown of TRIM29 in airway epithelial cells enhances type I interferon production, and in human nasopharyngeal carcinoma cells results in almost complete Epstein-Barr virus clearance. TRIM29 is also highly induced by cytosolic double-stranded DNA in myeloid dendritic cells. TRIM29 (-/-) mice have lower adenovirus titers in the lung, and are resistant to lethal herpes simplex virus-1 infection due to enhanced production of type I interferon. Mechanistically, TRIM29 induces K48-linked ubiquitination of Stimulator of interferon genes, a key adaptor in double-stranded DNA-sensing pathway, followed by its rapid degradation. These data demonstrate that Epstein-Barr virus and possible other double-stranded DNA viruses use TRIM29 to suppress local innate immunity, leading to the persistence of DNA virus infections.Proteins of the TRIM family have regulatory functions in immune signaling, often via ubiquitination of target proteins. Here, the authors show that TRIM29 is induced upon infection with DNA viruses, resulting in degradation of STING, decreased interferon signaling and increased pathogenicity in mice.

PMID: 29038422 [PubMed - in process]

Tuberculosis in recipients of solid-organ transplants during 1995-2015 in Cali, Colombia.

Thu, 10/19/2017 - 12:45
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Tuberculosis in recipients of solid-organ transplants during 1995-2015 in Cali, Colombia.

Int J Tuberc Lung Dis. 2017 Nov 01;21(11):1155-1159

Authors: García-Goez JF, Munera GA, Rojas V, Pacheco R, Caylá JA, Miro JM

Abstract
SETTING: Tuberculosis (TB) in solid-organ transplants (SOTs) is an important opportunistic infection associated with mortality and graft loss. SOT recipients carry a higher risk of contracting active TB than the general population. Clinical and radiographic presentations are non-specific, and sputum smear and culture have low yields. TB patients with SOTs require standard anti-tuberculosis treatment. However, rifampicin (RMP) use is associated with a 30% rate of acute graft rejection (AGR) and a 20% rate of transplant loss.
OBJECTIVE: To determine treatment outcomes in SOT recipients with active TB.
DESIGN: A retrospective study of clinical and microbiological data and TB treatment outcomes.
RESULTS: Among the 2349 transplants assessed, active TB was detected in 31 recipients; 55% had pulmonary TB and 40% were sputum smear-positive. In 32% of the patients, TB was diagnosed 30 days after symptom onset, 77% of the patients were cured and 10% died. AGR occurred in 13%.
CONCLUSION: TB was diagnosed in <30 days. Anti-tuberculosis treatment without RMP (80% vs. 67%; P = 0.48, OR 0.5, 95%CI 0.07-3.55) and with moxifloxacin yielded higher treatment success rates and a lower risk of AGR.

PMID: 29037296 [PubMed - in process]

Heparin improves BMSC cell therapy: Anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy.

Thu, 10/19/2017 - 12:45
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Heparin improves BMSC cell therapy: Anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy.

Theranostics. 2017;7(1):106-116

Authors: Liao L, Shi B, Chang H, Su X, Zhang L, Bi C, Shuai Y, Du X, Deng Z, Jin Y

Abstract
Systemic infusion of bone marrow-derived mesenchymal stem cells (BMSCs) has become a promising strategy for disease treatment and tissue regeneration. Strategies to enhance the efficiency of BMSC cell therapy are crucial to promote its clinical application. Here, we aimed to improve BMSC cell therapy by inhibiting the BMSC-induced coagulation reaction. Intravenous injection of gradient BMSCs into mice showed that BMSCs were not fully compatible with blood. Large doses of BMSCs induced a series of symptoms of respiratory failure and heart failure. Histological and homeostasis analysis confirmed that large doses of BMSCs induced disseminated intravascular thrombosis, exhaustion of platelets and coagulation factors, and prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT). Similar to mouse BMSCs, goat and human BMSCs also induced coagulation reactions in vitro and in vivo. The coagulation was induced mostly by tissue factor, the overexpression of which enhanced the procoagulant activity of BMSCs during in vitro culture. Notably, clinical doses of BMSCs in cell therapy also induced mild and reversible coagulation, which increased BMSC lung embolism and clearance. Anticoagulation treatment by heparin (400 U/kg) prevented BMSC-induced coagulation and the acute adverse effects of large-dose BMSCs infusion efficiently. Importantly, heparin treatment led to decreased BMSC lung embolism and enhanced migration and maintenance of BMSCs to target organs in cell therapy. Based on an experimental colitis model, we confirmed that heparin treatment enhanced the effect of BMSC therapy efficiently to reduce mortality, prevent weight loss, suppress inflammation reaction and alleviate tissue injury. In conclusion, BMSCs possess procoagulant activity that could induce disseminated coagulation and thrombosis in recipients. Anticoagulation treatment by heparin is a practical strategy to improve both the safety and therapeutic effect of BMSC therapy.

PMID: 28042320 [PubMed - indexed for MEDLINE]

X-Ray Induced Photodynamic Therapy: A Combination of Radiotherapy and Photodynamic Therapy.

Thu, 10/19/2017 - 12:45
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X-Ray Induced Photodynamic Therapy: A Combination of Radiotherapy and Photodynamic Therapy.

Theranostics. 2016;6(13):2295-2305

Authors: Wang GD, Nguyen HT, Chen H, Cox PB, Wang L, Nagata K, Hao Z, Wang A, Li Z, Xie J

Abstract
Conventional photodynamic therapy (PDT)'s clinical application is limited by depth of penetration by light. To address the issue, we have recently developed X-ray induced photodynamic therapy (X-PDT) which utilizes X-ray as an energy source to activate a PDT process. In addition to breaking the shallow tissue penetration dogma, our studies found more efficient tumor cell killing with X-PDT than with radiotherapy (RT) alone. The mechanisms behind the cytotoxicity, however, have not been elucidated. In the present study, we investigate the mechanisms of action of X-PDT on cancer cells. Our results demonstrate that X-PDT is more than just a PDT derivative but is essentially a PDT and RT combination. The two modalities target different cellular components (cell membrane and DNA, respectively), leading to enhanced therapy effects. As a result, X-PDT not only reduces short-term viability of cancer cells but also their clonogenecity in the long-run. From this perspective, X-PDT can also be viewed as a unique radiosensitizing method, and as such it affords clear advantages over RT in tumor therapy, especially for radioresistant cells. This is demonstrated not only in vitro but also in vivo with H1299 tumors that were either subcutaneously inoculated or implanted into the lung of mice. These findings and advances are of great importance to the developments of X-PDT as a novel treatment modality against cancer.

PMID: 27877235 [PubMed - indexed for MEDLINE]

Spironolactone-induced Degradation of the TFIIH Core Complex XPB Subunit Suppresses NF-κB and AP-1 Signaling.

Tue, 10/17/2017 - 12:45

Spironolactone-induced Degradation of the TFIIH Core Complex XPB Subunit Suppresses NF-κB and AP-1 Signaling.

Cardiovasc Res. 2017 Sep 27;:

Authors: Elinoff JM, Chen LY, Dougherty EJ, Awad KS, Wang S, Biancotto A, Siddiqui AH, Weir NA, Cai R, Sun J, Preston IR, Solomon MA, Danner RL

PMID: 29036418 [PubMed - as supplied by publisher]

The activity of nintedanib in an animal model of allogenic left lung transplantation resembling aspects of allograft rejection.

Tue, 10/17/2017 - 12:45

The activity of nintedanib in an animal model of allogenic left lung transplantation resembling aspects of allograft rejection.

Exp Lung Res. 2017 Oct 16;:1-12

Authors: von Suesskind-Schwendi M, Boxhammer E, Hirt SW, Schreml S, Schmid C, Wollin L, Lehle K

Abstract
AIM OF THE STUDY: The prevention and treatment of chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx) remain unsatisfactory. Growth factors may play an important role in the development of CLAD. This study evaluated the effects of nintedanib, a receptor tyrosine kinase inhibitor, in the treatment of CLAD after experimental LTx.
MATERIALS AND METHODS: A rat model of left lung allo-transplantation (Fisher 344 to Wistar Kyoto) was used to evaluate the effect of nintedanib (50 mg/kg per day) on the development of CLAD. Therapy with nintedanib began 2 days before LTx and ended on postoperative day (POD) 20 (n = 6) or 60 (n = 6). Nontreated animals who underwent LTx (n = 12) were used as controls, whereas naïve lungs (n = 24) served as reference for physiological healthy organs without transplantation damage or medical effects. Acute and chronic rejection were evaluated on POD 20 and 60, respectively.
RESULTS: Immunohistologic analysis showed a decrease in growth factors/receptors on POD 60 (nintedanib-treated vs. nontreated controls: platelet-derived growth factor (PDGF) A: [P ≤ 0.001]; PDGF receptor-α: [P ≤ 0.001]; vascular endothelial growth factor (VEGF) A: [P ≤ 0.001]; VEGF receptor-2: [P ≤ 0.001]). However, no reductions in fibrotic changes were observed in nintedanib-treated allografts compared with nontreated allografts. Although nintedanib treatment started before LTx none of the animals showed impaired wound healing. No dehiscence of the sutures of the bronchus, vessels or skin, or stenosis of the bronchus was found.
CONCLUSION: In conclusion, while nintedanib reduced the expression of growth factors/receptors in a rat LTx model, a reduction in fibrotic alterations was not observed at POD 60.

PMID: 29035589 [PubMed - as supplied by publisher]

Risks factors and timing of genital human papillomavirus (HPV) infection in female stem cell transplant survivors: a longitudinal study.

Tue, 10/17/2017 - 12:45

Risks factors and timing of genital human papillomavirus (HPV) infection in female stem cell transplant survivors: a longitudinal study.

Bone Marrow Transplant. 2017 Oct 16;:

Authors: Shanis D, Anandi P, Grant C, Bachi A, Vyas N, Merideth MA, Pophali PA, Koklanaris E, Ito S, Savani BN, Barrett AJ, Battiwalla M, Stratton P

Abstract
This longitudinal single-center study describes the timing and risk factors for genital human papillomavirus (HPV) disease in women after allogeneic hematopoietic cell transplantation (HCT). Between 1994 and 2014, 109 females underwent HCT of whom 82 surviving transplant for >1 year had regular, comprehensive genital tract assessment and treatment of HPV disease. The cumulative proportions of any genital HPV infection at 1, 3, 5, 10 and 20 years were 4.8%, 14.9%, 28.1%, 36.7% and 40.9%, respectively. Demographic, disease-related factors, chronic GvHD (cGvHD) and its treatment were analyzed for their association with persistent, multifocal or severe genital HPV disease. Pre-transplant HPV disease was strongly associated with any posttransplant HPV (odds ratio (OR)=6.5, 95% confidence interval (CI)=1.65-25.85, P=0.008). Having either extensive or genital cGvHD was associated with increased risk of any HPV disease (OR=5.7, 95% CI=1.90-17.16, P=0.002) and a higher risk for severe genital dysplasia (CIN II-III/VIN II-III; OR=13.1, 95% CI=1.59-108.26, P=0.017), but no one developed HPV-related genital cancer. Persistent, multifocal or severe HPV disease occurred more frequently than in healthy populations. Women with extensive cGvHD, genital cGvHD or pre-transplant HPV are at greatest risk for post-transplant HPV disease. Early initiation of annual screening, comprehensive genital tract assessment and active management are cornerstones of their gynecology care.Bone Marrow Transplantation advance online publication, 16 October 2017; doi:10.1038/bmt.2017.210.

PMID: 29035398 [PubMed - as supplied by publisher]

Use of sacubitril/valsartan in acute decompensated heart failure: a case report.

Tue, 10/17/2017 - 12:45

Use of sacubitril/valsartan in acute decompensated heart failure: a case report.

ESC Heart Fail. 2017 Oct 16;:

Authors: Bell TD, Mazer AJ, Miller PE, Strich JR, Sachdev V, Wright ME, Solomon MA

Abstract
Refractory heart failure typically requires costly long-term, continuous intravenous inodilator infusions while patients await mechanical circulatory support or cardiac transplantation. The combined angiotensin receptor blocker-neprilysin inhibitor, sacubitril/valsartan, is a novel therapy that can increase levels of endogenous vasoactive peptides. This therapy has been recommended as an alternative agent in patients with chronic heart failure with reduced ejection fraction and New York Heart Association class II-III symptoms. Here, we report a case of a patient with refractory stage D heart failure with reduced ejection fraction who was successfully weaned off continuous intravenous inodilator support using sacubitril/valsartan after prior failed attempts using standard therapies.

PMID: 29035000 [PubMed - as supplied by publisher]

Clodronate Improves Survival of Transplanted Hoxb8 Myeloid Progenitors with Constitutively Active GMCSFR in Immunocompetent Mice.

Tue, 10/17/2017 - 12:45
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Clodronate Improves Survival of Transplanted Hoxb8 Myeloid Progenitors with Constitutively Active GMCSFR in Immunocompetent Mice.

Mol Ther Methods Clin Dev. 2017 Dec 15;7:60-73

Authors: Lee S, Kivimäe S, Szoka FC

Abstract
New methods to produce large numbers of myeloid progenitor cells, precursors to macrophages (MΦs), by maintaining Hoxb8 transcription factor activity(1) has reinvigorated interest in MΦ cell therapies. We generated Hoxb8-dependent myeloid progenitors (HDPs) by transducing lineage-negative bone marrow cells with a constitutively expressed Hoxb8 flanked by loxP. HDPs proliferate indefinitely and differentiate into MΦ when Hoxb8 is removed by a tamoxifen-inducible Cre. We genetically modified HDPs with a constitutively active GMCSF receptor and the tamoxifen-induced transcription factor IRF8, which we have termed "HDP-on." The HDP-on proliferates without GMCSF and differentiates into the MΦ upon exposure to tamoxifen and ruxolitinib (GMCSF inhibitor via JAK1/2 blockade). We quantified the biodistribution of HDPs transplanted via intraperitoneal injection into immunodeficient NCG mice with a luciferase reporter; HDPs are detected for 14 days in the peritoneal cavity, liver, spleen, kidney, bone marrow, brain, lung, heart, and blood. In immunocompetent BALB/c mice, HDP-on cells, but not HDPs, are detected 1 day post-transplantation in the peritoneal cavity. Pretreatment of BALB/c mice with liposomal clodronate significantly enhances survival at day 7 for HDPs and HDP-on cells in the peritoneal cavity, spleen, and liver, but cells are undetectable at day 14. Short-term post-transplantation survival of HDPs is significantly improved using HDP-on and liposomal clodronate, opening a path for MΦ-based therapeutics.

PMID: 29034260 [PubMed]

The first Italian heart transplantation: The history of the pioneers' experience.

Tue, 10/17/2017 - 12:45
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The first Italian heart transplantation: The history of the pioneers' experience.

J Heart Lung Transplant. 2017 Sep 25;:

Authors: Zanatta A, Zampieri F

PMID: 29033163 [PubMed - as supplied by publisher]

Lung Transplantation for Pulmonary Hypertension and Strategies to Bridge to Transplant.

Tue, 10/17/2017 - 12:45
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Lung Transplantation for Pulmonary Hypertension and Strategies to Bridge to Transplant.

Semin Respir Crit Care Med. 2017 Oct;38(5):701-710

Authors: Baillie TJ, Granton JT

PMID: 29032570 [PubMed - in process]

Surgical Thoracic Transplant Training: Super Fellowship-Is It Super?

Tue, 10/17/2017 - 12:45
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Surgical Thoracic Transplant Training: Super Fellowship-Is It Super?

J Surg Educ. 2017 Oct 11;:

Authors: Makdisi G, Makdisi T, Caldeira CC, Wang IW

Abstract
OBJECTIVE: The quality of training provided to thoracic transplant fellows is a critical step in the care of complex patients undergoing transplant. The training varies since it is not an accreditation council for graduate medical education accredited fellowship.
METHOD: A total of 104 heart or lung transplant program directors throughout the United States were sent a survey of 24 questions focusing on key aspects of training, fellowship training content and thoracic transplant job satisfaction. Out of the 104 programs surveyed 45 surveys (43%) were returned.
RESULTS: In total, 26 programs offering a transplant fellowship were included in the survey. Among these programs 69% currently have fellows of which 56% are American Board of Thoracic Surgery board eligible. According to the United Network for Organ Sharing (UNOS) requirements, 46% of the programs do not meet the requirements to be qualified as a primary heart transplant surgeon. A total of 23% of lung transplant programs also perform less than the UNOS minimum requirements. Only 24% have extra-surgical curriculum. Out of the participating programs, only 38% of fellows secured a job in a hospital setting for performing transplants. An astounding 77% of replies site an unpredictable work schedule as the main reason that makes thoracic transplant a less than favorable profession among new graduates. Long hours were also a complaint of 69% of graduates who agreed that their personal life is affected by excessive work hours.
CONCLUSION: Annually, almost half of all thoracic transplant programs perform fewer than the UNOS requirements to be a primary thoracic surgeon. This results in a majority of transplant fellows not finding a suitable transplant career. The current and future needs for highly qualified thoracic transplant surgeons will not be met through our existing training mechanisms.

PMID: 29031521 [PubMed - as supplied by publisher]

Dynamic right ventricular outflow obstruction: A rare cause of hypotension during anestesia induction.

Tue, 10/17/2017 - 12:45
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Dynamic right ventricular outflow obstruction: A rare cause of hypotension during anestesia induction.

Int J Surg Case Rep. 2017 Oct 05;41:30-32

Authors: Antoniucci ME, Colizzi C, Arlotta G, Calabrese M, Corrado M, Guarneri S, Martinelli L, Scapigliati A, Zamparelli R, Cavaliere F

Abstract
INTRODUCTION: Dynamic obstruction of right ventricle outflow tract (RVOTO) is a rare condition that may acutely cause severe heart failure. It has been reported in some hypertrophic cardiomyopathies, after lung transplantation, and in some cases of hemodynamic instability after cardiopulmonary bypass.
PRESENTATION OF CASE: We report the case of a 71-year-old man who developed severe hypotension during the induction of general anesthesia for surgical coronary revascularization. Hypotension did not respond to the initial treatment with vasoconstrictors and fluids. RVOTO was suspected during pulmonary artery catheterization because of the difficulty of the catheter tip to move from the right ventricle to the pulmonary artery and, successively, because of the finding of a large gradient between the systolic pressure in the right ventricle and in the pulmonary artery. The diagnosis was confirmed by transesophageal echocardiogram (TEE). Hemodynamics recovered after the infusion of cristalloids, 1L, and the suspension of vasoconstrictors and inotropes.
DISCUSSION: This is the first case in which RVOTO was observed during the induction of general anesthesia. Although this is a rare condition, the diagnostic suspect is of outmost importance because treatment is mainly based on fluid administration, and drugs with positive inotropic properties (like most vasoconstrictors) are contraindicated.
CONCLUSIONS: RVOTO is an unusual, but possible cause of severe arterial hypotension during general anesthesia induction. TEE is useful for the evaluation of severely hypotensive patients who do not respond to routine treatment with fluids and vasoconstrictors.

PMID: 29031174 [PubMed - as supplied by publisher]

The competitive nature of STAT complex formation drives phenotype switching of T cells.

Tue, 10/17/2017 - 12:45
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The competitive nature of STAT complex formation drives phenotype switching of T cells.

Immunology. 2017 Oct 14;:

Authors: Sadreev II, Chen MZQ, Umezawa Y, Biktashev VN, Kemper C, Salakhieva DV, Welsh GI, Kotov NV

Abstract
Signal transducers and activators of transcription (STATs) are key molecular determinants of T cell fate and effector function. Several inflammatory diseases are characterized by an altered balance of T cell phenotypes and cytokine secretion. STATs, therefore, represent viable therapeutic targets in numerous pathologies. However, the underlying mechanisms by which the same STAT proteins regulate both the development of different T cell phenotypes and their plasticity during changes in extracellular conditions remain unclear. In this study, we investigated the STAT-mediated regulation of T cell phenotype formation and plasticity using mathematical modeling and experimental data for intracellular STAT signaling proteins. The close fit of our model predictions to the experimental data allows us to propose a potential mechanism for T cell switching. According to this mechanism, T cell phenotype switching is due to the relative redistribution of STAT dimer complexes caused by the extracellular cytokine-dependent STAT competition effects. The developed model predicts that the balance between the intracellular STAT species defines the amount of the produced cytokines and thereby T cell phenotypes. The model predictions are consistent with the experimentally observed IFN-γ to IL-10 switching that regulates human Th1/Tr1 responses. The proposed model is applicable to a number of STAT signaling circuits. This article is protected by copyright. All rights reserved.

PMID: 29030870 [PubMed - as supplied by publisher]

Survival of Idiopathic Pulmonary Arterial Hypertension Patients in the Modern Era in Australia and New Zealand.

Tue, 10/17/2017 - 12:45
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Survival of Idiopathic Pulmonary Arterial Hypertension Patients in the Modern Era in Australia and New Zealand.

Heart Lung Circ. 2017 Sep 20;:

Authors: Strange G, Lau EM, Giannoulatou E, Corrigan C, Kotlyar E, Kermeen F, Williams T, Celermajer DS, Dwyer N, Whitford H, Wrobel JP, Feenstra J, Lavender M, Whyte K, Collins N, Steele P, Proudman S, Thakkar V, Keating D, Keogh A, PHSANZ Registry

Abstract
BACKGROUND: Epidemiology and treatment strategies continue to evolve in pulmonary arterial hypertension (PAH). We sought to define the characteristics and survival of patients with idiopathic, heritable and drug-induced PAH in the current management era.
METHODS: Consecutive cases of idiopathic, heritable and drug-induced PAH were prospectively enrolled into an Australian and New Zealand Registry.
RESULTS: Between January 2012 and December 2016, a total of 220 incident cases were enrolled (mean age 57.2±18.7years, female 69.5%) and followed for a median duration of 26 months (IQR17-39). Co-morbidities were common such as obesity (34.1%), systemic hypertension (30.5%), coronary artery disease (16.4%) and diabetes mellitus (19.5%). Initial combination therapy was used in 54 patients (dual, n=50; triple, n=4). Estimated survival rates at 1-year, 2-years and 3-years were 95.6% (CI 92.8-98.5%), 87.3% (CI 82.5-92.4%) and 77.0% (CI 70.3-84.3%), respectively. Multivariate analysis showed that male sex and lower 6-minute distance at diagnosis independently predicted worse survival, whereas obesity was associated with improved survival. Co-morbidities other than obesity did not impact survival. Initial dual oral combination therapy was associated with a trend towards better survival compared with initial oral monotherapy (adjusted HR=0.27, CI 0.06-1.18, p=0.082) CONCLUSIONS: The epidemiology and survival of patients with idiopathic PAH in Australia and New Zealand are similar to contemporary registries reported in Europe and North America. Male sex and poorer exercise capacity are predictive of mortality whereas obesity appears to exert a protective effect. Despite current therapies, PAH remains a life-threatening disease associated with significant early mortality.

PMID: 29029950 [PubMed - as supplied by publisher]

Innovative Therapy, Monoclonal Antibodies and Beyond.

Tue, 10/17/2017 - 12:45
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Innovative Therapy, Monoclonal Antibodies and Beyond.

Cytokine Growth Factor Rev. 2017 Oct 05;:

Authors: Nicola MD, Apetoh L, Bellone M, Colombo MP, Dotti G, Ferrone S, Muscolini M, Hiscott J, Anichini A, Pupa SM, Braud F, Del Vecchio M

Abstract
The seventh Edition of "Innovative Therapy, Monoclonal Antibodies and Beyond" Meeting took place in Milan, Italy, on January 27, 2017. The two sessions of the meeting were focused on: 1) Preclinical assays and novel biotargets; and 2) monoclonal antibodies, cell therapies and targeted molecules. Between these two sessions, a lecture entitled "HLA-antigens modulation and response to immune checkpoint inhibitor immunotherapy" was also presented. Despite the impressive successes in cancer immunotherapy in recent years, the response to immune based interventions occurs only in a minority of patients (∼20%). Several basic and translational mechanisms of resistance to immune checkpoint blockers (ICBs) were discussed during the meeting: 1. the impact of tumor microenvironment on the activity of immune system; 2. strategies to inhibit the cross-talk between extracellular matrix and myeloid-derived suppressor cells (MDSC) in the preclinical setting; 3. microRNA expression as a biomarker and as a target of therapy in non-small cell lung cancer (NSCLC); 4. the significance of complement activation pathways in response to immune checkpoint inhibitors; 5. the immunosuppressive activity of the microbiota by inducing IL-17 producing cells; and 6. modulation of HLA antigens as possible markers of response to ICB therapy. In order to overcome the deficiency in active anti-tumor T cells, several clinically applicable combination strategies were also discussed: 1. strategies to enhance the anticancer effects of immunogenic cell death inducing-chemotherapy; 2. the use of CAR T-cells in solid tumors; 3. the use of combination strategies involving oncolytic viruses and ICBs; 4. combinations of new ICBs with anti-PD-1/CTLA-4 therapy; and 4. combinations of targeted therapies and ICBs in melanoma. Overall, this conference emphasized the many novel strategies that are being investigated to improve the overall patient response to cancer immunotherapy. Optimization of biomarkers to accurately select patients who will respond to immunotherapy, coupled with combination strategies to improve long term patient survival remain critical challenges in the immuno-oncology field.

PMID: 29029813 [PubMed - as supplied by publisher]

Throwing out the good with the bad: Declining potential donor hearts with left ventricular dysfunction.

Tue, 10/17/2017 - 12:45
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Throwing out the good with the bad: Declining potential donor hearts with left ventricular dysfunction.

J Heart Lung Transplant. 2017 Sep 25;:

Authors: Moayedi Y, Khush KK

PMID: 29029801 [PubMed - as supplied by publisher]

Gender Equity in Transplantation: A Report from the Women in Transplantation Workshop of The Transplantation Society of Australia and New Zealand.

Tue, 10/17/2017 - 12:45
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Gender Equity in Transplantation: A Report from the Women in Transplantation Workshop of The Transplantation Society of Australia and New Zealand.

Transplantation. 2017 Oct;101(10):2266-2270

Authors: Dwyer KM, Clark CJ, MacDonald K, Paraskeva MA, Rogers N, Ryan J, Webster AC, Wong G

Abstract
The exponential growth of young talented women choosing science and medicine as their professional career over the past decade is substantial. Currently, more than half of the Australian medical doctoral graduates and early career researchers are comprised of women, but less than 20% of all academic professorial staff are women. The loss of female talent in the hierarchical ladder of Australian academia is a considerable waste of government investment, productivity, and scientific innovation. Gender disparity in the professional workforce composition is even more striking within the field of transplantation. Women are grossly underrepresented in leadership roles, with currently no female heads of unit in any of the Australian and New Zealand transplanting centers. At the same time, there is also gender segregation with a greater concentration of women in lower-status academic position compared with their male counterparts. Given the extent and magnitude of the disparity, the Women in Transplantation Committee, a subcommittee of The Transplantation Society of Australia and New Zealand established a workshop comprising 8 female clinicians/scientists in transplantation. The key objectives were to (i) identify potential gender equity issues within the transplantation workforce; (ii) devise and implement potential strategies and interventions to address some of these challenges at a societal level; (iii) set realistic and achievable goals to enhance and facility gender equality, equity, and diversity in transplantation.

PMID: 28767533 [PubMed - indexed for MEDLINE]

MAN2A1-FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice.

Tue, 10/17/2017 - 12:45
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MAN2A1-FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice.

Gastroenterology. 2017 Oct;153(4):1120-1132.e15

Authors: Chen ZH, Yu YP, Tao J, Liu S, Tseng G, Nalesnik M, Hamilton R, Bhargava R, Nelson JB, Pennathur A, Monga SP, Luketich JD, Michalopoulos GK, Luo JH

Abstract
BACKGROUND & AIMS: Human tumors and liver cancer cell lines express the product of a fusion between the first 13 exons in the mannosidase α class 2A member 1 gene (MAN2A1) and the last 6 exons in the FER tyrosine kinase gene (FER), called MAN2A1-FER. We investigated whether MAN2A1-FER is expressed by human liver tumors and its role in liver carcinogenesis.
METHODS: We performed reverse transcription polymerase chain reaction analyses of 102 non-small cell lung tumors, 61 ovarian tumors, 70 liver tumors, 156 glioblastoma multiform samples, 27 esophageal adenocarcinomas, and 269 prostate cancer samples, as well as 10 nontumor liver tissues and 20 nontumor prostate tissues, collected at the University of Pittsburgh. We also measured expression by 15 human cancer cell lines. We expressed a tagged form of MAN2A1-FER in NIH3T3 and HEP3B (liver cancer) cells; Golgi were isolated for analysis. MAN2A1-FER was also overexpressed in PC3 or DU145 (prostate cancer), NIH3T3 (fibroblast), H23 (lung cancer), and A-172 (glioblastoma multiforme) cell lines and knocked out in HUH7 (liver cancer) cells. Cells were analyzed for proliferation and in invasion assays, and/or injected into flanks of severe combined immunodeficient mice; xenograft tumor growth and metastasis were assessed. Mice with hepatic deletion of PTEN were given tail-vein injections of MAN2A1-FER.
RESULTS: We detected MAN2A1-FER messenger RNA and fusion protein (114 kD) in the hepatocellular carcinoma cell line HUH7, as well as in liver tumors, esophageal adenocarcinoma, glioblastoma multiforme, prostate tumors, non-small cell lung tumors, and ovarian tumors, but not nontumor prostate or liver tissues. MAN2A1-FER protein retained the signal peptide for Golgi localization from MAN2A1 and translocated from the cytoplasm to Golgi in cancer cell lines. MAN2A1-FER had tyrosine kinase activity almost 4-fold higher than that of wild-type FER, and phosphorylated the epidermal growth factor receptor at tyrosine 88 in its N-terminus. Expression of MAN2A1-FER in 4 cell lines led to epidermal growth factor receptor activation of BRAF, MEK, and AKT; HUH7 cells with MAN2A1-FER knockout had significant decreases in phosphorylation of these proteins. Cell lines that expressed MAN2A1-FER had increased proliferation, colony formation, and invasiveness and formed larger (>2-fold) xenograft tumors in mice, with more metastases, than cells not expressing the fusion protein. HUH7 cells with MAN2A1-FER knockout formed smaller xenograft tumors, with fewer metastases, than control HUH7 cells. HUH7, A-172, and PC3 cells that expressed MAN2A1-FER were about 2-fold more sensitive to the FER kinase inhibitor crizotinib and the epidermal growth factor receptor kinase inhibitor canertinib; these drugs slowed growth of xenograft tumors from MAN2A1-FER cells and prevented their metastasis in mice. Hydrodynamic tail-vein injection of MAN2A1-FER resulted in rapid development of liver cancer in mice with hepatic disruption of Pten.
CONCLUSIONS: Many human tumor types and cancer cell lines express the MAN2A1-FER fusion, which increases proliferation and invasiveness of cancer cell lines and has liver oncogenic activity in mice.

PMID: 28245430 [PubMed - indexed for MEDLINE]

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