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BOS Is Associated With Increased Cytotoxic Proinflammatory CD8 T, NKT-Like, and NK Cells in the Small Airways.

Wed, 09/20/2017 - 12:45
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BOS Is Associated With Increased Cytotoxic Proinflammatory CD8 T, NKT-Like, and NK Cells in the Small Airways.

Transplantation. 2017 Oct;101(10):2469-2476

Authors: Hodge G, Hodge S, Yeo A, Nguyen P, Hopkins E, Holmes-Liew CL, Reynolds PN, Holmes M

Abstract
BACKGROUND: Immunosuppression therapy after lung transplantation fails to prevent bronchiolitis obliterans syndrome (BOS) in many patients, primarily a disease of the small airways. We have reported that BOS is associated with a lack of suppression of cytotoxic mediators, and proinflammatory cytokines, in peripheral blood T, NKT-like (particularly CD8+) and NK cells. We also showed a loss of glucocorticoid receptor (GCR) in proinflammatory lymphocytes after transplant. It is unknown whether these proinflammatory lymphocytes target the small and/or large airways in BOS.
METHODS: Blood, bronchoalveolar lavage, large proximal, and small distal airway brushings were collected from patients with BOS (n = 10), stable lung transplant patients (n = 18), and healthy aged-matched controls (n = 10). Intracellular cytotoxic mediators (perforin/granzyme B), proinflammatory cytokines (IFNγ/TNFα), and expression of GCR were determined in lymphocytes subsets from cultured blood using flow cytometry.
RESULTS: Increases in CD8 T cells, NKT-like cells, and NK cells were found in the small distal airways in BOS compared with stable patients and controls. An increase in perforin, granzyme B, IFNγ, TNFα, and a loss of GCR from these lymphocyte subsets was also found in BOS. GCR expression by CD8+ T cells from small airways correlated with FEV1 (R = 0.834, P = 0.039). Many of these changes significantly differed from those in the large airways.
CONCLUSIONS: BOS is associated with increased cytotoxic/proinflammatory CD8+ T, NKT-like, and NK cells in the small airways. Treatments that increase GCR in these lymphocyte subsets may improve graft survival.

PMID: 28926522 [PubMed - in process]

High Levels of Morbidity and Mortality Among Pediatric Hematopoietic Cell Transplant Recipients With Severe Sepsis: Insights From the Sepsis PRevalence, OUtcomes, and Therapies International Point Prevalence Study.

Wed, 09/20/2017 - 12:45
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High Levels of Morbidity and Mortality Among Pediatric Hematopoietic Cell Transplant Recipients With Severe Sepsis: Insights From the Sepsis PRevalence, OUtcomes, and Therapies International Point Prevalence Study.

Pediatr Crit Care Med. 2017 Sep 16;:

Authors: Lindell RB, Gertz SJ, Rowan CM, McArthur J, Beske F, Plunkett A, Weiss SL, Thomas NJ, Nadkarni VM, Fitzgerald JC, Sepsis PRevalence, OUtcomes, and Therapies Study Investigators and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network

Abstract
OBJECTIVES: Pediatric severe sepsis is a major cause of morbidity and mortality worldwide, and hematopoietic cell transplant patients represent a high-risk population. We assessed the epidemiology of severe sepsis in hematopoietic cell transplant patients, describing patient outcomes compared with children with no history of hematopoietic cell transplant.
DESIGN: Secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies point prevalence study, comparing demographics, sepsis etiology, illness severity, organ dysfunction, and sepsis-related treatments in patients with and without hematopoietic cell transplant. The primary outcome was hospital mortality. Multivariable logistic regression models were used to determine adjusted differences in mortality.
SETTING: International; 128 PICUs in 26 countries.
PATIENTS: Pediatric patients with severe sepsis prospectively identified over a 1-year period.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: In patients with severe sepsis, 37/567 (6.5%) had a history of hematopoietic cell transplant. Compared with patients without hematopoietic cell transplant, hematopoietic cell transplant patients had significantly higher hospital mortality (68% vs 23%; p < 0.001). Hematopoietic cell transplant patients were more likely to have hospital acquired sepsis and had more preexisting renal and hepatic dysfunction than non-hematopoietic cell transplant patients with severe sepsis. History of hematopoietic cell transplant, renal replacement therapy, admission from inpatient floor, and number of organ dysfunctions at severe sepsis recognition were independently associated with hospital mortality in multivariable analysis; hematopoietic cell transplant conferred the highest odds of mortality (odds ratio, 4.00; 95% CI, 1.78-8.98). In secondary analysis of hematopoietic cell transplant patients compared with other immunocompromised patients with severe sepsis, history of hematopoietic cell transplant remained independently associated with hospital mortality (odds ratio, 3.03; 95% CI, 1.11-8.27).
CONCLUSIONS: In an international study of pediatric severe sepsis, history of hematopoietic cell transplant is associated with a four-fold increased odds of hospital mortality after adjustment for potential measured confounders. Hematopoietic cell transplant patients more often originated from within the hospital compared to children with severe sepsis without hematopoietic cell transplant, possibly providing an earlier opportunity for sepsis recognition and intervention in this high-risk population.

PMID: 28926489 [PubMed - as supplied by publisher]

Clostridium difficile Infection in Intestinal Transplant Recipients.

Wed, 09/20/2017 - 12:45
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Clostridium difficile Infection in Intestinal Transplant Recipients.

Transpl Int. 2017 Sep 19;:

Authors: Goldenberg V, Berbel A, Camargo JF, Simkins J

Abstract
Clostridium difficile infection (CDI) is a common complication among solid organ transplant (SOT) recipients with an estimated incidence of 7-31% for lung recipients, 8-15% for heart, 3-19% for liver, 9% for intestinal, 4-16% for kidney and 2-8% for pancreas-kidney recipients (1) and it is associated with increased mortality (2). There is limited data on CDI in intestinal transplant (ITx) recipients. This is a retrospective study that was conducted at Jackson Memorial Hospital, a 1558-licensed bed tertiary care teaching hospital. Our study was approved by the Institutional Review Board of University of Miami. This article is protected by copyright. All rights reserved.

PMID: 28926130 [PubMed - as supplied by publisher]

Technical Advances in the Measurement of Residual Disease in Acute Myeloid Leukemia.

Wed, 09/20/2017 - 12:45
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Technical Advances in the Measurement of Residual Disease in Acute Myeloid Leukemia.

J Clin Med. 2017 Sep 19;6(9):

Authors: Roloff GW, Lai C, Hourigan CS, Dillon LW

Abstract
Outcomes for those diagnosed with acute myeloid leukemia (AML) remain poor. It has been widely established that persistent residual leukemic burden, often referred to as measurable or minimal residual disease (MRD), after induction therapy or at the time of hematopoietic stem cell transplant (HSCT) is highly predictive for adverse clinical outcomes and can be used to identify patients likely to experience clinically evident relapse. As a result of inherent genetic and molecular heterogeneity in AML, there is no uniform method or protocol for MRD measurement to encompass all cases. Several techniques focusing on identifying recurrent molecular and cytogenetic aberrations or leukemia-associated immunophenotypes have been described, each with their own strengths and weaknesses. Modern technologies enabling the digital quantification and tracking of individual DNA or RNA molecules, next-generation sequencing (NGS) platforms, and high-resolution imaging capabilities are among several new avenues under development to supplement or replace the current standard of flow cytometry. In this review, we outline emerging modalities positioned to enhance MRD detection and discuss factors surrounding their integration into clinical practice.

PMID: 28925935 [PubMed]

Decreasing incidence of cancer after liver transplantation - A Nordic population-based study over three decades.

Wed, 09/20/2017 - 12:45
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Decreasing incidence of cancer after liver transplantation - A Nordic population-based study over three decades.

Am J Transplant. 2017 Sep 19;:

Authors: Nordin A, Åberg F, Pukkala E, Pedersen CR, Storm HH, Rasmussen A, Bennet W, Olausson M, Wilczek H, Ericzon BG, Tretli S, Line PD, Karlsen TH, Boberg KM, Isoniemi H

Abstract
Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 was extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals out the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95%CI 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with PSC (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI 2.47-7.60), the 1990s: 3.17 (95%CI 2.70-3.71), to the 2000s: 1.76 (95%CI 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0 - 12.9 - 7.53, and for non-melanoma skin cancer 80.0 - 29.7 - 10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study. This article is protected by copyright. All rights reserved.

PMID: 28925583 [PubMed - as supplied by publisher]

The Dangers of Oversimplification - Quality Metrics and Lung Transplantation.

Wed, 09/20/2017 - 12:45
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The Dangers of Oversimplification - Quality Metrics and Lung Transplantation.

Am J Transplant. 2017 Sep 19;:

Authors: van Berkel V

Abstract
While many aspects of medical care are learning how to cope with the sudden proliferation of publicly reported quality metrics[1], the transplant community has been interpreting this type of data for over thirty years. Under the National Organ Transplantation Act of 1984, transplant centers are required to report their candidate and recipient information to the Organ Procurement and Transplantation Network (OPTN), and that data is then analyzed by the Scientific Registry of Transplant Recipients (SRTR), with outcomes reported on a twice yearly basis on a public website (www.srtr.org). This article is protected by copyright. All rights reserved.

PMID: 28925582 [PubMed - as supplied by publisher]

Generation of a gene-corrected isogenic control iPSC line from cystic fibrosis patient-specific iPSCs homozygous for p.Phe508del mutation mediated by TALENs and ssODN.

Wed, 09/20/2017 - 12:45
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Generation of a gene-corrected isogenic control iPSC line from cystic fibrosis patient-specific iPSCs homozygous for p.Phe508del mutation mediated by TALENs and ssODN.

Stem Cell Res. 2017 Aug;23:95-97

Authors: Merkert S, Bednarski C, Göhring G, Cathomen T, Martin U

Abstract
Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which affects multiple organs. Human induced pluripotent stem cells (iPSCs) derived from CF patients and the generation of isogeneic gene-corrected control cell lines enable disease modelling, drug discovery or toxicological studies and therefore the development of CF patient-specific therapies. We have previously generated a hiPSC line from a CF patient homozygous for the p.Phe508del mutation. Here we used TALENs and single-stranded oligonucleotides to correct the mutated triplet in our CF-iPSC line.

PMID: 28925369 [PubMed - in process]

Role of cardiopulmonary exercise testing in clinical stratification in heart failure. A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology.

Wed, 09/20/2017 - 12:45
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Role of cardiopulmonary exercise testing in clinical stratification in heart failure. A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology.

Eur J Heart Fail. 2017 Sep 18;:

Authors: Corrà U, Agostoni PG, Anker SD, Coats AJS, Crespo Leiro MG, de Boer RA, Hairola VP, Hill L, Lainscak M, Lund LH, Metra M, Ponikowski P, Riley J, Seferović PM, Piepoli MF

Abstract
Traditionally, the main indication for cardiopulmonary exercise testing (CPET) in heart failure (HF) was for the selection of candidates to heart transplantation: CPET was mainly performed in middle-aged male patients with HF and reduced left ventricular ejection fraction. Today, CPET is used in broader patients' populations, including women, elderly, patients with co-morbidities, those with preserved ejection fraction, or left ventricular assistance device recipients, i.e. individuals with different responses to incremental exercise and markedly different prognosis. Moreover, the diagnostic and prognostic utility of symptom-limited CPET parameters derived from submaximal tests is more and more considered, since many patients are unable to achieve maximal aerobic power. Repeated tests are also being used for risk stratification and evaluation of intervention, so that these data are now available. Finally, patients, physicians and healthcare decision makers are increasingly considering how treatments might impact morbidity and quality of life rather than focusing more exclusively on hard endpoints (such as mortality) as was often the case in the past. Innovative prognostic flowcharts, with CPET at their core, that help optimize risk stratification and the selection of management options in HF patients, have been developed.

PMID: 28925073 [PubMed - as supplied by publisher]

Extracorporeal Membrane Oxygenation Can Save Lives in Children With Heart or Lung Failure After Liver Transplantation.

Wed, 09/20/2017 - 12:45
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Extracorporeal Membrane Oxygenation Can Save Lives in Children With Heart or Lung Failure After Liver Transplantation.

Artif Organs. 2017 Sep;41(9):862-865

Authors: Jean S, Chardot C, Oualha M, Capito C, Bustarret O, Pouard P, Renolleau S, Lacaille F, Dupic L

Abstract
The risk of cardiac or lung failure after liver transplantation (LT) is significant. In rare cases, the usual intensive care techniques fail to maintain organ oxygenation with a risk of multiorgan dysfunction. Although extracorporeal membrane oxygenation (ECMO) is a difficult and risky procedure, it can be proposed as life-saving. Four children with either acute pulmonary (three) or cardiac (one) failure after LT, and the criteria that decided the use of ECMO (level of ventilation and results, dosage of inotropic drugs, cardiac ultrasound, blood lactate) were retrospectively reported. These patients, 1-11 years old, were treated with either veno-arterial (three) or veno-venous (one) ECMO. Two experienced a full recovery, with 3 and 6 years of follow-up. Two died of systemic inflammatory response syndrome (SIRS) due to ECMO, and relapse of heart failure due to the underlying disease. Although our patients' survival was only 50%, we showed that ECMO can be useful in children after LT. It should be considered before the development of irreversible multiorgan failure.

PMID: 28925053 [PubMed - in process]

The Relationship between Mortality of Lung Transplant Recipients and Serum Cyclosporine Levels: Joint Modeling of Time-to-Event Data and Longitudinal Data.

Wed, 09/20/2017 - 12:45
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The Relationship between Mortality of Lung Transplant Recipients and Serum Cyclosporine Levels: Joint Modeling of Time-to-Event Data and Longitudinal Data.

Int J Organ Transplant Med. 2017;8(3):157-163

Authors: Hosseini-Baharanchi FS, Hajizadeh E, Baghestani AR, Najafzadeh K

Abstract
BACKGROUND: Lung transplantation (LTx) is a well-accepted treatment that can prolong survival of patients with advanced lung disease.
OBJECTIVE: To evaluate the association between serum cyclosporine level (SCL) pattern and mortality of LTx recipients.
METHODS: This retrospective cohort study included 1019 observations on 38 patients who underwent LTx in Masih Daneshvari Hospital from 2000 to 2013. The analysis applied a joint model with shared random effects.
RESULTS: The mean±SD age of the recipients was 36±14.5 years. The findings indicated that sex, age, body mass index (BMI), the underlying disease, and cytomegalovirus infection were not associated with mortality. The mortality risk for the recipients with acute rejection (AR) history was 1.54 times that of the recipients who had none (95% CI: 1.08-2.19). The association parameter in the joint model (α = 0.8) showed that higher SCL was associated with lower mortality risk (95% CI: 1-1.011). A slightly linear decreasing trend in SCL mean was found after 10 months post-LTx; a significant 2% per month (95% CI: -0.03 to -0.019).
CONCLUSION: AR history was found to be a risk factor in mortality in Iranian LTx recipients. Given the association between the higher SCL and lower mortality found in this study, it is recommended to pay serious attention to SCL changes in the overall post-transplantation survival assessment in Iranian LTx recipients.

PMID: 28924464 [PubMed]

Feasibility of Lung Transplantation From Donation After Circulatory Death Donors Following Portable Ex Vivo Lung Perfusion: A Pilot Study.

Wed, 09/20/2017 - 12:45
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Feasibility of Lung Transplantation From Donation After Circulatory Death Donors Following Portable Ex Vivo Lung Perfusion: A Pilot Study.

Transplant Proc. 2017 Oct;49(8):1885-1892

Authors: Luc JGY, Jackson K, Weinkauf JG, Freed DH, Nagendran J

Abstract
BACKGROUND: Donation after circulatory death (DCD) has the potential to significantly alleviate the shortage of transplantable lungs. We report our initial experience with the use of portable ex vivo lung perfusion (EVLP) with the Organ Care System Lung device for evaluation of DCD lungs.
METHODS: We performed a retrospective review of the DCD lung transplantation (LTx) experience at a single institution through the use of a prospective database.
RESULTS: From 2011 to 2015, 208 LTx were performed at the University of Alberta, of which 11 were DCD LTx with 7 (64%) that underwent portable EVLP. DCD lungs preserved with portable EVLP had a significantly shorter cold ischemic time (161 ± 44 vs 234 ± 60 minutes, P = .045), lower grade of primary graft dysfunction at 72 hours after LTx (0.4 ± 0.5 vs 2.1 ± 0.7, P = .003), similar mechanical ventilation time (55 ± 44 vs 103 ± 97 hours, P = .281), and hospital length of stay (29 ± 11 vs 33 ± 10 days, P = .610). All patients were alive at 1-year follow-up after LTx with improved functional outcomes and acceptable quality of life compared with before LTx, although there were no intergroup differences.
CONCLUSIONS: In our pilot cohort, portable EVLP was a feasible modality to increase confidence in the use of DCD lungs with validated objective evidence of lung function during EVLP that translates to acceptable clinical outcomes and quality of life after LTx. Further studies are needed to validate these initial findings in a larger cohort.

PMID: 28923643 [PubMed - in process]

Deceased Organ Donation From Pediatric Donors: Does the Literature Really Help Us? Implication for More Powerful Guidelines.

Wed, 09/20/2017 - 12:45
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Deceased Organ Donation From Pediatric Donors: Does the Literature Really Help Us? Implication for More Powerful Guidelines.

Transplant Proc. 2017 Oct;49(8):1708-1711

Authors: Mojtabaee M, Sadegh Beigee F, Ghorbani F

Abstract
BACKGROUND: Brain-dead pediatric donors have always been the focus of attention because of the higher quality, utility, and possibility of their organ donation. However, donors under the age of 5 years always necessitate making more challenging management efforts, which are not clearly implied in most parts of the guidelines.
METHODS: The data obtained from 79 brain-dead pediatric donors of the Organ Procurement Unit of Masih Daneshvari Hospital, Tehran, Iran, were assessed. The donors were divided into 2 groups, including donors under 5 years of age (group A) and those between 5 and 12 years of age (group B). Metabolic, hemodynamic, hematologic, and electrolyte status as well as the suitability for donation were compared in the study groups.
RESULTS: Of 1252 donors, 6.3% were under 12 years of age. Trauma and drug toxicity were the two primary causes of brain death in group A. In comparison, trauma and brain tumor were the leading causes of brain death in group B. The prevalence of both hyperglycemia and respiratory acidosis was significantly higher in group A (P < .05). However, severe anemia and coagulopathy were more prevalent in group B (P < .05). The high-dose inotropic administration was used for 42.4% of the donors in group A, whereas only 26% of the donors in group B needed a high dose of inotropes (P < .05). The mean quantity of organ harvested per donor was 2.1 and 2.25 in groups A and B, respectively. Furthermore, donor loss was not significantly different in both groups.
CONCLUSIONS: The occurrence of different complications in donors under the age of 5 years requires special treatment considerations that should be the center of attention in the related guidelines. Organ donation per donor indicates that donors under the age of 5 years are a valuable resource for organ procurement.

PMID: 28923612 [PubMed - in process]

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.

Wed, 09/20/2017 - 12:45
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A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.

Lancet Respir Med. 2017 Sep 08;:

Authors: Birring SS, Wijsenbeek MS, Agrawal S, van den Berg JWK, Stone H, Maher TM, Tutuncu A, Morice AH

Abstract
BACKGROUND: Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied.
METHODS: This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants.
FINDINGS: Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported.
INTERPRETATION: This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation.
FUNDING: Patara Pharma.

PMID: 28923239 [PubMed - as supplied by publisher]

Heartbreak hotel: a convergence in cardiac regeneration.

Wed, 09/20/2017 - 12:45
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Heartbreak hotel: a convergence in cardiac regeneration.

Development. 2016 May 01;143(9):1435-41

Authors: Schneider MD

Abstract
In February 2016, The Company of Biologists hosted an intimate gathering of leading international researchers at the forefront of experimental cardiovascular regeneration, with its emphasis on 'Transdifferentiation and Tissue Plasticity in Cardiovascular Rejuvenation'. As I review here, participants at the workshop revealed how understanding cardiac growth and lineage decisions at their most fundamental level has transformed the strategies in hand that presently energize the prospects for human heart repair.

PMID: 27143752 [PubMed - indexed for MEDLINE]

[Current treatment of chronic obstructive pulmonary disease].

Wed, 09/20/2017 - 12:45
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[Current treatment of chronic obstructive pulmonary disease].

Med Clin (Barc). 2016 07 01;147(1):28-34

Authors: Pomares X, Montón C

PMID: 26961396 [PubMed - indexed for MEDLINE]

Nocardia infections in solid organ and hematopoietic stem cell transplant recipients.

Tue, 09/19/2017 - 12:45
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Nocardia infections in solid organ and hematopoietic stem cell transplant recipients.

Curr Opin Infect Dis. 2017 Sep 15;:

Authors: Coussement J, Lebeaux D, Rouzaud C, Lortholary O

Abstract
PURPOSE OF REVIEW: Nocardia spp. is a gram-positive bacteria that may cause infections in humans. Nocardiosis has been described since the early years of transplantation. This review aims to provide an overview of present knowledge regarding posttransplant nocardiosis, with a focus on recent findings.
RECENT FINDINGS: Nocardiosis is not rare among transplant recipients, especially after thoracic transplantation and/or in case of intense immunosuppressive regimen or use of tacrolimus. Low-dose cotrimoxazole is not effective to prevent nocardiosis. Although lung is the most common site of infection, more than 40% of organ transplant patients have a disseminated infection. As central nervous system involvement is frequent (about 1/3 of the patients) and possibly asymptomatic, brain imaging is mandatory. Diagnosis relies on direct examination and culture; molecular species identification is useful to guide treatment. Although cotrimoxazole is the drug for which we have the strongest clinical experience, other antibiotics such as linezolid, parenteral cephalosporins, carbapenems, and amikacin can be used to treat nocardiosis. Although treatment duration has historically been set to at least 6 months, shorter durations (<120 days) seem associated with a good outcome in selected patients.
SUMMARY: Physicians in charge of transplant patients should be aware of nocardiosis. Diagnosis and management of transplant recipients with nocardiosis require a multidisciplinary approach.

PMID: 28922286 [PubMed - as supplied by publisher]

Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options.

Tue, 09/19/2017 - 12:45
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Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options.

Cell Oncol (Dordr). 2017 Sep 18;:

Authors: Yousefi M, Bahrami T, Salmaninejad A, Nosrati R, Ghaffari P, Ghaffari SH

Abstract
BACKGROUND: Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies.
CONCLUSIONS: The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

PMID: 28921309 [PubMed - as supplied by publisher]

The Effect of Intraoperative Alkali Treatment on Recovery from Atracurium-Induced Neuromuscular Blockade in Renal Transplantation: A Randomized Trial.

Tue, 09/19/2017 - 12:45
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The Effect of Intraoperative Alkali Treatment on Recovery from Atracurium-Induced Neuromuscular Blockade in Renal Transplantation: A Randomized Trial.

Anesth Pain Med. 2017 Feb;7(1):e42660

Authors: Noraee N, Fathi M, Golestani Eraghi M, Dabbagh A, Massoudi N

Abstract
BACKGROUND: Intraoperative care and anesthesia method in patients undergoing allograft renal transplantation surgery are very necessary. Acid-base imbalance can alter neuromuscular blockade and recovery time.
OBJECTIVES: The aim of the present study was to investigate the effect of acid-base balance on atracurium blockade in renal transplantation.
METHODS: In this randomized-controlled trial, 31 end-stage renal disease (ESRD) patients undergoing renal transplantation were randomly assigned into two equal groups. The case group received intravenous sodium bicarbonate based on base excess in the first ABG sample, while the control group received sterile water for injection during the interval between anesthesia and beginning of surgery. Arterial blood gas (ABG) sample was drawn first prior to surgery and again at declamping time. Train-of-four (TOF) was measured before anesthesia and repeatedly after declamping time until acceptable recovery (TOF 3 of 4). The time of achieving TOF 3 was recorded and compared between the groups.
RESULTS: There was no significant difference in blood pH between the groups in the first evaluation (P = 0.649). The pH and base excess (BE) in the case group significantly increased after the intervention. There was a significant decrease in after-surgery measurement of pH in the control group (P = 0.011). The mean time to achieve TOF = 3 was 23.75 ± 5.32 and 41.80 ± 5.2 minutes after declamping in the case and control groups, respectively. Patients in the sodium bicarbonate group achieved TOF = 3 significantly faster than the control group.
CONCLUSIONS: Based on our results, intraoperative alkali and acid-base imbalance treatment can reduce neuromuscular blockade and recovery time, and it can be regarded as a potential casual factor to enhance transplantation outcome.

PMID: 28920046 [PubMed]

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study.

Tue, 09/19/2017 - 12:45
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Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study.

Lancet Respir Med. 2017 Sep 08;:

Authors: Ghofrani HA, Simonneau G, D'Armini AM, Fedullo P, Howard LS, Jaïs X, Jenkins DP, Jing ZC, Madani MM, Martin N, Mayer E, Papadakis K, Richard D, Kim NH, MERIT study investigators

Abstract
BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar.
METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm(5) and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292.
FINDINGS: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70-0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]).
INTERPRETATION: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated.
FUNDING: Actelion Pharmaceuticals Ltd.

PMID: 28919201 [PubMed - as supplied by publisher]

Regulator of Calcineurin 1 Gene Isoform 4, Down-regulated in Hepatocellular Carcinoma, Prevents Proliferation, Migration, and Invasive Activity of Cancer Cells and Metastasis of Orthotopic Tumors by Inhibiting Nuclear Translocation of NFAT1.

Tue, 09/19/2017 - 12:45
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Regulator of Calcineurin 1 Gene Isoform 4, Down-regulated in Hepatocellular Carcinoma, Prevents Proliferation, Migration, and Invasive Activity of Cancer Cells and Metastasis of Orthotopic Tumors by Inhibiting Nuclear Translocation of NFAT1.

Gastroenterology. 2017 Sep;153(3):799-811.e33

Authors: Jin H, Wang C, Jin G, Ruan H, Gu D, Wei L, Wang H, Wang N, Arunachalam E, Zhang Y, Deng X, Yang C, Xiong Y, Feng H, Yao M, Fang J, Gu J, Cong W, Qin W

Abstract
BACKGROUND & AIMS: Individuals with Down syndrome have a low risk for many solid tumors, prompting the search for tumor suppressor genes on human chromosome 21 (HSA21). We aimed to identify and explore potential mechanisms of tumor suppressors on HSA21 in hepatocellular carcinoma (HCC).
METHODS: We compared expression of HSA21 genes in 14 pairs of primary HCC and adjacent noncancer liver tissues using the Affymetrix HG-U133 Plus 2.0 array (Affymetrix, Santa Clara, CA). HCC tissues and adjacent normal liver tissues were collected from 108 patients at a hospital in China for real-time polymerase chain reaction and immunohistochemical analyses; expression levels of regulator of calcineurin 1 (RCAN1) isoform 4 (RCAN1.4) were associated with clinical features. We overexpressed RCAN1.4 from lentiviral vectors in MHCC97H and HCCLM3 cells and knocked expression down using small interfering RNAs in SMMC7721 and Huh7 cells. Cells were analyzed in proliferation, migration, and invasion assays. HCC cells that overexpressed RCAN1.4 or with RCAN1.4 knockdown were injected into livers or tail veins of nude mice; tumor growth and numbers of lung metastases were quantified. We performed bisulfite pyrosequencing and methylation-specific polymerase chain reaction analyses to analyze CpG island methylation. We measured phosphatase activity of calcineurin in HCC cells.
RESULTS: RCAN1.4 mRNA and protein levels were significantly decreased in primary HCC compared with adjacent noncancer liver tissues. Reduced levels of RCAN1.4 mRNA were significantly associated with advanced tumor stages, poor differentiation, larger tumor size, and vascular invasion. Kaplan-Meier survival analysis showed that patients with HCCs with lower levels of RCAN1.4 mRNA had shorter time of overall survival and time to recurrence than patients whose tumors had high levels of RCAN1.4 mRNA. In HCC cell lines, expression of RCAN1.4 significantly reduced proliferation, migration, and invasive activity. HCC cells that overexpressed RCAN1.4 formed smaller xenograft tumors, with fewer metastases and blood vessels, than control HCC cells. In HCC cells, RCAN1.4 inhibited expression of insulin-like growth factor 1 and vascular endothelial growth factor A by reducing calcineurin activity and blocking nuclear translocation of nuclear factor of activated T cells (NFAT1). HCC cells incubated with the calcineurin inhibitor cyclosporin A had decreased nuclear level of NFAT1. HCC cells had hypermethylation of a CpG island in the 5' regulatory region of RCAN1.4, which reduced its expression.
CONCLUSIONS: RCAN1.4 is down-regulated in HCC tissues, compared with non-tumor liver tissues. RCAN1.4 prevents cell proliferation, migration, and invasion in vitro; overexpressed RCAN1.4 in HCC cells prevents growth, angiogenesis, and metastases of xenograft tumors by inhibiting calcineurin activity and nuclear translocation of NFAT1.

PMID: 28583823 [PubMed - indexed for MEDLINE]

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