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Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras(G12D-LSL) mice.

Sat, 10/20/2012 - 12:45
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Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras(G12D-LSL) mice.

Cancer Chemother Pharmacol. 2012 Aug;70(2):213-20

Authors: Simmons BH, Lee JH, Lalwani K, Giddabasappa A, Snider BA, Wong A, Lappin PB, Eswaraka J, Kan JL, Christensen JG, Shojaei F

Abstract
The role of PI3K and MAPK pathways in tumor initiation and progression is well established; hence, several inhibitors of these pathways are currently in different stages of clinical trials. Recent studies identified a PI3K/mTOR (PF-04691502) and a MEK inhibitor (PD-0325901) with strong potency and efficacy in different cell lines and tumor models. PD-0325901, however, showed adverse effects when administered at or above MTD (maximum tolerated dose) in the clinic. Here, we show in preclinical models that PD-0325901 at doses well below MTD (sub-MTD 1.5 mg/kg SID) is still a potent compound as single agent or in combination with PF-04691502. We first observed that PD-0325901 at 1.5 mg/kg SID and in combination with PF-04691502 (7.5 mg/kg; SID) significantly inhibited growth of H460 (carry Kras and PIK3CA mutations) orthotopic lung tumors. Additionally, we tested efficacy of PD-0325901 in Kras(G12D-LSL) conditional GEMMs (genetically engineered mouse models) which are a valuable tool in translational research to study tumor progression. Intranasal delivery of adenoviruses expressing Cre recombinase (Adeno-Cre) resulted in expression of mutant Kras leading to development of tumor lesions in lungs including adenomatous hyperplasia, large adenoma, and adenocarcinoma. Similar to H460 tumors, PD-0325901 as single agent or in combination with PF-04691502 significantly inhibited growth of tumor lesions in lungs in Kras(G12D-LSL) mice when treatment started at adenocarcinoma stage (at 14 weeks post-Adeno-Cre inhalation). In addition, immunohistochemistry showed inhibition of pS6 (phosphorylated ribosomal S6) in the treated animals particularly in the combination group providing a proof of mechanism for tumor growth inhibition. Finally, m-CT imaging in live Kras(G12D-LSL) mice showed reduction of tumor burdens in PD-0325901-treated animals at sub-MTD dose. In conclusion, our data suggest that PD-0325901 at doses below MTD is still a potent compound capable of tumor growth inhibition where Kras and/or PI3K are drivers of tumor growth and progression.

PMID: 22684718 [PubMed - indexed for MEDLINE]

An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation.

Sat, 10/20/2012 - 12:45
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An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation.

Int J Oncol. 2012 Aug;41(2):661-9

Authors: Zhu L, Zhao Z, Wei Y, Marcotte W, Wagner TE, Yu X

Abstract
The dependency of activated natural killer (NK) cells on the continuous support of exogenous interleukin (IL)-2 for their in vivo survival, tumor localization and consequently, their antitumor effect, is a major obstacle for NK cell-mediated tumor therapy. In the present study, a fusion gene between IL-12 and mouse sonic hedgehog C-terminal domain (Shh-C) was constructed. The fusion protein was autocatalytically processed to form cholesterol-modified IL-12 molecules and an autocrine loop of IL-12 was established for the sustained activation of NK cells. The transduced NK cells matured more rapidly in vitro with the enhanced expression of granule-related proteins. NKIL-12/Shh-C cells reached the same proliferation rate as NK cells transduced with enhanced green fluorescent protein (EGFP)/Shh-C (NKEGFP/Shh-C) with <10-fold IL-2 supplementation, suggesting that the fusion protein reduced the dependency of NK cells on IL-2. The amount of interferon‑γ (IFN-γ) in the supernatants of NKIL-12/Shh-C cells 5 and 7 days after transduction was significantly higher than that in the supernatants of NKIL-12 cells. Immunofluorescent staining of lung tissues from B16-bearing mice which had received an intravenous injection of lentivirus-transduced NK cells without exogenous IL-2 confirmed that donor NK cells successfully infiltrated into the lung tissues. The survival time of the mice which had received NKIL-12/Shh-C cells was significantly prolonged compared to the mice which had received NKEGFP/Shh-C cells.

PMID: 22581115 [PubMed - indexed for MEDLINE]

Children's conceptions of their parent's lung transplant.

Wed, 10/10/2012 - 12:04
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Children's conceptions of their parent's lung transplant.

J Child Health Care. 2012 Oct 8;

Authors: Fulbrook P, Leisfield T, Wiggins K

Abstract
There has been no research that has investigated the psychosocial impact on children whose parents have undergone a lung transplant. The aim of this qualitative study was to describe children's concerns and understandings of their parent's transplant surgery. Artwork was used as a creative medium to enable children to portray their experiences in a safe, non-threatening environment. This was used as a visual primer for follow-up interviews. All children expressed similar and complementary views about uncertainty and anxiety, separation, disruption to family life, their desire for normality, and the importance of social support. Differences were evident in the way that some children managed well by adapting to the changing situations, whereas others tended towards avoidance. The findings provide several themes that may be used as a framework for family support and counselling by nurses, social workers, and other healthcare professionals who are caring for patients and their families during the transplant process.

PMID: 23045292 [PubMed - as supplied by publisher]

Assessment of control tissue for gene and protein expression studies: a comparison of three alternative lung sources.

Wed, 10/10/2012 - 12:04
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Assessment of control tissue for gene and protein expression studies: a comparison of three alternative lung sources.

ScientificWorldJournal. 2012;2012:523840

Authors: Passmore MR, Nataatmadja M, Fraser JF

Abstract
The use of an appropriate control group in human research is essential in investigating the level of a pathological disorder. This study aimed to compare three alternative sources of control lung tissue and to determine their suitability for gene and protein expression studies. Gene and protein expression levels of the vascular endothelial growth factor (VEGF) and gelatinase families and their receptors were measured using real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The gene expression levels of VEGFA, placental growth factor (PGF), and their receptors, fms-related tyrosine kinase 1 (FLT1), and kinase insert domain receptor (KDR) as well as matrix metalloproteinase-2 (MMP-2) and the inhibitors, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and TIMP-2 were significantly higher in lung cancer resections. The gene expression level of MMP-9 was significantly lower in the corresponding samples. Altered protein expression was also detected, depending on the area assessed. The results of this study show that none of the three control groups studied are completely suitable for gene and protein studies associated with the VEGF and gelatinase families, highlighting the need for researchers to be selective in which controls they opt for.

PMID: 22593690 [PubMed - indexed for MEDLINE]

PSMA7 inhibits the tumorigenicity of A549 human lung adenocarcinoma cells.

Wed, 10/10/2012 - 12:04
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PSMA7 inhibits the tumorigenicity of A549 human lung adenocarcinoma cells.

Mol Cell Biochem. 2012 Jul;366(1-2):131-7

Authors: Tan JY, Huang X, Luo YL

Abstract
The gene for proteasome subunit alpha type-7 (PSMA7) is located in chromosomal 20q13.33, a region frequently amplified in tumor. In this study, we employed A549 human lung adenocarcinoma cells and showed that PSMA7 inhibits the proliferation, tumorigenicity and invasion of A549 cells in vitro. Moreover, both gain and loss of function studies demonstrated that PSMA7 modulates the tumorigenicity of A549 cells in a xenograft nude mice model. In conclusion, these results identify inhibitory effects associated with PSMA7 that affect the tumorigenicity of A549 cells, suggesting PSMA7 as a potential tumor biomarker.

PMID: 22584585 [PubMed - indexed for MEDLINE]

A pilot study to examine the effect of chronic treatment with immunosuppressive drugs on mucociliary clearance in a vagotomized murine model.

Tue, 10/09/2012 - 11:58
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A pilot study to examine the effect of chronic treatment with immunosuppressive drugs on mucociliary clearance in a vagotomized murine model.

PLoS One. 2012;7(9):e45312

Authors: Bhashyam AR, Mogayzel PJ, McGrath-Morrow S, Neptune E, Malinina A, Fox J, Laube BL

Abstract
BACKGROUND: Previously, we have demonstrated that mucociliary clearance (MCC) is diminished within the first months after surgery in lung transplant patients and the explanation for the reduction in MCC is unknown. We hypothesized that chronic treatment with a commonly prescribed regimen of immunosuppressive drugs significantly impairs MCC. We tested this hypothesis in a murine model of lung transplantation.
METHODS: Fifteen C57BL/6 mice underwent vagotomy on the right side to simulate denervation associated with lung transplantation in humans. For 6 days, seven mice (controls) were intraperitoneally injected with three 100 µL doses of phosphate buffered saline and eight mice (immunosuppressed) were injected with three 100 µL injections of tacrolimus (1 mg/kg), mycophenolate mofetil (30 mg/kg), and prednisone (2 mg/kg) once daily. Then, mice inhaled the radioisotope (99m)technetium and underwent gamma camera imaging of their lungs for 6.5 hrs. Counts in the right lung at 1-1.5 hrs and at 6-6.5 hrs were first background-corrected and then decay-corrected to time 0 counts. Decay-corrected counts were then divided by time 0 counts. Retention at each time point was subtracted from 1.00 and multiplied by 100% to obtain percent removed by mucociliary clearance.
RESULTS: Although there was a slowing of MCC at 1-1.5 hrs for the immunosuppressed mice, there was no statistical difference in MCC measured at 1-1.5 hrs for the two groups of mice. At 6-6.5 hrs, MCC was significantly slower in the immunosuppressed mice, compared to controls, with 7.78±5.9% cleared versus 23.01±11.7% cleared, respectively (p = 0.006).
CONCLUSIONS: These preliminary results suggest that chronic treatment with immunosuppressive medications significantly slows MCC in vagotomized C57BL/6 mice. These findings could shed light on why MCC is reduced in lung transplant patients whose lungs are denervated during surgery and who are chronically treated with immunosuppressive drugs post surgery.

PMID: 23028925 [PubMed - in process]

Clinical year in review I: quality improvement for pulmonary and critical care medicine, lung transplantation, rehabilitation for pulmonary and critically ill patients, and sleep medicine.

Tue, 10/09/2012 - 11:58
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Clinical year in review I: quality improvement for pulmonary and critical care medicine, lung transplantation, rehabilitation for pulmonary and critically ill patients, and sleep medicine.

Proc Am Thorac Soc. 2012 Oct;9(4):183-9

Authors: Kahn JM, Palmer SM, Spruit MA, Punjabi NM, Sutherland ER

PMID: 23028007 [PubMed - in process]

Effects of prednisone on mucociliary clearance in a murine model.

Tue, 10/09/2012 - 11:58
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Effects of prednisone on mucociliary clearance in a murine model.

Transplant Proc. 2012 Oct;44(8):2486-9

Authors: Oliveira-Braga KA, Nepomuceno NA, Correia AT, Jatene FB, Pêgo-Fernandes PM

Abstract
All transplant patients are at increased risk of developing pulmonary infections, a significant cause of morbidity and mortality. Immunosuppressants increase the incidence of lung infection by acting not only directly on the inflammatory cells, but also on the native immune system. Experimental studies have shown corticosteroid therapy, which is used in most immunosuppressive protocols after transplantation, to suppress mucus production by inhibiting calceiform. The objective of this study was to evaluate the effects of prednisone on mucociliary clearance. A total of 120 male Wistar rats were distributed into 4 groups. Animals in P1, P2, and P3 groups received daily doses of prednisone (0.625, 1.25, and 2.5 mg/kg/d), and hosts in the Sal group underwent gavage with saline solution (2.5 mL/d). After 7, 15, and 30 days, treatment, animals were killed. We assessed ciliary beating frequency (CBF), mucociliary transport velocity (MCTV), and mucus transportability (MT). There was no significant difference for CBF regarding dose (P = .089) or treatment duration (P = .175). MCTV values of 0.60 ± 0.14 in group P1, 0.59 ± 0.13 in group P2, 0.51 ± 0.19 in group P3, and 0.61 ± 0.08 Group Sal, showed P3 to significantly differ from P1 (P = .048) and Sal (P = .007) groups. Regardless of the prednisone dose, all groups displayed impaired MT compared with the Sal group: P1 (P = .02); P2 (P = .02) P3 (P = .03). There was no interaction between the therapy and the treatment time for CBF (P = .10), MCTV (P = .71), and MT (P = .64). Prednisone reduced the transportability of mucus even when administered at low doses; however, this change was not sufficient to alter the mucociliary clearance. Only high doses of prednisone impaired mucociliary clearance.

PMID: 23026626 [PubMed - in process]

Risk factors and survival impact of primary graft dysfunction after lung transplantation in a single institution.

Tue, 10/09/2012 - 11:58
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Risk factors and survival impact of primary graft dysfunction after lung transplantation in a single institution.

Transplant Proc. 2012 Oct;44(8):2462-8

Authors: Samano MN, Fernandes LM, Baranauskas JC, Correia AT, Afonso JE, Teixeira RH, Caramori ML, Pêgo-Fernandes PM, Jatene FB

Abstract
BACKGROUND: Lung transplantation has become a standard procedure for some end-stage lung diseases, but primary graft dysfunction (PGD) is an inherent problem that impacts early and late outcomes. The aim of this study was to define the incidence, risk factors, and impact of mechanical ventilation time on mortality rates among a retrospective cohort of lung transplantations performed in a single institution.
METHODS: We performed a retrospective study of 118 lung transplantations performed between January 2003 and July 2010. The most severe form of PGD (grade III) as defined at 48 and 72 hours was examined for risk factors by multivariable logistic regression models using donor, recipient, and transplant variables.
RESULTS: The overall incidence of PGD at 48 hours was 19.8%, and 15.4% at 72 hours. According multivariate analysis, risk factors associated with PGD were donor smoking history for 48 hours (adjusted odds ratio [OR], 4.83; 95% confidence interval [CI], 1.236-18.896; P = .022) and older donors for 72 hours (adjusted OR, 1.046; 95% CI, 0.997-1.098; P = .022). The operative mortality was 52.9% among patients with PGD versus 20.3% at 48 hours (P = .012). At 72 hours, the mortality rate was 58.3% versus 21.2% (P = .013). The 90-days mortality was also higher among patients with PGD. The mechanical ventilation time was longer in patients with PGD III at 48 hours namely, a mean time of 72 versus 24 hours (P = .001). When PGD was defined at 72 hours, the mean ventilation time was even longer, namely 151 versus 24 hours (P < .001). The mean overall survival for patients who developed PGD at 48 hours was 490.9 versus 1665.5 days for subjects without PGD (P = .001). Considering PGD only at 72 hours, the mean survival was 177.7 days for the PGD group and 1628.9 days for the other patients (P < .001).
CONCLUSION: PGD showed an important impacts on operative and 90-day mortality rates, mechanical ventilation time, and overall survival among lung transplant patients. PGD at 72 hours was a better predictor of lung transplant outcomes than at 48 hours. The use of donors with a smoking history or of advanced age were risk factors for the development of PGD.

PMID: 23026621 [PubMed - in process]

Hepatocellular carcinoma recurrence among liver transplant recipients within the milan criteria.

Tue, 10/09/2012 - 11:58
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Hepatocellular carcinoma recurrence among liver transplant recipients within the milan criteria.

Transplant Proc. 2012 Oct;44(8):2459-61

Authors: Felga G, Evangelista AS, Salvalaggio PR, Curvelo LA, Della Guardia B, Almeida MD, Afonso RC, Ferraz-Neto BH

Abstract
INTRODUCTION: Orthotopic liver transplantation (OLT) is an excellent option for patients with unresectable hepatocellular carcinoma (HCC) within the Milan criteria. Recurrence of HCC has a severe impact on post-OLT survival. In this study, we performed an analysis of post-OLT recurrence pattern of HCC.
METHODS: The prospective cohort of OLT patients included those with unresectable HCC within the Milan criteria, and those beyond the Milan criteria who were downstaged with transcatheter arterial embolization until they achieved the Milan criteria.
RESULTS: Between May 2006 and May 2011, we performed 130 OLT for unresectable HCC within the Milan Criteria among whom 9 patients (6.9%) experienced tumor recurrence. Two (22.2%) had undergone preoperative downstaging. At the time of OLT, mean serum alpha-fetoprotein levels were 623.8 ± 682.9 ng/mL. The liver explants showed 7 (77.8%) subjects were within the Milan criteria, with an average 2.6 ± 2.2 tumors, most of which (89%) were moderately differentiated. Microvascular and macrovascular invasion were observed in 5 (55.6%) and 2 (22.2%) cases, respectively. Liver explants were beyond the Milan criteria in both patients who had undergone preoperative downstaging. Recurrence occurred 23.1 ± 14.3 months after OLT, having been detected in the liver (n = 3; 33.3%), lung (n = 3; 33.3%), brain, peritoneum, and adrenal gland (n = 1 each; 11.1% each). Mean survival after detection of recurrence was 137.4 ± 96.4 days.
CONCLUSIONS: Despite strict candidate selection criteria, HCC recurrence may occur after OLT, bearing a significant impact on posttransplant outcomes to optimize results requires refinements in candidate selection, as well as well-defined cost-effective post-OLT surveillance protocols.

PMID: 23026620 [PubMed - in process]

Impact of model for end-stage liver disease score on long-term survival following liver transplantation for hepatocellular carcinoma.

Tue, 10/09/2012 - 11:58
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Impact of model for end-stage liver disease score on long-term survival following liver transplantation for hepatocellular carcinoma.

Transplant Proc. 2012 Oct;44(8):2423-7

Authors: Roma J, Balbi E, Pacheco-Moreira L, Zyngier I, Araujo A, Agoglia L, Steinbruck K, Velaverde LG, Martinho JM

Abstract
BACKGROUND AND AIMS: Survival rates after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) have significantly increased after Milan criteria and Model for End-Stage Liver Disease (MELD) score implementation. However, few studies have reported this survival in countries with organ donor shortages over a period of 10 years and long waiting lists.
METHODS: This retrospective analysis of clinical data from 93 consecutive HCC patients who underwent OLT from June 2001 to September 2011 excluded 22 who underwent living donor liver transplantation (LDLT). Seventy-one deceased donor liver transplantations (DDLT) were evaluated before and after the MELD era. Kaplan-Meier analysis was used to plot survival rates. The follow-up was 2 months to 10 years.
RESULTS: The overall survival and recurrence rates at 10 years were 67% and 12.2%, respectively. After MELD, patient survival at 5 years decreased from 70% to 64% and the recurrence rate decreased from 15.3% to 12.5%. The most frequent recurrence sites were lung and liver.
CONCLUSION: In our center MELD score implementation had a small impact on long-term survival post OLT for HCC.

PMID: 23026611 [PubMed - in process]

Contemporary management of esophageal malignancy.

Tue, 10/09/2012 - 11:58
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Contemporary management of esophageal malignancy.

Surg Clin North Am. 2012 Oct;92(5):xvii-xviii

Authors: Denlinger CE, Reed CE

PMID: 23026287 [PubMed - in process]

Clinical significance of quantitative cytomegalovirus detection in bronchoalveolar lavage fluid in lung transplant recipients.

Tue, 10/09/2012 - 11:58
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Clinical significance of quantitative cytomegalovirus detection in bronchoalveolar lavage fluid in lung transplant recipients.

Transpl Infect Dis. 2012 Oct 2;

Authors: Schlischewsky E, Fuehner T, Warnecke G, Welte T, Haverich A, Ganzenmueller T, Heim A, Gottlieb J

Abstract
OBJECTIVES: Cytomegalovirus (CMV) is an important pathogen after lung transplant (LTx) and may be associated with bronchiolitis obliterans syndrome (BOS). We assessed the outcome of LTx patients with CMV DNA-positive bronchoalveolar lavage (BAL) during surveillance. METHODS: A single-center retrospective study was performed. Outpatients transplanted between September 2007 and February 2010, who had undergone at least 3 BALs, were included. CMV DNA load in BAL was measured by polymerase chain reaction (PCR). Monitoring of peripheral blood antigenemia was performed simultaneously. RESULTS: In total, 103 LTx patients underwent 1118 BALs. During median follow-up of 639 days (interquartile range, 495-780), 53 (51%) patients exhibited at least 1 positive CMV PCR in BAL. The incidence of positive CMV PCR varied post transplantation, with 6%, 30%, and 25% of BALs testing positive at <6 months, 6-24 months, and >24 months, respectively. Neither CMV BAL positivity, positive CMV antigenemia, nor dual positivity were significantly associated with BOS-free survival during follow-up. Patients with CMV-positive BAL more frequently developed CMV antigenemia in the first year (44% vs. 5%, respectively, log-rank P < 0.001). CONCLUSIONS: Detection of CMV-positive BAL after the sixth month appears common, but did not correlate with BOS-free survival after LTx in this study. An increased risk of developing blood antigenemia was observed in patients with positive CMV PCR in BAL, warranting close follow-up.

PMID: 23025532 [PubMed - as supplied by publisher]

The Alveolar Epithelium Determines Susceptibility to Lung Fibrosis in Hermansky-Pudlak Syndrome.

Tue, 10/09/2012 - 11:58
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The Alveolar Epithelium Determines Susceptibility to Lung Fibrosis in Hermansky-Pudlak Syndrome.

Am J Respir Crit Care Med. 2012 Oct 4;

Authors: Young LR, Gulleman PM, Bridges JP, Weaver TE, Deutsch GH, Blackwell TS, McCormack FX

Abstract
RATIONALE: Hermansky-Pudlak Syndrome (HPS) is a family of recessive disorders of ubiquitous intracellular trafficking defects which are associated with highly penetrant pulmonary fibrosis. Naturally-occurring HPS mice reliably model important features of the human disease, including constitutive alveolar macrophage activation and susceptibility to pro-fibrotic stimuli. OBJECTIVE: To decipher which cell lineage(s) in the alveolar compartment is the predominant driver of fibrotic susceptibility in HPS METHODS: We utilized five different HPS and Chediak-Higashi mouse models to evaluate genotype-specific fibrotic susceptibility. To determine whether intrinsic defects in HPS alveolar macrophages cause fibrotic susceptibility, we generated bone marrow chimeras in HPS and wildtype mice. To directly test the contribution of the pulmonary epithelium, we developed a transgenic model with epithelial-specific correction of the HPS2 defect. MEASUREMENTS AND MAIN RESULTS: Bone marrow transplantation experiments demonstrated that both constitutive alveolar macrophage activation and increased susceptibility to bleomycin-induced fibrosis were conferred by the genotype of the lung epithelium, rather than the bone marrow-derived, cellular compartment. Further, transgenic epithelial-specific correction of the HPS defect significantly attenuated early alveolar epithelial apoptosis, fibrotic susceptibility, and macrophage activation. Bleomycin-induced type II cell apoptosis was genotype-specific, caspase-dependent, and correlated with the degree of fibrotic susceptibility. CONCLUSION: We conclude that pulmonary fibrosis in naturally-occurring HPS mice is driven by intracellular trafficking defects that lower the threshold for pulmonary epithelial apoptosis. Our findings demonstrate a pivotal role for the alveolar epithelium in the maintenance of alveolar homeostasis and regulation of alveolar macrophage activation.

PMID: 23043085 [PubMed - as supplied by publisher]

Update in HIV infection in organ transplantation.

Tue, 10/09/2012 - 11:58
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Update in HIV infection in organ transplantation.

Curr Opin Organ Transplant. 2012 Oct 4;

Authors: Grossi PA

Abstract
PURPOSE OF REVIEW: With reductions in AIDS-related mortality, patients with HIV infection are dying and experiencing significant morbidity from end-stage organ disease. However, patients infected with HIV have traditionally been excluded from organ transplantation. Recent advances have had a significant impact on the potential transplant candidacy of these patients. This review will highlight the major issues associated with transplantation in individuals who are infected with HIV. RECENT FINDINGS: Recently published studies showing promising preliminary outcomes among transplant recipients with HIV infection, suggest that it is not any more justifiable to deny transplantation based solely on HIV-infection status. These studies consistently describe stable HIV disease following liver and kidney transplantation. Furthermore, combined pancreas-kidney, heart, and lung transplantation has been successfully reported, although in a much smaller number of patients. Despite these scientific and policy advances, many healthcare providers and patients remain unaware of ongoing progress in this field. SUMMARY: The experience with organ transplantation in HIV-infected patients is evolving and successful outcomes have been observed when specific criteria are used to select candidates.

PMID: 23042207 [PubMed - as supplied by publisher]

Heart or lung transplanted patients' retrospective views on information and support while waiting for transplantation.

Tue, 10/09/2012 - 11:58
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Heart or lung transplanted patients' retrospective views on information and support while waiting for transplantation.

J Clin Nurs. 2012 Oct 8;

Authors: Ivarsson B, Ekmehag B, Sjöberg T

Abstract
AIMS AND OBJECTIVES: To describe the patients' retrospective experiences of the information and support they received while on the heart or lung transplant waiting list. BACKGROUND: Patients differ in the way that they cope with the time spent waiting for a heart or lung transplant. Patients must already before the transplantation be taught about a new lifestyle, risk factors, medication, food restrictions and exercise, so they can take an active role and responsibility for disease management after transplantation. Little is known about patients' experiences of information and support in these situations. DESIGN: Qualitative descriptive design. METHODS: Sixteen patients (16-67 year) were strategically selected from one transplant centre in Sweden and interviewed six months after heart or lung transplantation. Using content analysis, transcribed data were organised into subcategories that reflected emerging categories. RESULTS: Three categories that describe patients' experiences of information and support have been identified: 'Achieving confidence and trust by information and support', 'Experiencing a lack of input and understanding' and 'Struggling with a life-threatening illness and an insecure future'. Each category consists of different subcategories. CONCLUSIONS: Information and support in connection to heart or lung transplantation are a complex and multifaceted issue involving patient-related, family-related, disease-related and treatment-related factors as well as experiences related to the social situation, the healthcare system and society. Transplant patients are very vulnerable, and a deeper understanding of patients' experiences should help healthcare providers in optimising the care for these very sick patients. RELEVANCE TO CLINICAL PRACTICE: A holistic approach to the patient is necessary in meeting the needs of patients with chronic illness, especially patients with children at home, as well as the needs of their families. An important implication is the necessity to enhance awareness about transplant patients in society in general, in particular in other institutions, by sharing knowledge and by improving cooperation.

PMID: 23039262 [PubMed - as supplied by publisher]

Recovery from AKI and Short- and Long-Term Outcomes after Lung Transplantation.

Tue, 10/09/2012 - 11:58
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Recovery from AKI and Short- and Long-Term Outcomes after Lung Transplantation.

Clin J Am Soc Nephrol. 2012 Oct 4;

Authors: Wehbe E, Duncan AE, Dar G, Budev M, Stephany B

Abstract
BACKGROUND AND OBJECTIVES: Patients with AKI after lung transplantation are at increased risk for CKD and death. Whether patients who completely recover from AKI have improved long-term outcome compared with patients who do not completely recover remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study retrospectively evaluated data on 657 patients who underwent lung transplantation from 1997 to 2009. Outcomes analyzed were the incidence of renal recovery after AKI and the association of this recovery with short- and long-term mortality. AKI was defined by an absolute increase in serum creatinine of ≥0.3 mg/dl or a percent increase in serum creatinine of ≥50% from baseline at any time during the first 2 weeks after transplantation. RESULTS: Four hundred twenty-four (65%) patients experienced AKI in the first 2 weeks after transplantation. Of these patients, complete renal recovery occurred in 142 (33%) patients. The incidence of in-hospital complications was similar between patients who recovered renal function and patients without recovery. At 1 year, the cumulative incidence of CKD was 14% and 22% (P=0.10) and patient survival rate was 81% and 76% (P=0.20) in patients with complete recovery from AKI and patients without recovery, respectively. Patients with completely recovered AKI had similar risk-adjusted long-term mortality compared with patients who did not recover (hazard ratio [95% confidence interval]=1.42 [1.15-2.05] versus 1.53 [1.01-2.00]). CONCLUSIONS: Patients who recover completely from early AKI after lung transplantation have a similar risk for CKD and long-term mortality compared with patients who do not recover.

PMID: 23037982 [PubMed - as supplied by publisher]

Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer.

Tue, 10/09/2012 - 11:58
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Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer.

Clin Cancer Res. 2012 Oct 4;

Authors: Kondo S, Iwata S, Yamada T, Inoue Y, Ichihara H, Kichikawa Y, Katayose T, Souta-Kuribara A, Yamazaki H, Hosono O, Kawasaki H, Tanaka H, Hayashi Y, Sakamoto M, Kamiya K, Dang NH, Morimoto C

Abstract
PURPOSE: In substantial population of non-small cell lung cancer (NSCLC), expression and activation of EGFR has been reported, and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins. EXPERIMENTAL DESIGN: Using NSCLC cell lines, we performed immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of NSCLC patients. RESULTS: We demonstrated that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively-active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of a NSCLC cell line in NOG mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival. CONCLUSIONS: Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLC, and its expression can promote NSCLC metastasis.

PMID: 23037767 [PubMed - as supplied by publisher]

The Pathophysiology of Endothelin in Complications After Solid Organ Transplantation: A Potential Novel Therapeutic Role for Endothelin Receptor Antagonists.

Tue, 10/09/2012 - 11:58
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The Pathophysiology of Endothelin in Complications After Solid Organ Transplantation: A Potential Novel Therapeutic Role for Endothelin Receptor Antagonists.

Transplantation. 2012 Oct 3;

Authors: Raina A, Horn ET, Benza RL

Abstract
: Although short-term allograft survival after solid organ transplantation has improved during the past two decades, improvement in long-term graft survival has been less pronounced. Common complications after transplantation include chronic allograft rejection, nephrotoxicity from calcineurin inhibitors (CNIs), and systemic hypertension, which all impact posttransplantation morbidity and mortality. Endothelin (ET)-1, a potent endogenous vasoconstrictor, inducer of fibrosis, and vascular smooth muscle cell proliferation, may play a key role in both the development of CNI-induced nephrotoxicity and endothelial vasculopathy in chronic allograft rejection. ET-1 levels increase after isograft implantation, and ET-1 plays a key role in CNI-induced renal vasoconstriction, sodium retention, and hypertension. Preclinical studies have demonstrated that endothelin receptor antagonists (ERAs) can reduce or prevent CNI-induced hypertension after renal transplantation. In addition, ERAs can ameliorate CNI-induced renal vasoconstriction and improve proteinuria and preserve renal function in animal models of renal transplantation. ET-1 may also play a significant role in cardiac allograft vasculopathy, and in animal models, ERAs improve pulmonary function and ischemic-reperfusion injury in lung transplantation and hepatic function and structure in liver transplantation. Emerging pharmacokinetic data suggest that the selective ERA ambrisentan may be used safely in conjunction with the most commonly used immunosuppressive agents tacrolimus and mycophenolate, albeit with appropriate dose adjustment. The weight of available evidence pointing toward a potential beneficial role of ERAs in ameliorating common complications after solid organ transplantation must be balanced with potential toxicities of ERAs but suggests that a randomized clinical trial of ERAs in transplant patients is warranted.

PMID: 23037008 [PubMed - as supplied by publisher]

Disseminated Trichosporon mycotoxinivorans, Aspergillus fumigatus and Scedosporium apiospermum co-infection after lung and liver transplantation in a cystic fibrosis patient.

Fri, 10/05/2012 - 12:32

Disseminated Trichosporon mycotoxinivorans, Aspergillus fumigatus and Scedosporium apiospermum co-infection after lung and liver transplantation in a cystic fibrosis patient.

J Clin Microbiol. 2012 Oct 3;

Authors: Hirschi S, Letscher-Bru V, Pottecher J, Lannes B, Jeung MY, Degot T, Santelmo N, Sabou AM, Herbrecht R, Kessler R

Abstract
Trichosporon mycotoxinivorans is a novel pathogen recently described in cystic fibrosis patients. We report the first case of a disseminated fatal infection with T. mycotoxinivorans associated with invasive Aspergillus fumigatus and Scedosporium apiospermum infection after lung and liver transplantation in a cystic fibrosis patient.

PMID: 23035187 [PubMed - as supplied by publisher]

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