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Updated: 57 min 31 sec ago

Combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 improves survival and tumor control in CLL mouse model.

57 min 31 sec ago
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Combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 improves survival and tumor control in CLL mouse model.

Clin Cancer Res. 2017 Jun 23;:

Authors: Niemann CU, Mora-Jensen HI, Dadashian EL, Krantz F, Covey T, Chen SS, Chiorazzi N, Izumi R, Ulrich R, Lannutti BJ, Wiestner A, Herman SEM

Abstract
Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of BTK and PI3K-delta is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3K-delta and BTK inhibitors. <p>Experimental design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3K-delta inhibitor ACP-319 in vivo We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL.</p> <p>Results: We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. While single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over two weeks compared to either single agent. The combination reduced tumor proliferation, NF-KB signaling and expression of BCL-xL and MCL-1 more potently than single-agent therapy.</p> <p>Conclusion: The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies.

PMID: 28645939 [PubMed - as supplied by publisher]

Pulmonary Artery Embolization after Blunt Trauma.

57 min 31 sec ago
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Pulmonary Artery Embolization after Blunt Trauma.

J Vasc Interv Radiol. 2017 Jul;28(7):1011

Authors: Maury JM, Saiedi H, Revel D

PMID: 28645498 [PubMed - in process]

A rapid and quantitative method to detect human circulating tumor cells in a preclinical animal model.

57 min 31 sec ago
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A rapid and quantitative method to detect human circulating tumor cells in a preclinical animal model.

BMC Cancer. 2017 Jun 23;17(1):440

Authors: Tu SH, Hsieh YC, Huang LC, Lin CY, Hsu KW, Hsieh WS, Chi WM, Lee CH

Abstract
BACKGROUND: As cancer metastasis is the deadliest aspect of cancer, causing 90% of human deaths, evaluating the molecular mechanisms underlying this process is the major interest to those in the drug development field. Both therapeutic target identification and proof-of-concept experimentation in anti-cancer drug development require appropriate animal models, such as xenograft tumor transplantation in transgenic and knockout mice. In the progression of cancer metastasis, circulating tumor cells (CTCs) are the most critical factor in determining the prognosis of cancer patients. Several studies have demonstrated that measuring CTC-specific markers in a clinical setting (e.g., flow cytometry) can provide a current status of cancer development in patients. However, this useful technique has rarely been applied in the real-time monitoring of CTCs in preclinical animal models.
METHODS: In this study, we designed a rapid and reliable detection method by combining a bioluminescent in vivo imaging system (IVIS) and quantitative polymerase chain reaction (QPCR)-based analysis to measure CTCs in animal blood. Using the IVIS Spectrum CT System with 3D-imaging on orthotropic-developed breast-tumor-bearing mice.
RESULTS: In this manuscript, we established a quick and reliable method for measuring CTCs in a preclinical animal mode. The key to this technique is the use of specific human and mouse GUS primers on DNA/RNA of mouse peripheral blood under an absolute qPCR system. First, the high sensitivity of cancer cell detection on IVIS was presented by measuring the luciferase carried MDA-MB-231 cells from 5 to 5x10(11) cell numbers with great correlation (R(2) = 0.999). Next, the MDA-MB-231 cell numbers injected by tail vein and their IVIS radiance signals were strongly corrected with qPCR-calculated copy numbers (R(2) > 0.99). Furthermore, by applying an orthotropic implantation animal model, we successfully distinguished xenograft tumor-bearing mice and control mice with a significant difference (p < 0.001), whereas IVIS Spectrum-CT 3D-visualization showed that blood of mice with lung metastasis contained more than twice the CTC numbers than ordinary tumor-bearing mice. We demonstrated a positive correlation between lung metastasis status and CTC numbers in peripheral mouse blood.
CONCLUSION: Collectively, the techniques developed for this study resulted in the integration of CTC assessments into preclinical models both in vivo and ex vivo, which will facilitate translational targeted therapy in clinical practice.

PMID: 28645267 [PubMed - in process]

Carbonic anhydrase inhibitor attenuates ischemia-reperfusion induced acute lung injury.

Sat, 06/24/2017 - 12:45
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Carbonic anhydrase inhibitor attenuates ischemia-reperfusion induced acute lung injury.

PLoS One. 2017;12(6):e0179822

Authors: Lan CC, Peng CK, Tang SE, Huang KL, Wu CP

Abstract
Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA), in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group): sham, sham + AZA 200 mg/kg body weight (BW), IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6 and IL-17) and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression.

PMID: 28644844 [PubMed - in process]

Regarding mechanical circulatory support in adults with congenital heart disease: Is it time to lower the threshold for use?

Sat, 06/24/2017 - 12:45
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Regarding mechanical circulatory support in adults with congenital heart disease: Is it time to lower the threshold for use?

J Heart Lung Transplant. 2017 May 29;:

Authors: Bryant R, Morales DLS

PMID: 28642001 [PubMed - as supplied by publisher]

Initial experience with the HeartMate percutaneous heart pump in circulatory failure.

Sat, 06/24/2017 - 12:45
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Initial experience with the HeartMate percutaneous heart pump in circulatory failure.

J Heart Lung Transplant. 2017 May 20;:

Authors: Maly J, Ivak P, Netuka I, Herman A, Kettner J, Sood P, Jorde UP

PMID: 28642000 [PubMed - as supplied by publisher]

Effect of everolimus versus calcineurin inhibitors on quality of life in heart transplant recipients during a 3-year follow up: results of a randomized controlled trial (SCHEDULE).

Sat, 06/24/2017 - 12:45
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Effect of everolimus versus calcineurin inhibitors on quality of life in heart transplant recipients during a 3-year follow up: results of a randomized controlled trial (SCHEDULE).

Clin Transplant. 2017 Jun 22;:

Authors: Relbo Authen A, Grov I, Karason K, Gustafsson F, Eiskjaer H, Rådegran G, Gude E, Jansson K, Dellgren G, Solbu D, Arora S, Andreassen AK, Gullestad L, SCHEDULE investigators

Abstract
The SCHEDULE trial was a 12-month, randomized, open-label, parallel-group trial that compared everolimus (EVR; n=56) to conventional CsA (n=59) immunosuppression. Previously, we reported that EVR outperformed CsA in improving renal function and coronary artery vasculopathy, despite a higher rejection rate with EVR. The present study aimed to compare the effects of these treatments on quality of life (QoL). Within 5 postoperative days, patients (mean age 50±13 years, 27% women) were randomized to EVR or a standard CsA dosage (CsA group). This. study assessed quality of life (QoL), based on the Short Form-36, EuroQol-5D, and Beck Depression Inventory (BDI). Assessments were performed pre-HTx and 12 and 36 months post-HTx. At 12 and 36 months, the groups showed similar improvements in Short Form-36 measures (at pre-HTx, 12 and 36 months the values were: physical component summary: EVR: 31.5±110.9, 49.1±9.7 and 47.9± 10.6; p<0.01; CsA: 32.5±8.2, 48.4±8.5 and 46.5±11.5; p<0.01; mental component summary: EVR: 46.0±12.0, 51.7±11.9 and 52.1±13.0; p<0.01; CsA: 38.2±12.5, 53.4±7.1 and 54.3±13.0; p<0.01); similar decrease in mean BDI (EVE:10.9±10.2, 5.4±4.7 and 8.1±9.0; p<0.01; CsA: 11.8±7.1, 6.3±5.4 and 6.2±6.5; p<0.01); and similar Euro Qol- improvements. Thus, in this small-sized study, EVE-based and conventional CsA immunosuppressive strategies produced similar QoL improvements. This article is protected by copyright. All rights reserved.

PMID: 28640529 [PubMed - as supplied by publisher]

Epstein-Barr viral loads do not predict post-transplant lymphoproliferative disorder in pediatric lung transplant recipients: A multicenter prospective cohort study.

Sat, 06/24/2017 - 12:45
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Epstein-Barr viral loads do not predict post-transplant lymphoproliferative disorder in pediatric lung transplant recipients: A multicenter prospective cohort study.

Pediatr Transplant. 2017 Jun 21;:

Authors: Parrish A, Fenchel M, Storch GA, Buller R, Mason S, Williams N, Ikle D, Conrad C, Faro A, Goldfarb S, Hayes D, Melicoff-Portillo E, Schecter M, Visner G, Sweet S, Danziger-Isakov L, Clinical Trials in Organ Transplantation in Children (CTOTC-03)

Abstract
Prediction of PTLD after pediatric lung transplant remains difficult. Use of EBV VL in WB has been poorly predictive, while measurement of VL in BAL fluid has been suggested to have enhanced utility. The NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) prospectively obtained serial quantitative measurements of EBV PCR in both WB and BAL fluid after pediatric lung transplantation. Descriptive statistics, contingency analyses, and Kaplan-Meier analyses evaluated possible association between EBV and PTLD. Of 61 patients, 34 (56%) had an EBV+PCR (at least once in WB or BAL). EBV donor (D)+patients more often had a positive PCR (D+/recipient (R)-: 13/18; D+/R+: 14/23) compared to EBV D- patients (6/17). Several D-/R- (5/12) patients developed EBV, but none developed PTLD. All four PTLD patients were D+/R- with EBV+PCR. Neither the time to first EBV+PCR nor the CT for PCR positivity in BAL or WB was statistically different between those with and without PTLD. Having an EBV-seropositive donor was associated with increased risk of EBV+PCR in WB. EBV load in BAL was not predictive of PTLD.

PMID: 28639398 [PubMed - as supplied by publisher]

Bright Polymer Dots Tracking Stem Cell Engraftment and Migration to Injured Mouse Liver.

Sat, 06/24/2017 - 12:45
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Bright Polymer Dots Tracking Stem Cell Engraftment and Migration to Injured Mouse Liver.

Theranostics. 2017;7(7):1820-1834

Authors: Chen D, Li Q, Meng Z, Guo L, Tang Y, Liu Z, Yin S, Qin W, Yuan Z, Zhang X, Wu C

Abstract
Stem cell therapy holds promise for treatment of intractable diseases and injured organs. For clinical translation, it is pivotal to understand the homing, engraftment, and differentiation processes of stem cells in a living body. Here we report near-infrared (NIR) fluorescent semiconductor polymer dots (Pdots) for bright labeling and tracking of human mesenchymal stem cells (MSCs). The Pdots exhibit narrow-band emission at 775 nm with a quantum yield of 22%, among the highest value for various NIR probes. The Pdots together with a cell penetrating peptide are able to track stem cells over two weeks without disturbing their multipotent properties, as confirmed by the analyses on cell proliferation, differentiation, stem-cell markers, and immunophenotyping. The in vivo cell tracking was demonstrated in a liver-resection mouse model, which indicated that the Pdot-labeled MSCs after tail-vein transplantation were initially trapped in lung, gradually migrated to the injured liver, and then proliferated into cell clusters. Liver-function analysis and histological examination revealed that the inflammation induced by liver resection was apparently decreased after stem cell transplantation. With the bright labeling, superior biocompatibility, and long-term tracking performance, the Pdot probes are promising for stem cell research and regenerative medicine.

PMID: 28638470 [PubMed - in process]

Colopharyngoplasty in Patients with Severe Pharyngoesophageal Corrosive Injury: A Complicated but Worthwhile Procedure to Restore GI Tract Continuity, A Case Series.

Sat, 06/24/2017 - 12:45
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Colopharyngoplasty in Patients with Severe Pharyngoesophageal Corrosive Injury: A Complicated but Worthwhile Procedure to Restore GI Tract Continuity, A Case Series.

Tanaffos. 2017;16(1):68-75

Authors: Zangi M, Saghebi SR, Biharas Monfared A, Lajevardi S, Shadmehr MB

Abstract
BACKGROUND: Pharyngoesophageal strictures (PES) after corrosive injury impose a problematic condition for both physicians and patients in terms of their management and patients' quality of life. Colopharyngoplasty is a complex procedure, which is used to restore swallowing in these severely disabled patients. We describe our experience in treating nine patients with severe PES after corrosive injuries in a referral center.
MATERIALS AND METHODS: A retrospective analysis of our database from 2009 to 2014 showed nine patients (seven men; age range: 18 to 47 years) with severe PES who underwent colopharyngoplasty ∼6 months (range: 4-10) after caustic material ingestion. All patients had a feeding jejunostomy tube before reconstruction. Esophagectomy with or without gastrectomy was performed in all patients, except for one; thereafter, an isoperistaltic segment of the left colon was pulled up, and a pharyngocolic anastomosis was performed. Eight patients had a tracheostomy created either before reconstruction due to respiratory symptoms or at the time of definitive surgery to prevent aspiration in the early post-operative period.
RESULTS: Almost all survivors had a satisfactory swallowing at the end of the follow-up (range: 4-60 months). The jejunostomy tube could be removed in all of the patients after a median of 5 months. One patient died of sepsis due to graft necrosis in the immediate post-operative period. Another patient died 5 months after the first surgery following a revision surgery for intractable dysphagia. At the end of the follow-up, only one patient tolerated tracheostomy tube decannulation. Two patients required laryngotracheal dissociation because of massive aspiration and recurrent episodes of pneumonia. Five patients still had a tracheostomy because of an severely destroyed larynx (two patients) and aspiration (three patients).
CONCLUSION: Colopharyngoplasty is considered a complicated but trustworthy procedure to restore gastrointestinal tract continuity after severe corrosive injury. Undeniably, laryngeal involvement adversely affects the functional outcome. The post-operative course is frequently protracted, accompanied with several problems. Aspiration is nearly the most problematic event in the early post-operative period, which mandates a multidisciplinary approach to manage it.

PMID: 28638427 [PubMed - in process]

Extracorporeal carbon dioxide removal (ECCO2R) in patients with acute respiratory failure.

Sat, 06/24/2017 - 12:45
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Extracorporeal carbon dioxide removal (ECCO2R) in patients with acute respiratory failure.

Intensive Care Med. 2017 Apr;43(4):519-530

Authors: Morelli A, Del Sorbo L, Pesenti A, Ranieri VM, Fan E

Abstract
PURPOSE: To review the available knowledge related to the use of ECCO2R as adjuvant strategy to mechanical ventilation (MV) in various clinical settings of acute respiratory failure (ARF).
METHODS: Expert opinion and review of the literature.
RESULTS: ECCO2R may be a promising adjuvant therapeutic strategy for the management of patients with severe exacerbations of COPD and for the achievement of protective or ultra-protective ventilation in patients with ARDS without life-threatening hypoxemia. Given the observational nature of most of the available clinical data and differences in technical features and performances of current devices, the balance of risks and benefits for or against ECCO2R in such patient populations remains unclear CONCLUSIONS: ECCO2R is currently an experimental technique rather than an accepted therapeutic strategy in ARF-its safety and efficacy require confirmation in clinical trials.

PMID: 28132075 [PubMed - indexed for MEDLINE]

Injection of Syngeneic Murine Melanoma Cells to Determine Their Metastatic Potential in the Lungs.

Sat, 06/24/2017 - 12:45
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Injection of Syngeneic Murine Melanoma Cells to Determine Their Metastatic Potential in the Lungs.

J Vis Exp. 2016 May 24;(111):

Authors: Timmons JJ, Cohessy S, Wong ET

Abstract
Approximately 90% of human cancer deaths are linked to metastasis. Despite the prevalence and relative harm of metastasis, therapeutics for treatment or prevention are lacking. We report a method for the establishment of pulmonary metastases in mice, useful for the study of this phenomenon. Tail vein injection of B57BL/6J mice with B16-BL6 is among the most used models for melanoma metastases. Some of the circulating tumor cells establish themselves in the lungs of the mouse, creating "experimental" metastatic foci. With this model it is possible to measure the relative effects of therapeutic agents on the development of cancer metastasis. The difference in enumerated lung foci between treated and untreated mice indicates the efficacy of metastases neutralization. However, prior to the investigation of a therapeutic agent, it is necessary to determine an optimal number of injected B16-BL6 cells for the quantitative analysis of metastatic foci. Injection of too many cells may result in an overabundance of metastatic foci, impairing proper quantification and overwhelming the effects of anti-cancer therapies, while injection of too few cells will hinder the comparison between treated and controls.

PMID: 27285567 [PubMed - indexed for MEDLINE]

Transcriptional signature induced by a metastasis-promoting c-Src mutant in a human breast cell line.

Sat, 06/24/2017 - 12:45
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Transcriptional signature induced by a metastasis-promoting c-Src mutant in a human breast cell line.

FEBS J. 2016 May;283(9):1669-88

Authors: Broecker F, Hardt C, Herwig R, Timmermann B, Kerick M, Wunderlich A, Schweiger MR, Borsig L, Heikenwalder M, Lehrach H, Moelling K

Abstract
UNLABELLED: Deletions at the C-terminus of the proto-oncogene protein c-Src kinase are found in the viral oncogene protein v-Src as well as in some advanced human colon cancers. They are associated with increased kinase activity and cellular invasiveness. Here, we analyzed the mRNA expression signature of a constitutively active C-terminal mutant of c-Src, c-Src(mt), in comparison with its wild-type protein, c-Src(wt), in the human non-transformed breast epithelial cell line MCF-10A. We demonstrated previously that the mutant altered migratory and metastatic properties. Genome-wide transcriptome analysis revealed that c-Src(mt) de-regulated the expression levels of approximately 430 mRNAs whose gene products are mainly involved in the cellular processes of migration and adhesion, apoptosis and protein synthesis. 82.9% of these genes have previously been linked to cellular migration, while the others play roles in RNA transport and splicing processes, for instance. Consistent with the transcriptome data, cells expressing c-Src(mt), but not those expressing c-Src(wt), showed the capacity to metastasize into the lungs of mice in vivo. The mRNA expression profile of c-Src(mt)-expressing cells shows significant overlap with that of various primary human tumor samples, possibly reflecting elevated Src activity in some cancerous cells. Expression of c-Src(mt) led to elevated migratory potential. We used this model system to analyze the transcriptional changes associated with an invasive cellular phenotype. These genes and pathways de-regulated by c-Src(mt) may provide suitable biomarkers or targets of therapeutic approaches for metastatic cells.
DATABASE: This project was submitted to the National Center for Biotechnology Information BioProject under ID PRJNA288540. The Illumina RNA-Seq reads are available in the National Center for Biotechnology Information Sequence Read Archive under study ID SRP060008 with accession numbers SRS977414 for MCF-10A cells, SRS977717 for mock cells, SRS978053 for c-Src(wt) cells and SRS978046 for c-Src(mt) cells.

PMID: 26919036 [PubMed - indexed for MEDLINE]

The prognostic importance of bronchoalveolar lavage fluid CXCL9 during minimal acute rejection on the risk of chronic lung allograft dysfunction.

Thu, 06/22/2017 - 12:45
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The prognostic importance of bronchoalveolar lavage fluid CXCL9 during minimal acute rejection on the risk of chronic lung allograft dysfunction.

Am J Transplant. 2017 Jun 21;:

Authors: Shino MY, Weigt SS, Li N, Derhovanessian A, Sayah DM, Saggar R, Huynh RH, Gregson AL, Ardehali A, Ross DJ, Lynch JP, Elashoff RM, Belperio JA

Abstract
The clinical significance and treatment strategies for minimal acute rejection (grade A1), the most common form of acute rejection (AR), remains controversial. In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between minimal AR and chronic lung allograft dysfunction (CLAD) and test a novel hypothesis using BAL CXCL9 concentration during minimal AR as a biomarker of subsequent CLAD development. In univariable and multivariable models adjusted for all histopathologic injury patterns, minimal AR was not associated with CLAD development. However, minimal AR with elevated BAL CXCL9 concentrations markedly increased CLAD risk in a dose-response manner. Minimal AR with CXCL9 concentrations greater than the 25(th) , 50(th) , and 75(th) percentile had an adjusted HRs for CLAD of 1.1 (95% CI 0.8-1.6), 1.6 (95% CI 1.1-2.3) and 2.2 (95% CI 1.4-3.4), respectively. Thus, we demonstrate the utility of BAL CXCL9 measurement as a prognostic biomarker that allows discrimination of recipients at increased risk of CLAD development after minimal AR. BAL CXCL9 measurement during transbronchial biopsies may provide clinically useful prognostic data and potentially guide treatment decisions for this common form of AR, as a possible strategy to minimize CLAD development. This article is protected by copyright. All rights reserved.

PMID: 28637080 [PubMed - as supplied by publisher]

Oxidative stress mediated by nitrogen at elevated pressure inhibits non-small cell lung cancer growth.

Thu, 06/22/2017 - 12:45
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Oxidative stress mediated by nitrogen at elevated pressure inhibits non-small cell lung cancer growth.

Exp Lung Res. 2017 Jun 21;:1-6

Authors: Thom SR, Ma M, Bhopale VM, Zhou C, Mao L

Abstract
Purpose/Aim: High pressures of gases such as nitrogen enhance production of singlet oxygen. Therefore, we hypothesized that growth of non-small cell lung cancer (NSCLC) A549 cells and a human-derived NSCLC explant could be inhibited by an oxidative stress mechanism using high-pressure nitrogen.
MATERIALS AND METHODS: Growth of human NSCLC explants and A549 cells in Matrigel were assessed after implantation into nude mice who were exposed to elevated pressures.
RESULTS: Subcutaneous implant growth of NSCLC in nude mice was inhibited by a daily 78-minute protocol using nitrogen/oxygen breathing mixture such that at the maximum pressure of 2.78 atmospheres over ambient, mice breathed oxygen at normal atmospheric pressure. In vivo growth inhibition of A549 cells by high-pressure nitrogen could be abrogated in subcutaneous Matrigel implants when supplemented with 10-mM N-acetylcysteine as an antioxidant. Ex vivo A549 cell exposures exhibited elevated singlet oxygen production, and reactive oxygen species were produced for up to 4 hours after short-term high-pressure nitrogen exposure.
CONCLUSIONS: This pilot study demonstrates that elevated normoxic nitrogen pressure can exacerbate oxidative stress in NSCLC to inhibit growth.

PMID: 28636438 [PubMed - as supplied by publisher]

Covariate selection with group lasso and doubly robust estimation of causal effects.

Thu, 06/22/2017 - 12:45
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Covariate selection with group lasso and doubly robust estimation of causal effects.

Biometrics. 2017 Jun 21;:

Authors: Koch B, Vock DM, Wolfson J

Abstract
The efficiency of doubly robust estimators of the average causal effect (ACE) of a treatment can be improved by including in the treatment and outcome models only those covariates which are related to both treatment and outcome (i.e., confounders) or related only to the outcome. However, it is often challenging to identify such covariates among the large number that may be measured in a given study. In this article, we propose GLiDeR (Group Lasso and Doubly Robust Estimation), a novel variable selection technique for identifying confounders and predictors of outcome using an adaptive group lasso approach that simultaneously performs coefficient selection, regularization, and estimation across the treatment and outcome models. The selected variables and corresponding coefficient estimates are used in a standard doubly robust ACE estimator. We provide asymptotic results showing that, for a broad class of data generating mechanisms, GLiDeR yields a consistent estimator of the ACE when either the outcome or treatment model is correctly specified. A comprehensive simulation study shows that GLiDeR is more efficient than doubly robust methods using standard variable selection techniques and has substantial computational advantages over a recently proposed doubly robust Bayesian model averaging method. We illustrate our method by estimating the causal treatment effect of bilateral versus single-lung transplant on forced expiratory volume in one year after transplant using an observational registry.

PMID: 28636276 [PubMed - as supplied by publisher]

Papers of note in Science Translational Medicine9 (394).

Thu, 06/22/2017 - 12:45
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Papers of note in Science Translational Medicine9 (394).

Sci Signal. 2017 Jun 20;10(484):

Authors: Ferrarelli LK

Abstract
This week's articles describe how broccoli can combat type 2 diabetes, how monocytes contribute to the failure of organ transplant grafts, and how to more durably treat RET- or KRAS-driven lung cancer.

PMID: 28634206 [PubMed - in process]

Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice.

Thu, 06/22/2017 - 12:45
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Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice.

Biochem Biophys Res Commun. 2017 Jun 17;:

Authors: Hara T, Murakami Y, Seiki M, Sakamoto T

Abstract
Breast cancer is one of the most common cancers in women in the world. Although breast cancer is well treatable at the early stage, patients with distant metastases show a poor prognosis. Data from recent studies using transplantation models indicate that Mint3/APBA3 might promote breast cancer malignancy. However, whether Mint3 indeed contributes to tumor development, progression, or metastasis in vivo remains unclear. To address this, here we examined whether Mint3 depletion affects tumor malignancy in MMTV-PyMT breast cancer model mice. In MMTV-PyMT mice, Mint3 depletion did not affect tumor onset and tumor growth, but attenuated lung metastases. Experimental lung metastasis of breast cancer Met-1 cells derived from MMTV-PyMT mice also decreased in Mint3-depleted mice, indicating that host Mint3 expression affected lung metastasis of MMTV-PyMT-derived breast cancer cells. Further bone marrow transplant experiments revealed that Mint3 in bone marrow-derived cells promoted lung metastasis in MMTV-PyMT mice. Thus, targeting Mint3 in bone marrow-derived cells might be a good strategy for preventing metastasis and improving the prognosis of breast cancer patients.

PMID: 28634075 [PubMed - as supplied by publisher]

Risk factors for pulmonary complications after hepatic resection: role of intraoperative hemodynamic instability and hepatic ischemia.

Thu, 06/22/2017 - 12:45
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Risk factors for pulmonary complications after hepatic resection: role of intraoperative hemodynamic instability and hepatic ischemia.

BMC Anesthesiol. 2017 Jun 20;17(1):84

Authors: Lepere V, Vanier A, Loncar Y, Lemoine L, Vaillant JC, Monsel A, Savier E, Coriat P, Eyraud D

Abstract
BACKGROUND: Postoperative operative pulmonary complications (PPCs) after hepatic surgery are associated with increased length of hospital stays. Intraoperative blood transfusion, extensive resection and different comorbidities have been identified. Other parameters, like time of hepatic ischemia, have neither been clinically studied, though experimental studies show that hepatic ischemia can provide lung injury. The objective of this study was to determinate the risk factors of postoperative pulmonary complications (PPCs) after hepatic resection within 7 postoperative days.
METHOD: Ninety-four patients consecutively who underwent elective hepatectomy between January and December 2013. Demographic data, pathological variables, and preoperative, intraoperative, and postoperative variables had been prospectively collected in a data base. The dependant variables studied were the occurrence of PPCs, defined before analysis of the data.
RESULTS: PPCs occurred in 32 (34%) patients. A multivariate analysis allowed identifying the risk factors for PPCs. On multivariate analysis, preoperative gamma-glutamyltransferase (GGT) elevation OR =5,12 [1,85-15,69] p = 0,002, liver ischemia duration OR = 1,03 [1,01-1,06] p = 0,01 and the intraoperative use of vasopressor OR = 4,40 [1,58-13,36] p = 0,006 were independently associated with PPCs. For every 10 min added in ischemia duration, the OR of the risk of PPCs was estimated to be 1.37 (CI95% = [1.08-1.81], p = 0.01).
CONCLUSION: Three risk factors for PPCs have been identified in a population undergoing liver resection: preoperative GGT elevation, ischemia duration and the intraoperative use of vasopressor. PPCs after liver surgery could be related to lung injury induced by liver ischemia reperfusion and not solely by direct infectious process. That could explain why factors influencing directly or indirectly liver ischemia were independently associated with PPCs.

PMID: 28633644 [PubMed - in process]

Successful Lung Transplantation for Pulmonary Disease Associated With Erdheim-Chester Disease.

Thu, 06/22/2017 - 12:45
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Successful Lung Transplantation for Pulmonary Disease Associated With Erdheim-Chester Disease.

Ann Thorac Surg. 2017 Jul;104(1):e13-e15

Authors: Hashimoto K, Miyoshi K, Mizutani H, Otani S, Sugimoto S, Yamane M, Oto T

Abstract
A 53-year-old man with pulmonary fibrosis associated with Erdheim-Chester disease achieved long-term survival after lung transplantation. Major clinical manifestations included lung and bone injuries, and other vital organs were functionally unaffected by the disease. After a careful observation for the disease progression, he underwent bilateral deceased-donor lung transplantation. He has returned to his normal social life and is doing well without recurrence of Erdheim-Chester disease in the lung allograft or progression in other organs 5 years after transplant. Lung transplantation is a potentially reasonable treatment option for Erdheim-Chester disease involving the lungs if the functions of other vital organs remain stable.

PMID: 28633251 [PubMed - in process]

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