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Impact of a modified anti-thrombotic guideline on stroke in children supported with a pediatric ventricular assist device.

Wed, 06/14/2017 - 12:45

Impact of a modified anti-thrombotic guideline on stroke in children supported with a pediatric ventricular assist device.

J Heart Lung Transplant. 2017 May 20;:

Authors: Rosenthal DN, Lancaster CA, McElhinney DB, Chen S, Stein M, Lin A, Doan L, Murray JM, Gowan MA, Maeda K, Reinhartz O, Almond CS

Abstract
BACKGROUND: Stroke is the most feared complication associated with the Berlin Heart EXCOR pediatric ventricular assist device (VAD), the most commonly used VAD in children, and affects 1 in 3 children. We sought to determine whether a modified anti-thrombotic guideline, involving more intense platelet inhibition and less reliance on platelet function testing, is associated with a lower incidence of stroke.
METHODS: All children supported with the EXCOR at Stanford from 2009 to 2014 were divided into 2 cohorts based on the primary anti-thrombotic guideline used to prevent pump thrombosis: (1) the Edmonton Anti-thrombotic Guideline (EG) cohort, which included children implanted before September 2012 when dual anti-platelet therapy was used with doses titrated to Thromboelastrography/PlateletMapping (TEG/PM); and (2) the Stanford Modified Anti-thrombotic Guideline (SG) cohort, which included children implanted on or after September 2012 when triple anti-platelet therapy was used routinely and where doses were uptitrated to high, weight-based dosing targets, with low-dose steroids administered as needed for inflammation.
RESULTS: At baseline, the EG (N = 16) and SG (N = 11) cohorts were similar. The incidence rate of stroke in the SG cohort was 84% lower than in the EG cohort (0.8 vs 4.9 events per 1,000 days of support, p = 0.031), and 86% lower than in the previous Investigational Device Exemption trial (p = 0.006). The bleeding rate was also lower in the SG cohort (p = 0.015). Target doses of aspirin, clopidogrel and dipyridamole were higher (all p < 0.003), with less dosing variability in the SG cohort than in the EG cohort. There was no difference in adenosine diphosphate inhibition by TEG/PM, but arachidonic acid inhibition was higher in the SG cohort (median 75% vs 39%, p = 0.008).
CONCLUSIONS: Stroke was significantly less common in pediatric patients supported with the Berlin Heart EXCOR VAD using a triple anti-platelet regimen uptitrated to high, weight-based dosing targets as compared with the dual anti-platelet regimen titrated to PM, and without a higher risk of bleeding. Larger studies are needed to confirm these findings.

PMID: 28606584 [PubMed - as supplied by publisher]

Endothelial Cells Require CD98 for Efficient Angiogenesis-Brief Report.

Wed, 06/14/2017 - 12:45
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Endothelial Cells Require CD98 for Efficient Angiogenesis-Brief Report.

Arterioscler Thromb Vasc Biol. 2016 Nov;36(11):2163-2166

Authors: Liao Z, Cantor JM

Abstract
OBJECTIVE: CD98 regulates integrin signaling and is critical for tumor cell proliferation. It is also expressed on endothelial cells (EC), but its role in angiogenesis is unclear.
APPROACH AND RESULTS: We used specific genetic targeting and antibody blockade approaches to examine the function of CD98 in EC proliferation, blood vessel growth, and tumor angiogenesis. It is upregulated on angiogenic ECs, and EC-specific deletion of CD98 in mice inhibited tumor growth, retinal angiogenesis, and EC proliferation. Reconstitution with CD98 mutants showed that integrin and CD98 interaction is necessary for EC survival and growth. Moreover, anti-CD98 treatment inhibited vessel formation and reversed EC-assisted tumor growth.
CONCLUSIONS: Our findings demonstrate a requirement for CD98 in EC growth and suggest that CD98-specific reagents could have a dual anticancer effect: directly by inhibiting tumor cell proliferation and indirectly by preventing tumor angiogenesis.

PMID: 27687603 [PubMed - indexed for MEDLINE]

Lung regeneration by fetal lung tissue implantation in a mouse pulmonary emphysema model.

Wed, 06/14/2017 - 12:45
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Lung regeneration by fetal lung tissue implantation in a mouse pulmonary emphysema model.

J Med Invest. 2016;63(3-4):182-6

Authors: Uyama K, Sakiyama S, Yoshida M, Kenzaki K, Toba H, Kawakami Y, Okumura K, Takizawa H, Kondo K, Tangoku A

Abstract
The mortality and morbidity of chronic obstructive pulmonary disease are high. However, no radical therapy has been developed to date. The purpose of this study was to evaluate whether fetal mouse lung tissue can grow and differentiate in the emphysematous lung. Fetal lung tissue from green fluorescent protein C57BL/6 mice at 16 days' gestation was used as donor material. Twelve-month-old pallid mice were used as recipients. Donor lungs were cut into small pieces and implanted into the recipient left lung by performing thoracotomy under anesthesia. The recipient mice were sacrificed at day 7, 14, and 28 after implantation and used for histological examination. Well-developed spontaneous pulmonary emphysema was seen in 12-month-old pallid mice. Smooth and continuous connection between implanted fetal lung tissue and recipient lung was recognized. Air space expansion and donor tissue differentiation were observed over time. We could clearly distinguish the border zones between injected tissue and native tissue by the green fluorescence of grafts. Fetal mouse lung fragments survived and differentiated in the emphysematous lung of pallid mice. Implantation of fetal lung tissue in pallid mice might lead to further lung regeneration research from the perspective of respiratory and exercise function. J. Med. Invest. 63: 182-186, August, 2016.

PMID: 27644555 [PubMed - indexed for MEDLINE]

The E3 ubiquitin ligase CHIP selectively regulates mutant epidermal growth factor receptor by ubiquitination and degradation.

Wed, 06/14/2017 - 12:45
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The E3 ubiquitin ligase CHIP selectively regulates mutant epidermal growth factor receptor by ubiquitination and degradation.

Biochem Biophys Res Commun. 2016 Oct 14;479(2):152-158

Authors: Chung C, Yoo G, Kim T, Lee D, Lee CS, Cha HR, Park YH, Moon JY, Jung SS, Kim JO, Lee JC, Kim SY, Park HS, Park M, Park DI, Lim DS, Jang KW, Lee JE

Abstract
Somatic mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is a decisive factor for the therapeutic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma. The stability of mutant EGFR is maintained by various regulators, including heat shock protein 90 (Hsp90). The C terminus of Hsc70-interacting protein (CHIP) is a Hsp70/Hsp90 co-chaperone and exhibits E3 ubiquitin ligase activity. The high-affinity Hsp90-CHIP complex recognizes and selectively regulates their client proteins. CHIP also works with its own E3 ligase activity independently of Hsp70/Hsp90. Here, we investigated the role of CHIP in regulating EGFR in lung adenocarcinoma and also evaluated the specificity of CHIP's effects on mutant EGFR. In HEK 293T cells transfected with either WT EGFR or EGFR mutants, the overexpression of CHIP selectively decreased the expression of certain EGFR mutants (G719S, L747_E749del A750P and L858R) but not WT EGFR. In a pull-down assay, CHIP selectively interacted with EGFR mutants and simultaneously induced their ubiquitination and proteasomal degradation. The expressions of mutant EGFR in PC9 and H1975 were diminished by CHIP, while the expression of WT EGFR in A549 was nearly not affected. In addition, CHIP overexpression inhibited cell proliferation and xenograft's tumor growth of EGFR mutant cell lines, but not WT EGFR cell lines. EGFR mutant specific ubiquitination by CHIP may provide a crucial regulating mechanism for EGFR in lung adenocarcinoma. Our results suggest that CHIP can be novel therapeutic target for overcoming the EGFR TKI resistance.

PMID: 27475501 [PubMed - indexed for MEDLINE]

Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop.

Tue, 06/13/2017 - 12:45

Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop.

Radiat Res. 2017 Jun 12;:

Authors: DiCarlo AL, Tamarat R, Rios CI, Benderitter M, Czarniecki CW, Allio TC, Macchiarini F, Maidment BW, Jourdain JR

Abstract
In recent years, there has been increasing concern over the possibility of a radiological or nuclear incident occurring somewhere in the world. Intelligence agencies frequently report that terrorist groups and rogue nations are seeking to obtain radiological or nuclear weapons of mass destruction. In addition, there exists the real possibility that safety of nuclear power reactors could be compromised by natural (such as the tsunami and subsequent Fukushima accident in Japan in March, 2011) or accidental (Three Mile Island, 1979 and Chernobyl, 1986) events. Although progress has been made by governments around the world to prepare for these events, including the stockpiling of radiation countermeasures, there are still challenges concerning care of patients injured during a radiation incident. Because the deleterious and pathological effects of radiation are so broad, it is desirable to identify medical countermeasures that can have a beneficial impact on several tissues and organ systems. Cellular therapies have the potential to impact recovery and tissue/organ regeneration for both early and late complications of radiation exposure. These therapies, which could include stem or blood progenitor cells, mesenchymal stromal cells (MSCs) or cells derived from other tissues (e.g., endothelium or placenta), have shown great promise in treating other nonradiation injuries to and diseases of the bone marrow, skin, gastrointestinal tract, brain, lung and heart. To explore the potential use of these therapies in the treatment of victims after acute radiation exposure, the National Institute of Allergy and Infectious Diseases co-sponsored an international workshop in July, 2015 in Paris, France with the Institut de Radioprotection et de Sûreté Nucléaire. The workshop included discussions of data available from testing in preclinical models of radiation injury to different organs, logistics associated with the practical use of cellular therapies for a mass casualty incident, as well as international regulatory requirements for authorizing such drug products to be legally and readily used in such incidents. This report reviews the data presented, as well as key discussion points from the meeting.

PMID: 28605260 [PubMed - as supplied by publisher]

Reduction of lung congestion following arteriovenous fistula flow reduction in renal graft recipient.

Tue, 06/13/2017 - 12:45

Reduction of lung congestion following arteriovenous fistula flow reduction in renal graft recipient.

J Vasc Access. 2017 Jun 06;:0

Authors: Letachowicz K, Mazanowska O, Boratyńska M, Obremska M, Goździk A, Kusztal M, Krajewska M, Gołębiowski T, Klinger M

PMID: 28604986 [PubMed - as supplied by publisher]

Evaluation of potential changes in liver and lung tissue of rats in an ischemia-reperfusion injury model (modified pringle maneuver).

Tue, 06/13/2017 - 12:45

Evaluation of potential changes in liver and lung tissue of rats in an ischemia-reperfusion injury model (modified pringle maneuver).

PLoS One. 2017;12(6):e0178665

Authors: Freitas SH, Dória RGS, Bueno RS, Rocha WB, Filho JRE, Moraes JRE, Vidane AS, Ambrósio CE

Abstract
In surgical procedures involving the liver, such as transplantation, resection, and trauma, a temporary occlusion of hepatic vessels may be required. This study was designed to analyze the lesions promoted by ischemia and reperfusion injury of the hepatic pedicle, in the liver and lung, using histopathological and immunohistochemical techniques. In total, 39 Wistar rats were divided into four groups: control group (C n = 3) and ischemia groups subjected to 10, 20, and 30 minutes of hepatic pedicle clamping (I10, n = 12; I20, n = 12; I30, n = 12). Each ischemia group was subdivided into four subgroups of reperfusion (R15, n = 3; R30, n = 3; R60, n = 3; R120, n = 3), after 15, 30, 60, and 120 minutes of reperfusion, respectively. Significant differences were observed in the liver parenchyma (P < 0.05) between the values of microvesicles and hydropic degeneration at different times of ischemia and reperfusion. However, the values of vascular congestion, necrosis, and pyknotic nuclei showed no significant differences (P > 0.05). In the lung parenchyma, a significant difference was observed (P < 0.05) between the values of alveolar septal wall thickening and inflammatory infiltration at different times of ischemia and reperfusion. However, there was no significant difference (P < 0.05) between the values of vascular congestion, bronchial epithelial degeneration, interstitial edema, and hemorrhage. The positive immunoreactivity of caspase-3 protein in the liver parenchyma (indication of ongoing apoptosis), showed no significant differences (P > 0.05) at different times of ischemia and reperfusion. In the pulmonary parenchyma, the immunoreactivity was not specific, and was not quantified. This study demonstrated that the longer the duration of ischemia and reperfusion, the greater are the morphological lesions found in the hepatic and pulmonary parenchyma.

PMID: 28604841 [PubMed - in process]

Multicentric study of endobronchial ultrasound-transbronchial needle aspiration for lung cancer staging in Italy.

Tue, 06/13/2017 - 12:45
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Multicentric study of endobronchial ultrasound-transbronchial needle aspiration for lung cancer staging in Italy.

J Thorac Dis. 2017 May;9(Suppl 5):S370-S375

Authors: Rotolo N, Imperatori A, Nosotti M, Santambrogio L, Palleschi A, Dominioni L, Crosta G, Foccoli P, Pariscenti G, Passera E, Bortolotti L, Falezza G, Infante M, Daffrè E, Cattoni M, Rosso L

Abstract
BACKGROUND: Multi-institutional studies of endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) for mediastinal staging in lung cancer are scarce. It is unclear if the high diagnostic performance of EBUS-TBNA reported by experts' guidelines can be generally achieved.
METHODS: This is a retrospective study performed in five tertiary referral centers of thoracic surgery in Italy, to assess the EBUS-TBNA diagnostic performance in patients with non-small cell lung cancer (NSCLC). Patient inclusion criteria were: both genders; >18 years old; with suspect/confirmed NSCLC; undergoing EBUS-TBNA for mediastinal node enlargement at computed tomography (size >1 cm, ≤3 cm) and/or pathological uptake at positron emission tomography. Altogether we included 485 patients [male, 366; female, 119; median age, 68 years (IQR, 61-74 years)] undergoing mediastinal staging between January 2011 and July 2016. All EBUS-TBNAs were performed by experienced bronchoscopists, without pre-defined quality standards. Depending on usual practice in each center, EBUS-TBNA was done under conscious sedation, with 21- or 22-Gauge (G) needle, and specimen preparation was cell-block, or cytology slides, or core-tissue. Sampling was classified inadequate in absence of lymphocytes, or when sample was insufficient. We analyzed the EBUS-TBNA procedural steps likely to influence the rate of adequate samplings (diagnostic yield).
RESULTS: EBUS-TBNA sensitivity, negative predictive value (NPV) and accuracy respectively were 90%, 78% and 93% in the whole cohort. At multivariate analysis, use of 21-G needle was associated with better diagnostic yield (P<0.001). Center and specimen processing technique were not independent factors affecting EBUS-TBNA diagnostic yield.
CONCLUSIONS: In this multicentric study, EBUS-TBNA was a highly sensitive and accurate method for NSCLC mediastinal node staging. Results indicate better performance of EBUS-TBNA with 21-G needle, and suggest that specimen processing technique could be chosen according to the local practice preference.

PMID: 28603647 [PubMed - in process]

Ten-year experience with endobronchial ultrasound-guided transbronchial needle aspiration: single center results in mediastinal diagnostic and staging.

Tue, 06/13/2017 - 12:45
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Ten-year experience with endobronchial ultrasound-guided transbronchial needle aspiration: single center results in mediastinal diagnostic and staging.

J Thorac Dis. 2017 May;9(Suppl 5):S363-S369

Authors: Rosso L, Ferrero S, Mendogni P, Bonaparte E, Carrinola R, Palleschi A, Righi I, Montoli M, Damarco F, Tosi D

Abstract
BACKGROUND: Endobronchial ultrasonography with transbronchial needle aspiration (EBUS-TBNA) is recognized as an accurate and minimal invasive procedure for diagnosis and staging of lung cancer and lymph nodal malignancies. EBUS is recommended as the first choice procedure for mediastinal staging in lung cancer in international guidelines.
METHODS: A retrospective evaluation was performed on single center experience with EBUS-TBNA in our thoracic surgery department in a 10-year time frame. Main indication for the procedure was suspected non-lymphomatous malignancy in intrathoracic lymph-nodes on computed tomography (CT) or positron emission tomography (PET) scan. All procedures were performed under conscious sedation in a day-hospital setting. All the aspirated specimens were obtained with a 22-gauge needle and were fixed in 10% formalin and paraffin embedded. Sections of 3 micron in thickness were cut and hematoxylin-eosin stained.
RESULTS: From October 2005 to August 2016, 496 patients were submitted to EBUS-TBNA. Number of nodal stations punctured was 592 with a mean of 2.25 punctures per patient. Diagnosis of malignancy was obtained in 291 patients (58.6%). In 25 cases a nodal metastasis from an extrathoracic primary tumor was diagnosed. Sensitivity, specificity and diagnostic accuracy were 95%, 100% and 96% respectively. Negative predictive value was 90% and positive predictive value (PPV) was 100%. When molecular tests were requested, mutational analysis was successfully performed on cell block derived material in 55 out of 56 cases (98.2%), and fluorescence in situ hybridization (FISH) analysis in 26 out of 27 cases (96.2%).
CONCLUSIONS: EBUS-TBNA in our setting was an accurate and safe tool to diagnose non-lymphomatous nodal malignancies. Interestingly, in our series EBUS-TBNA has demonstrated to yield sufficient tissue for molecular analysis.

PMID: 28603646 [PubMed - in process]

Increased Proangiogenic Activity of Mobilized CD34+ Progenitor Cells of Patients With Acute ST-Segment-Elevation Myocardial Infarction: Role of Differential MicroRNA-378 Expression.

Tue, 06/13/2017 - 12:45
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Increased Proangiogenic Activity of Mobilized CD34+ Progenitor Cells of Patients With Acute ST-Segment-Elevation Myocardial Infarction: Role of Differential MicroRNA-378 Expression.

Arterioscler Thromb Vasc Biol. 2017 Feb;37(2):341-349

Authors: Templin C, Volkmann J, Emmert MY, Mocharla P, Müller M, Kraenkel N, Ghadri JR, Meyer M, Styp-Rekowska B, Briand S, Klingenberg R, Jaguszewski M, Matter CM, Djonov V, Mach F, Windecker S, Hoerstrup SP, Thum T, Lüscher TF, Landmesser U

Abstract
OBJECTIVE: Proangiogenic effects of mobilized bone marrow-derived stem/progenitor cells are essential for cardiac repair after myocardial infarction. MicroRNAs (miRNA/miR) are key regulators of angiogenesis. We investigated the differential regulation of angio-miRs, that is, miRNAs regulating neovascularization, in mobilized CD34(+) progenitor cells obtained from patients with an acute ST-segment-elevation myocardial infarction (STEMI) as compared with those with stable coronary artery disease or healthy subjects.
APPROACH AND RESULTS: CD34(+) progenitor cells were isolated from patients with STEMI (on day 0 and day 5), stable coronary artery disease, and healthy subjects (n=27). CD34(+) progenitor cells of patients with STEMI exhibited increased proangiogenic activity as compared with CD34(+) cells from the other groups. Using a polymerase chain reaction-based miRNA-array and real-time polymerase chain reaction validation, we identified a profound upregulation of 2 known angio-miRs, that are, miR-378 and let-7b, in CD34(+) cells of patients with STEMI. Especially, we demonstrate that miR-378 is a critical regulator of the proangiogenic capacity of CD34(+) progenitor cells and its stimulatory effects on endothelial cells in vitro and in vivo, whereas let-7b upregulation in CD34(+) cells failed to proof its effect on endothelial cells in vivo.
CONCLUSIONS: The present study demonstrates a significant upregulation of the angio-miRs miR-378 and let-7b in mobilized CD34(+) progenitor cells of patients with STEMI. The increased proangiogenic activity of these cells in patients with STEMI and the observation that in particular miR-378 regulates the angiogenic capacity of CD34(+) progenitor cells in vivo suggest that this unique miRNA expression pattern represents a novel endogenous repair mechanism activated in acute myocardial infarction.

PMID: 28062497 [PubMed - indexed for MEDLINE]

Pulmonary Rehabilitation Outcomes after Single or Double Lung Transplantation in Patients with Chronic Obstructive Pulmonary Disease or Interstitial Lung Disease.

Mon, 06/12/2017 - 12:45
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Pulmonary Rehabilitation Outcomes after Single or Double Lung Transplantation in Patients with Chronic Obstructive Pulmonary Disease or Interstitial Lung Disease.

Respiration. 2017 Jun 10;:

Authors: Schneeberger T, Gloeckl R, Welte T, Kenn K

Abstract
BACKGROUND: Pulmonary rehabilitation (PR) following lung transplantation (LTx) has been shown to be effective with regard to exercise capacity and health-related quality of life (HRQL). However, outcome data is limited with respect to LTx as a population. Differences concerning the effects of PR in patients with single LTx (SLTx) or double LTx (DLTx) have not been studied yet.
OBJECTIVES: The aim was to compare possible differences concerning PR outcomes between SLTx and DLTx.
METHODS: In a retrospective analysis (period: 1997-2016), data from 722 patients with either chronic obstructive pulmonary disease (COPD; SLTx: n = 129, FEV1 51 ± 17% pred.; DLTx: n = 204, FEV1 74 ± 20% pred.) or interstitial lung disease (ILD; SLTx: n = 135, FVC 58 ± 18% pred.; DLTx: n = 254, FVC 63 ± 18% pred.) after LTx were included. All patients underwent a specialized inpatient PR program. The data of the 6-minute walk distance (6MWD) and HRQL (physical [PCS] and mental [MCS] component summary of the SF- 36 questionnaire) were analyzed.
RESULTS: Independently from the procedure and pretransplant diagnosis, patients significantly (p < 0.05) improved the 6MWD without any differences between SLTx and DLTx (COPD: SLTx: +109 ± 68 m, DLTx: +117 ± 82 m; ILD: SLTx: +115 ± 80 m, DLTx: +132 ± 77 m). The PCS (COPD: SLTx: +9 ± 9 points, DLTx: +7 ± 9 points; ILD: SLTx: +6 ± 9 points, DLTx: +9 ± 9 points) and MCS (COPD: SLTx: +8 ± 15 points, DLTx: +7 ± 15 points; ILD: SLTx: +10 ± 13 points, DLTx: +8 ± 12 points) also improved significantly without any group differences.
CONCLUSIONS: LTx patients with a pretransplant diagnosis of COPD or ILD all benefitted significantly and with clinical relevance with regard to exercise capacity and HRQL from an inpatient PR performed within 1 year postoperatively. PR outcomes were similar regardless of SLTx or DLTx.

PMID: 28601868 [PubMed - as supplied by publisher]

Empagliflozin in the management of diabetes mellitus after cardiac transplantationResearch Correspondenceretain-->.

Mon, 06/12/2017 - 12:45
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Empagliflozin in the management of diabetes mellitus after cardiac transplantationResearch Correspondenceretain-->.

J Heart Lung Transplant. 2017 May 04;:

Authors: Muir CA, Greenfield JR, MacDonald PS

PMID: 28601371 [PubMed - as supplied by publisher]

Intracellular complement - the complosome - in immune cell regulation.

Mon, 06/12/2017 - 12:45
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Intracellular complement - the complosome - in immune cell regulation.

Mol Immunol. 2017 Jun 07;:

Authors: Arbore G, Kemper C, Kolev M

Abstract
The complement system was defined over a century ago based on its ability to "complement" the antibody-mediated and cell-mediated immune responses against pathogens. Today our understanding of this ancient part of innate immunity has changed substantially and we know now that complement plays an undisputed pivotal role in the regulation of both innate and adaptive immunity. The complement system consists of over 50 blood-circulating, cell-surface expressed and intracellular proteins. It is key in the recognition and elimination of invading pathogens, also in the removal of self-derived danger such as apoptotic cells, and it supports innate immune responses and the initiation of the general inflammatory reactions. The long prevailing classic view of complement was that of a serum-operative danger sensor and first line of defence system, however, recent experimental and clinical evidences have demonstrated that "local" tissue and surprisingly intracellular complement (the complosome) activation impacts on normal cell physiology. This review will focus on novel aspects of intracellular complement activation and its unexpected roles in basic cell processes such as metabolism. We also discuss what the existence of the complosome potentially means for how the host handles intracellular pathogens such as viruses.

PMID: 28601357 [PubMed - as supplied by publisher]

Setting out into practice: Preparing for the future, today.

Sun, 06/11/2017 - 10:03
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Setting out into practice: Preparing for the future, today.

J Thorac Cardiovasc Surg. 2017 May 17;:

Authors: Hayanga JWA, Amin P

PMID: 28599975 [PubMed - as supplied by publisher]

Minimally invasive posterior basilar segmentectomy by a posterior approach: Should we start flipping?

Sun, 06/11/2017 - 10:03
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Minimally invasive posterior basilar segmentectomy by a posterior approach: Should we start flipping?

J Thorac Cardiovasc Surg. 2017 May 17;:

Authors: Podgaetz E, Schwartz GS, Mason DP

PMID: 28599974 [PubMed - as supplied by publisher]

Statins in lung transplantation: A treatment option for every patient?

Sun, 06/11/2017 - 10:03
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Statins in lung transplantation: A treatment option for every patient?

J Heart Lung Transplant. 2017 May 25;:

Authors: Verleden GM, Vos R

PMID: 28599875 [PubMed - as supplied by publisher]

Pulmonary Function Tests for the Radiologist.

Sat, 06/10/2017 - 12:45
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Pulmonary Function Tests for the Radiologist.

Radiographics. 2017 Jun 09;:160174

Authors: Tseng HJ, Henry TS, Veeraraghavan S, Mittal PK, Little BP

Abstract
Pulmonary function tests (PFTs) provide important quantitative information about lung function and can be used to elucidate pathologic conditions responsible for respiratory symptoms, assess the severity and course of disease, and evaluate the patient for suitability and timing for lung transplantation. They are typically used in tandem with chest imaging, along with other ancillary data, to arrive at a specific diagnosis. PFTs may provide the radiologist with clues to the diagnosis and grading of a wide variety of pulmonary diseases. In this review, the authors discuss the clinical use of PFTs, their major components, and important measurements and graphical representations that are essential for understanding and interpreting the results. The key components of PFT panels-static lung volumes, dynamic lung function (spirometry), and diffusion capacity-are explained. The authors present a general algorithmic approach for problem solving, with recognition of common patterns of results (obstructive, restrictive, mixed, nonspecific, and normal). Pulmonary diseases from each of the major patterns and chest imaging are illustrated, and correlations between particular PFT results and disease severity and morphology at imaging are examined. Common pitfalls encountered during interpretation are also highlighted. A basic understanding of the mechanics of PFTs, characteristic patterns in important diseases, and correlation between lung function and imaging findings may assist the radiologist in diagnosis and follow-up of key pulmonary diseases and strengthen the radiologist's role as part of a multidisciplinary diagnostic team. Online supplemental material is available for this article. (©)RSNA, 2017.

PMID: 28598732 [PubMed - as supplied by publisher]

Epithelioid hemangioendotheliomas of the liver and lung in children and adolescents.

Sat, 06/10/2017 - 12:45
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Epithelioid hemangioendotheliomas of the liver and lung in children and adolescents.

Pediatr Blood Cancer. 2017 Jun 09;:

Authors: Hettmer S, Andrieux G, Hochrein J, Kurz P, Rössler J, Lassmann S, Werner M, von Bubnoff N, Peters C, Koscielniak E, Sparber-Sauer M, Niemeyer C, Mentzel T, Busch H, Boerries M

Abstract
Epithelioid hemangioendothelioma (EHE) is a rare, vascular sarcoma. Visceral forms arise in the liver/ lungs. We review the clinical and molecular phenotype of pediatric visceral EHE based on the case of a 9-year-old male child with EHE of the liver/lungs. His tumor expressed the EHE-specific fusion oncogene WWTR1-CAMTA1. Molecular characterization revealed a low somatic mutation rate and activated interferon signaling, angiogenesis regulation, and blood vessel remodeling. After polychemotherapy and resection of lung tumors, residual disease remained stable on oral lenalidomide. Literature review identified another 24 children with EHE of the liver/lungs. Most presented with multifocal, systemic disease. Only those who underwent complete resection achieved complete remission. Four children experienced rapid progression and died. In six children, disease remained stable for years without therapy. Two patients died from progressive EHE 21 and 24 years after first diagnosis. Natural evolution of pediatric visceral EHE is variable, and long-term prognosis remains unclear.

PMID: 28598585 [PubMed - as supplied by publisher]

Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis.

Sat, 06/10/2017 - 12:45
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Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis.

Mol Med. 2017 Jun 07;23:

Authors: Lorentz CA, Liang Z, Meng M, Chen CW, Yoseph BP, Breed ER, Mittal R, Klingensmith NJ, Farris AB, Burd EM, Koval M, Ford ML, Coopersmith CM

Abstract
Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the peri-junctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK(-/-) and wild type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK(-/-) mice (95% vs. 24%, p<0.0001). Intestinal permeability increased in septic WT mice compared to unmanipulated mice. In contrast, permeability in septic MLCK(-/-) mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK(-/-) mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8, 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK(-/-) mice; however, survival was similar between septic MLCK(-/-) mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

PMID: 28598488 [PubMed - as supplied by publisher]

A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action.

Sat, 06/10/2017 - 12:45
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A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action.

Nat Commun. 2017 Jun 09;8:15772

Authors: Campaner E, Rustighi A, Zannini A, Cristiani A, Piazza S, Ciani Y, Kalid O, Golan G, Baloglu E, Shacham S, Valsasina B, Cucchi U, Pippione AC, Lolli ML, Giabbai B, Storici P, Carloni P, Rossetti G, Benvenuti F, Bello E, D'Incalci M, Cappuzzello E, Rosato A, Del Sal G

Abstract
The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

PMID: 28598431 [PubMed - in process]

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