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Human HER2 overexpressing mouse breast cancer cell lines derived from MMTV.f.HuHER2 mice: characterization and use in a model of metastatic breast cancer.

Fri, 10/06/2017 - 12:45
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Human HER2 overexpressing mouse breast cancer cell lines derived from MMTV.f.HuHER2 mice: characterization and use in a model of metastatic breast cancer.

Oncotarget. 2017 Sep 15;8(40):68071-68082

Authors: Park S, Nedrow JR, Josefsson A, Sgouros G

Abstract
Preclinical evaluation of therapeutic agents against metastatic breast cancer require cell lines and animal models that recapitulate clinical metastatic breast cancer as much as possible. We have previously used cell lines derived from the neu-N transgenic model to investigate anti-neu targeting of metastatic breast cancer using an alpha-emitter labeled antibody reactive with the rat variant of HER2/neu expressed by the neu-N model. To investigate alpha-particle emitter targeting of metastatic breast cancer using clinically relevant, commercially available anti-HER2/neu antibodies, we have developed cell lines derived from primary tumors and lung metastases from HuHER2 transgenic mice. We extracted primary mammary gland tumors, isolated the epithelial breast cancer cells, and established seven different cell lines. We also established 2 different cell lines from spontaneous lung metastases and cell lines from a serial transplantation of tumor tissues in HuHER2 transgenic mice. HuHER2 protein was overexpressed in all of the established cell lines. The mRNA level of ER (estrogen receptor) and PR (progesterone receptor) was relatively low in the cell lines compared to normal mammary gland (MG). As EMT markers, the expression of E-Cadherin in the cell lines was downregulated while the expression of TWIST1 and Vimentin were upregulated, relative to MG. Furthermore, trastuzumab directly inhibited cellular viability. Biodistribution studies with (111)In-DTPA-trastuzumab in HuHER2 cell tumor xenografts demonstrated specific targeting with a clinically relevant antibody. Collectively, these cell lines show all the hallmarks of highly aggressive, metastatic breast cancer and are being used to evaluate combination therapy with alpha-particle emitter labeled HER2/neu reactive antibodies.

PMID: 28978097 [PubMed]

Addition of bevacizumab for malignant pleural effusion as the manifestation of acquired EGFR-TKI resistance in NSCLC patients.

Fri, 10/06/2017 - 12:45
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Addition of bevacizumab for malignant pleural effusion as the manifestation of acquired EGFR-TKI resistance in NSCLC patients.

Oncotarget. 2017 Sep 22;8(37):62648-62657

Authors: Jiang T, Li A, Su C, Li X, Zhao C, Ren S, Zhou C, Zhang J

Abstract
This study aimed to investigate the role of bevacizumab in patients with advanced non-small cell lung cancer (NSCLC) who had developed acquired resistance to EGFR-TKIs therapy that manifested as malignant pleural effusion (MPE). In total, 86 patients were included. 47 patients received bevacizumab plus continued EGFR-TKIs and 39 patients received bevacizumab plus chemotherapy. The curative efficacy rate for MPE in bevacizumab plus EGFR-TKIs group was significantly higher than that in bevacizumab plus chemotherapy group (89.4% vs. 64.1%, respectively; P = 0.005). Patients in bevacizumab plus EGFR-TKIs group had longer progression-free survival (PFS) than those in bevacizumab plus chemotherapy group (median PFS 6.3 vs. 4.8 months, P = 0.042). While patients with acquired T790M mutation in bevacizumab plus EGFR-TKIs group had a significantly longer PFS than those in bevacizumab plus chemotherapy group (median PFS 6.9 vs. 4.6 months, P = 0.022), patients with negative T790M had similar PFS (median PFS 6.1 vs. 5.5 months, P = 0.588). Overall survival (OS) was similar between two groups (P = 0.480). In multivariate analysis, curative efficacy was an independent prognostic factor (HR 0.275, P = 0.047). In conclusion bevacizumab plus EGFR-TKIs could be a valuable treatment for NSCLC patients presenting with MPE upon resistant to EGFR-TKIs therapy, especially for those with acquired T790M mutation.

PMID: 28977977 [PubMed]

microRNA-219-5p inhibits epithelial-mesenchymal transition and metastasis of colorectal cancer by targeting lymphoid enhancer-binding factor 1.

Fri, 10/06/2017 - 12:45
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microRNA-219-5p inhibits epithelial-mesenchymal transition and metastasis of colorectal cancer by targeting lymphoid enhancer-binding factor 1.

Cancer Sci. 2017 Oct;108(10):1985-1995

Authors: Huang LX, Hu CY, Jing L, Wang MC, Xu M, Wang J, Wang Y, Nan KJ, Wang SH

Abstract
Aberrant expression of microRNAs (miRs) has been shown to play a critical role in the pathogenesis and progression of tumors. microRNA-219-5p (miR-219-5p) has been reported to be abnormally expressed in some types of human tumors. However, the mechanism between miR-219-5p and colorectal cancer (CRC) metastasis remains unclear. In the present study, miR-219-5p was found to be downregulated in CRC tissue compared with matched normal tissue. Through luciferase reporter assay, we demonstrated lymphoid enhancer-binding factor 1 (LEF1) as a direct target of miR-219-5p. Overexpression of miR-219-5p could inhibit motility, migration and invasion of CRC cells, and inhibit epithelial-mesenchymal transition (EMT). Furthermore, silencing LEF1 phenocopied this metastasis-suppressive function. The recovery experiment showed that re-expression of LEF1 rescued this suppressive effect on tumor metastasis and reversed the expression of EMT markers caused by miR-219-5p. Additionally, we demonstrated that miR-219-5p exerted this tumor-suppressive function by blocking activation of the AKT and ERK pathways. Finally, a nude mice experiment showed that miR-219-5p reduced the lung metastasis ability of CRC cells. Taken together, our findings indicate that miR-219-5p inhibits metastasis and EMT of CRC by targeting LEF1 and suppressing the AKT and ERK pathways, which may provide a new antitumor strategy to delay CRC metastasis.

PMID: 28771881 [PubMed - indexed for MEDLINE]

Cinnamomum cassia extracts reverses TGF-β1-induced epithelial-mesenchymal transition in human lung adenocarcinoma cells and suppresses tumor growth in vivo.

Fri, 10/06/2017 - 12:45
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Cinnamomum cassia extracts reverses TGF-β1-induced epithelial-mesenchymal transition in human lung adenocarcinoma cells and suppresses tumor growth in vivo.

Environ Toxicol. 2017 Jul;32(7):1878-1887

Authors: Lin CY, Hsieh YH, Yang SF, Chu SC, Chen PN, Hsieh YS

Abstract
Metastasis is the most common cause of cancer-related mortality in patients, and epithelial-mesenchymal transition (EMT) is essential for cancer metastasis and antidrug resistance. Cinnamomum cassia has several antioxidative, anti-inflammatory, and anticancer biological effects. However, the anti-EMT effect of C. cassia in human lung carcinoma is rarely reported. In this study, we determined whether C. cassia extracts (CCE) reduces the EMT and tumor growth of human lung adenocarcinoma cells. CCE inhibited the transforming growth factor (TGF)-β1-induced cell motility and invasiveness of A549 and H1299 cells by repressing matrix metalloproteinase-2 and urokinase-type plasminogen activator as well as impaired cell adhesion to collagen. CCE also affected the TGF-β1-induced EMT by downregulating the expression of vimentin and fibronectin and upregulating E-cadherin. The nude mice xenograft model showed that CCE reduced A549 tumor growth. Thus, CCE possesses antimetastatic activity of A549 and H1299 cells by affecting EMT and suppressing A549 tumor growth in vivo. This result suggested that CCE could be used as an antimetastatic agent or as an adjuvant for anticancer therapy.

PMID: 28258635 [PubMed - indexed for MEDLINE]

Ribcage kinematics during exercise justifies thoracoscopic versus postero-lateral thoracotomy lobectomy prompt recovery.

Thu, 10/05/2017 - 12:45

Ribcage kinematics during exercise justifies thoracoscopic versus postero-lateral thoracotomy lobectomy prompt recovery.

Eur J Cardiothorac Surg. 2017 Jun 19;:

Authors: LoMauro A, Aliverti A, Chiesa M, Cattaneo M, Privitera E, Tosi D, Nosotti M, Santambrogio L, Palleschi A

Abstract
OBJECTIVES: The video-assisted thoracic surgery (VATS) approach is encouraged over postero-lateral thoracotomy (PLT) for lobectomy in lung cancer. We compare the ribcage kinematics during exercise before and after both procedures, assuming that VATS, being minimally invasive, could better preserve ribcage expansion.
METHODS: Thirty-one patients undergoing lobectomy by means of VATS ( n  = 20) or PLT ( n  = 11) were compared presurgery, after chest drainage removal ( T 1 ) and 2 months post-surgery ( T 2 ) during quiet breathing and incremental exercise. Spirometry, chest pain, ventilatory pattern and expansions of the ribcage (Δ V RC ) and abdomen were measured. Furthermore, the expansion of the ribcage and abdomen in the operated (Δ V RC-OP and Δ V AB-OP , respectively) and non-operated (Δ V RC-NO and Δ V AB-NO , respectively) sides was also considered.
RESULTS: At T 1 , in both groups, spirometry worsened and chest pain increased, being higher after PLT. Tidal volume ( V T ) decreased after PLT because the ribcage expanded less due to reduced Δ V RC-OP . Contrary to this, in VATS, there were no changes in V T and Δ V RC , although Δ V RC-OP was lower, because Δ V RC-NO increased at high level of exercise. At T 2 , Δ V RC-OP was completely restored after VATS. At high levels of exercise following PLT, although patients still showed reduced Δ V RC and Δ V RC-OP , V T was restored owing to increased Δ V AB-NO .
CONCLUSIONS: We demonstrate VATS to have a reduced impact on ribcage kinematics while PLT induced restriction more markedly during exercise and still present 2 months after surgery. Patients adopt 2 different compensatory mechanisms, by shifting the expansion toward the contralateral ribcage after VATS and toward the abdomen after PLT. Our study justifies thoracoscopic lobectomy prompt recovery.
Clinical trial registration: clinicaltrials.gov (NCT02910453).

PMID: 28977548 [PubMed - as supplied by publisher]

Transabdominal robot-assisted diaphragmatic plication: a 3.5-year experience.

Thu, 10/05/2017 - 12:45

Transabdominal robot-assisted diaphragmatic plication: a 3.5-year experience.

Eur J Cardiothorac Surg. 2017 Jul 25;:

Authors: Biswas Roy S, Haworth C, Ipsen T, Kang P, Hill D, Do A, Kuo E

Abstract
OBJECTIVES: Diaphragmatic paralysis, a known cause of dyspnoea, can drastically reduce breathing efficiency, diminishing quality of life. We report our 3.5-year experience with 22 consecutive patients who underwent transabdominal, robot-assisted diaphragmatic plication for diaphragmatic paralysis.
METHODS: We retrospectively reviewed 22 consecutive patients who underwent this procedure by a single surgeon from 5 September 2012 to 12 May 2016. The primary outcome measure was change in dyspnoea severity, which was measured with the 5-point Medical Research Council dyspnoea scale (a score of 5 indicates breathlessness so severe, the individual is homebound).
RESULTS: Of the 22 patients who underwent robotic diaphragmatic plication, 17 (77.3%) patients were male. Median body mass index was 30 kg/m 2 (range 24.2-42.17 kg/m 2 ). Most plications (13 of 22, 59.1%) were left sided; one (4.6%) was bilateral. Median operating time was 161 min (range 107-293 min), but this time was higher for the first 3 procedures (255 min, range 239-293 min). Median length of stay was 2 days, and median time to chest tube removal was 1 day. At follow-up, 20 of the 22 (91%) patients reported improved breathing and 2 reported no change. No patient reported worsened dyspnoea. The median Medical Research Council score changed from 4.0 preoperatively to 2.0 postoperatively ( P  = 0.001).
CONCLUSIONS: Transabdominal robotic diaphragmatic plication involves small incisions but improves surgical dexterity. Surgical times are reasonable, and this surgical technique can be adopted with a quick but steep learning curve. Early results show good functional outcomes.

PMID: 28977536 [PubMed - as supplied by publisher]

Even mild reversible myocardial perfusion defects predict mortality in patients evaluated for kidney transplantation.

Thu, 10/05/2017 - 12:45

Even mild reversible myocardial perfusion defects predict mortality in patients evaluated for kidney transplantation.

Eur Heart J Cardiovasc Imaging. 2017 Aug 04;:

Authors: Helve S, Laine M, Sinisalo J, Helanterä I, Hänninen H, Lammintausta O, Lehtonen J, Finne P, Nieminen T

Abstract
Aims: The value of single-photon emission tomography (SPECT) in patients with severe chronic kidney disease is controversial, and the implications of SPECT finding with lower level of ischaemia are unknown. We assessed the prognostic value of SPECT in patients evaluated for kidney transplantation.
Methods and results: Five hundred and forty-eight patients underwent SPECT as a part of routine evaluation for kidney transplantation. During the median follow-up of 43.7 months (IQR 22.4-68.4 months), 112 patients (20.4%) died, 49 of cardiovascular (CV) causes (8.9%). In comparison to those with no perfusion defects, mild perfusion abnormalities (1%-9.9%) had an adjusted Cox hazard ratio (HR) of 1.80 [95% confidence interval (95% CI) 1.02-3.17, P = 0.041] for all-cause mortality, while large perfusion defects (≥10%) demonstrated an HR of 2.20 (95% CI 1.38-3.50, P = 0.001). A competing risk analysis produced a similar prognostic capacity for CV mortality. SPECT also offered incremental prognostic impact with two reclassification methods. Revascularization was performed clearly more often on patients with severely than mildly abnormal or normal SPECT (28.0%, 4.3%, and 1.3%, respectively, P < 0.001). However, revascularization was not linked with better survival. Patients with a normal SPECT received a kidney transplant more often than patients with a mildly or severely abnormal SPECT (50.5%, 36.2%, and 36.6%, respectively, P = 0.010).
Conclusion: Myocardial ischaemia in SPECT is clearly linked with mortality in patients screened for kidney transplantation. Contrary to populations with coronary artery disease, even a mild perfusion defect in SPECT predicts poor prognosis in this patient population. The finding deserves further attention in forthcoming trials.

PMID: 28977433 [PubMed - as supplied by publisher]

Use of very old donors for lung transplantation: a dual-centre retrospective analysis.

Thu, 10/05/2017 - 12:45

Use of very old donors for lung transplantation: a dual-centre retrospective analysis.

Eur J Cardiothorac Surg. 2017 Jul 17;:

Authors: Hecker M, Hecker A, Kramm T, Askevold I, Kuhnert S, Reichert M, Mayer E, Seeger W, Padberg W, Mayer K

Abstract
OBJECTIVES: To reduce the shortage of organs for transplantation by expanding organ selection criteria as a means to increase the pool of potential lung donors. In this study, we sought to investigate the impact of using lungs from very old donors aged >70 years on outcomes after lung transplantation.
METHODS: Between January 2010 and November 2016, 96 patients with end-stage lung disease underwent lung transplantation in our centres. Lung donors were divided into 3 groups according to age (donor aged <60 years, 60-69 years and ≥70 years). We examined the effect of donor age on various short- and long-term outcome parameters.
RESULTS: Lungs harvested from very old donors had a lower percentage of smoking history and shorter ventilation time. Survival rates of recipients did not show significant differences between older and younger donor groups. Most of the short- and long-term outcome parameters in recipients of lungs from very old donors did not differ significantly among the 3 age groups, except for post-transplant best forced expiratory volume in 1 s and treated acute rejections, which were lower and higher, respectively, in donors aged ≥70 years.
CONCLUSIONS: This dual-centre analysis showed that lung transplantation from donors aged ≥70 years was not associated with worse outcomes compared with the younger donors. This study supports the idea that it might be possible to use an extraordinarily cautious selection of lungs from very old donors to increase the pool of suitable donors, given the shortage of suitable organ donors available for lung transplantation.

PMID: 28977370 [PubMed - as supplied by publisher]

Novel mouse model of cardiopulmonary bypass.

Thu, 10/05/2017 - 12:45

Novel mouse model of cardiopulmonary bypass.

Eur J Cardiothorac Surg. 2017 Jul 18;:

Authors: Madrahimov N, Boyle EC, Gueler F, Goecke T, Knöfel AK, Irkha V, Maegel L, Höffler K, Natanov R, Ismail I, Maus U, Kühn C, Warnecke G, Shrestha ML, Cebotari S, Haverich A

Abstract
OBJECTIVES: Cardiopulmonary bypass (CPB) is an essential component of many cardiac interventions, and therefore, there is an increasing critical demand to minimize organ damage resulting from prolonged extracorporeal circulation. Our goal was to develop the first clinically relevant mouse model of CPB and to examine the course of extracorporeal circulation by closely monitoring haemodynamic and oxygenation parameters.
METHODS: Here, we report the optimization of device design, perfusion circuit and microsurgical techniques as well as validation of physiological functions during CPB in mice after circulatory arrest and reperfusion. Validation of the model required multiple blood gas analyses, and therefore, this initial report describes an acute model that is incompatible with survival due to the need of repetitive blood draws.
RESULTS: Biochemical and histopathological assessment of organ damage revealed only mild changes in the heart and lungs and signs of the beginning of acute organ failure in the liver and kidneys.
CONCLUSIONS: This new CPB mouse model will facilitate preclinical testing of therapeutic strategies in cardiovascular diseases and investigation of CPB in relation to different insults and pre-existing comorbidities. In combination with genetically modified mice, this model will be an important tool to dissect the molecular mechanisms involved in organ damage related to extracorporeal circulation.

PMID: 28977367 [PubMed - as supplied by publisher]

Reintubation of patients submitted to cardiac surgery: a retrospective analysis.

Thu, 10/05/2017 - 12:45

Reintubation of patients submitted to cardiac surgery: a retrospective analysis.

Rev Bras Ter Intensiva. 2017 Apr-Jun;29(2):180-187

Authors: Shoji CY, Figuereido LC, Calixtre EM, Rodrigues CDA, Falcão ALE, Martins PP, Anjos APRD, Dragosavac D

Abstract
OBJECTIVES: To analyze patients after cardiac surgery that needed endotracheal reintubation and identify factors associated with death and its relation with the severity scores.
METHODS: Retrospective analysis of information of 1,640 patients in the postoperative period of cardiac surgery between 2007 and 2015.
RESULTS: The reintubation rate was 7.26%. Of those who were reintubated, 36 (30.3%) underwent coronary artery bypass surgery, 27 (22.7%) underwent valve replacement, 25 (21.0%) underwent correction of an aneurysm, and 8 (6.7%) underwent a heart transplant. Among those with comorbidities, 54 (51.9%) were hypertensive, 22 (21.2%) were diabetic, and 10 (9.6%) had lung diseases. Among those who had complications, 61 (52.6%) had pneumonia, 50 (42.4%) developed renal failure, and 49 (51.0%) had a moderate form of the transient disturbance of gas exchange. Noninvasive ventilation was performed in 53 (44.5%) patients. The death rate was 40.3%, and mortality was higher in the group that did not receive noninvasive ventilation before reintubation (53.5%). Within the reintubated patients who died, the SOFA and APACHE II values were 7.9 ± 3.0 and 16.9 ± 4.5, respectively. Most of the reintubated patients (47.5%) belonged to the high-risk group, EuroSCORE (> 6 points).
CONCLUSION: The reintubation rate was high, and it was related to worse SOFA, APACHE II and EuroSCORE scores. Mortality was higher in the group that did not receive noninvasive ventilation before reintubation.

PMID: 28977259 [PubMed - in process]

Pain, fatigue and well-being one to five years after lung transplantation - a nationwide cross-sectional study.

Thu, 10/05/2017 - 12:45

Pain, fatigue and well-being one to five years after lung transplantation - a nationwide cross-sectional study.

Scand J Caring Sci. 2017 Oct 04;:

Authors: Forsberg A, Claëson M, Dahlman GB, Lennerling A

Abstract
RATIONALE AND AIM: Little is known about persistent pain after lung transplantation. Therefore, the aim was to present a multidimensional assessment of self-reported pain 1-5 years after lung transplantation and its relationship with fatigue and transplant-specific well-being.
METHODS: This nationwide, cross-sectional cohort study is part of the self-management after thoracic transplantation study. A total of 117 lung recipients, all White, who were due for their annual follow-up at one (n = 35), two (n = 28), three (n = 23), four (n = 20) and 5 years (n = 11) after lung transplantation were included. We used three instruments; the Pain-O-Meter (POM), which provides information about pain intensity, sensation, location and duration, the MFI-19 fatigue instrument and the Organ Transplant Symptom and Well-being Instrument (OTSWI). Permission to carry out this study was granted by the Regional Ethical Review Board in southern Sweden (D-nr 2014-124).
RESULTS: The prevalence of pain was 51% after 1 year, 68% after 2 years, 69.5% after 3 years, 75% after 4 years and 54.5% after 5 years. Women experienced more pain than men. Lung recipients with pain reported lower well-being and higher symptom distress but were not more fatigued than those without pain.
STUDY LIMITATIONS: The limitations of this study are due to the cross-sectional design. The recruitment of patients during the study period was probably affected by the different conditions regarding staffing at the outpatient lung transplant clinic in the two thoracic transplant centres in Sweden. The slightly different approach to the care of these patients in the pre, peri and postoperative setting contributes to the heterogeneity of the study population.
CONCLUSION: Chronic bodily pain up to 5 years after lung transplantation reduces perceived well-being. Lung recipients with pain report higher symptom distress than those without pain.

PMID: 28976009 [PubMed - as supplied by publisher]

Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation.

Thu, 10/05/2017 - 12:45

Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation.

MBio. 2017 Oct 03;8(5):

Authors: Farrell HE, Bruce K, Lawler C, Oliveira M, Cardin R, Davis-Poynter N, Stevenson PG

Abstract
Herpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology. Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells, and it has been hypothesized that systemic dissemination arises from infected stem cells in bone marrow. However, poor CMV transfer by stem cell transplantation argues against this being the main reservoir. To identify alternative pathways for CMV spread, we tracked murine CMV (MCMV) colonization after mucosal entry. We show that following intranasal MCMV infection, lung CD11c(+) dendritic cells (DC) migrated sequentially to lymph nodes (LN), blood, and then salivary glands. Replication-deficient virus followed the same route, and thus, DC infected peripherally traversed LN to enter the blood. Given that DC are thought to die locally following their arrival and integration into LN, recirculation into blood represents a new pathway. We examined host and viral factors that facilitated this LN traverse. We show that MCMV-infected DC exited LN by a distinct route to lymphocytes, entering high endothelial venules and bypassing the efferent lymph. LN exit required CD44 and the viral M33 chemokine receptor, without which infected DC accumulated in LN and systemic spread was greatly reduced. Taken together, our studies provide the first demonstration of virus-driven DC recirculation. As viruses follow host-defined pathways, high endothelial venules may normally allow DC to pass from LN back into blood.IMPORTANCE Human cytomegalovirus (HCMV) causes devastating disease in the unborn fetus and in the immunocompromised. There is no licensed vaccine, and preventive measures are impeded by our poor understanding of early events in host colonization. HCMV and murine CMV (MCMV) both infect blood-borne myeloid cells. HCMV-infected blood cells are thought to derive from infected bone marrow stem cells. However, infected stem cells have not been visualized in vivo nor shown to produce virus ex vivo, and hematopoietic transplants poorly transfer infection. We show that MCMV-infected dendritic cells in the lungs reach the blood via lymph nodes, surprisingly migrating into high endothelial venules. Dissemination did not require viral replication. It depended on the constitutively active viral chemokine receptor M33 and on the host hyaluronan receptor CD44. Thus, viral chemokine receptors are a possible target to limit systemic CMV infections.

PMID: 28974616 [PubMed - in process]

Establishment of highly metastatic KRAS mutant lung cancer cell sublines in long-term three-dimensional low attachment cultures.

Thu, 10/05/2017 - 12:45
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Establishment of highly metastatic KRAS mutant lung cancer cell sublines in long-term three-dimensional low attachment cultures.

PLoS One. 2017;12(8):e0181342

Authors: Nakano T, Kanai Y, Amano Y, Yoshimoto T, Matsubara D, Shibano T, Tamura T, Oguni S, Katashiba S, Ito T, Murakami Y, Fukayama M, Murakami T, Endo S, Niki T

Abstract
Decreased cell-substratum adhesion is crucially involved in metastasis. Previous studies demonstrated that lung cancer with floating cell clusters in histology is more likely to develop metastasis. In the present study, we investigated whether cancer cells in long-term, three-dimensional low attachment cultures acquire high metastatic potential; these cells were then used to examine the mechanisms underlying metastasis. Two KRAS-mutated adenocarcinoma cell lines (A549 and H441) were cultured and selected on ultra-low attachment culture dishes, and the resulting cells were defined as FL (for floating) sublines. Cancer cells were inoculated into NOD/SCID mice via an intracardiac injection, and metastasis was evaluated using luciferase-based imaging and histopathology. In vitro cell growth (in attachment or suspension cultures), migration, and invasion were assayed. A whole genomic analysis was performed to identify key molecular alterations in FL sublines. Upon detachment on low-binding dishes, parental cells initially formed rounded spheroids with limited growth activity. However, over time in cultures, cells gradually formed smaller spheroids that grew slowly, and, after 3-4 months, we obtained FL sublines that regained prominent growth potential in suspension cultures. On ordinary dishes, FL cells reattached and exhibited a more spindle-shaped morphology than parental cells. No marked differences were observed in cell growth with attachment, migration, or invasion between FL sublines and parental cell lines; however, FL cells exhibited markedly increased growth potential under suspended conditions in vitro and stronger metastatic abilities in vivo. A genomic analysis identified epithelial-mesenchymal transition (EMT) and c-Myc amplification in A549-FL and H441-FL cells, respectively, as candidate mechanisms for metastasis. The growth potential of FL cells was markedly inhibited by lentiviral ZEB1 knockdown in A549-FL cells and by the inhibition of c-Myc through lentiviral knockdown or the pharmacological inhibitor JQ1 in H441-FL cells. Long-term three-dimensional low attachment cultures may become a useful method for investigating the mechanisms underlying metastasis mediated by decreased cell-substratum adhesion.

PMID: 28786996 [PubMed - indexed for MEDLINE]

Ski regulates Smads and TAZ signaling to suppress lung cancer progression.

Thu, 10/05/2017 - 12:45
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Ski regulates Smads and TAZ signaling to suppress lung cancer progression.

Mol Carcinog. 2017 Oct;56(10):2178-2189

Authors: Xie M, Wu X, Zhang J, Zhang J, Li X

Abstract
Ski, the transforming protein of the avian Sloan-Kettering retrovirus, displays both pro- and anti-oncogenic activities in human cancer. The mechanisms underlying these conflicting observations have not been fully understood. Herein, we investigated the mechanism underlying the tumor suppressor activity of Ski. To investigate the effect of Ski re-activation on TGF-β and Hippo/TAZ pathway, we measured its effect on the endogenous Smad target genes (PAI-1 and P15(INK4B) ) and TAZ target gene CTGF. The results revealed that Ski exerted its inhibitory activity in TGF-β1/Smad signaling pathway. Ski inhibited TAZ by increasing their phosphorylation by Lats2 and did not alter the localization of TAZ. Ski inhibited lung cancer growth and invasion. Ski methylation correlated with decreased mRNA expression in human lung cancer cell lines. Thus, Ski inhibited the function of TGF-β and TAZ through multiple mechanisms in human lung cancer.

PMID: 28398634 [PubMed - indexed for MEDLINE]

Duchesnea indica extract suppresses the migration of human lung adenocarcinoma cells by inhibiting epithelial-mesenchymal transition.

Thu, 10/05/2017 - 12:45
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Duchesnea indica extract suppresses the migration of human lung adenocarcinoma cells by inhibiting epithelial-mesenchymal transition.

Environ Toxicol. 2017 Aug;32(8):2053-2063

Authors: Chen PN, Yang SF, Yu CC, Lin CY, Huang SH, Chu SC, Hsieh YS

Abstract
Epithelial-mesenchymal transition (EMT) is a process through which epithelial cells are transformed into mesenchymal cells; EMT diminishes cell polarity and cell-cell adhesion in cancer cells, leading to enhanced migratory and invasive properties. In this experiment, zymography, cell invasion, and migration assays were performed. Results indicated that Duchesnea indica extracts (DIE) inhibited highly metastatic A549 and H1299 cells by reducing the secretions of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Cell adhesion assay also demonstrated that DIE reduced the cell adhesion properties. Western blot analysis showed that DIE down-regulated the expression of N-cadherin, fibronectin, and vimentin, which are mesenchymal markers, and enhanced that of E-cadherin, which is an epithelial marker. In vivo study showed that tumor growth was significantly reduced in BALB/c nude mouse xenograft model administered with oral gavage of DIE. Therefore, DIE could be exhibits potential as a phytochemical-based platform for prevention and treatment of lung cancer. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2053-2063, 2017.

PMID: 28371048 [PubMed - indexed for MEDLINE]

Imaging of the Lungs in Organ Donors and its Clinical Relevance: A Retrospective Analysis.

Thu, 10/05/2017 - 12:45
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Imaging of the Lungs in Organ Donors and its Clinical Relevance: A Retrospective Analysis.

J Thorac Imaging. 2017 Mar;32(2):107-114

Authors: Bozovic G, Adlercreutz C, Höglund P, Björkman-Burtscher I, Reinstrup P, Ingemansson R, Schaefer-Prokop C, Siemund R, Geijer M

Abstract
PURPOSE: The aim of the study was to retrospectively evaluate the diagnostic imaging that potential lung donors undergo, the reader variability of image interpretation and its relevance for donation, and the potential information gained from imaging studies not primarily intended for lung evaluation but partially including them.
MATERIALS AND METHODS: Bedside chest radiography and computed tomography (CT), completely or incompletely including the lungs, of 110 brain-dead potential organ donors in a single institution during 2007 to 2014 were reviewed from a donation perspective. Two chest radiologists in consensus analyzed catheters and cardiovascular, parenchymal, and pleural findings. Clinical reports and study review were compared for substantial differences in findings that could have led to a treatment change, triggered additional examinations such as bronchoscopy, or were considered important for donation.
RESULTS: Among 136 bedside chest radiographs, no differences between clinical reports and study reviews were found in 37 (27%), minor differences were found in 28 (21%), and substantial differences were found in 71 (52%) examinations (P<0.0001). In 31 of 42 (74%) complete or incomplete CT examinations, 50 of 74 findings with relevance for lung donation were not primarily reported (P<0.0001).
CONCLUSIONS: The majority of donor patients undergo only chest radiography. A targeted imaging review of abnormalities affecting the decision to use donor lungs may be useful in the preoperative stage. With a targeted list, substantial changes were made from initial clinical interpretations. CT can provide valuable information on donor lung pathology, even if the lungs are only partially imaged.

PMID: 28060192 [PubMed - indexed for MEDLINE]

Single center experience in urgent lung transplantation program in a country with a shortage of donors: does the end justify the means?

Wed, 10/04/2017 - 12:45

Single center experience in urgent lung transplantation program in a country with a shortage of donors: does the end justify the means?

Clin Transplant. 2017 Oct 03;:

Authors: Schiavon M, Faggi G, Di Gregorio G, Francesca C, Lunardi F, Marulli G, Feltracco P, Loy M, Damin M, Cozzi E, Gregori D, Calabrese F, Rea F

Abstract
In rapidly deteriorating patients awaiting lung transplantation (LT), supportive strategies are only temporary and Urgent LT (ULT) remains the last option. The few publications on this topic report conflicting results. According to the Italian national program, patients on mechanical ventilation and/or extracorporeal membrane oxygenation may be included in urgent list. We reviewed our experience from January 2012 to December 2014 with ULT and Elective LT (ELT), focusing on outcomes. In the study period, 16 patients received ULT, while 51 received ELT. Among ULT, 1 patient (5.8%) died in waiting list (WL) while 16 patients underwent LT with a median WL time of 6 days. ELT WL mortality was 13.5%, and median WL time 368 days. In hospital mortality was lower in ELT group (5.8%vs37.5%, p<0.01), while the other post-operative outcomes were not significantly different. For ULT patients the highest impact risk factors for in-hospital mortality were pre-transplant plasma transfusion, recipient Pseudomonas Aeruginosa colonization and high level of reactive C-protein and lactic acid. A ULT program with an accurate recipient selection allows earlier transplantation, reducing WL mortality, with acceptable outcomes, although with a higher in-hospital mortality. Larger studies are needed to validate our results. This article is protected by copyright. All rights reserved.

PMID: 28972662 [PubMed - as supplied by publisher]

Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension.

Wed, 10/04/2017 - 12:45

Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension.

Circulation. 2017 Sep 28;:

Authors: Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift AJ, Dorfmüller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J, Treacy C, Yates K, Bogaard H, Church C, Coghlan G, Condliffe R, Corris PA, Gibbs SR, Girerd B, Holden S, Humbert M, Kiely DG, Lawrie A, Machado RD, MacKenzie Ross R, Moledina S, Montani D, Newnham M, Peacock AJ, Pepke-Zaba J, Rayner-Matthews PJ, Shamardina O, Soubrier F, Southgate L, Suntharalingam J, Toshner MR, Trembath RC, Vonk Noordegraaf A, Wilkins MR, Wort SJ, Wharton J, Gräf S, Morrell NW, NIHR BioResource - Rare Diseases Consortium & UK National Cohort Study of Idiopathic and Heritable PAH

Abstract
Background -Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis (PVOD/PCH). Here, we determined the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods -Whole genome sequencing was performed on DNA from patients with idiopathic and heritable PAH, as well as PVOD/PCH recruited to the NIHR BioResource - Rare Diseases Study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of < 1:10,000 in control data sets and predicted to be deleterious (by CADD, PolyPhen-2 and SIFT predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results -Eight hundred and sixty-four patients with idiopathic or heritable PAH and 16 with PVOD/PCH were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of PVOD/PCH. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (KCO: 33 [IQR: 30 - 35] % predicted) and younger age at diagnosis (29 [23 - 38] years) as well as more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest, compared to PAH patients without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. PAH patients with biallelic EIF2AK4 mutations had a shorter survival. Conclusions -Biallelic EIF2AK4 mutations are found in patients classified clinically as idiopathic and heritable PAH. These patients cannot be identified reliably by CT, but a low KCO and a young age of diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

PMID: 28972005 [PubMed - as supplied by publisher]

Preventing Refractory Hypoxemia after Lung Transplantation by Prone Positioning: A New Agenda for Research.

Wed, 10/04/2017 - 12:45

Preventing Refractory Hypoxemia after Lung Transplantation by Prone Positioning: A New Agenda for Research.

Indian J Crit Care Med. 2017 Sep;21(9):617-618

Authors: Kiasari AZ

PMID: 28970667 [PubMed]

Aspergillus galactomannan detection in exhaled breath condensate compared to bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in immunocompromised patients.

Wed, 10/04/2017 - 12:45

Aspergillus galactomannan detection in exhaled breath condensate compared to bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in immunocompromised patients.

Clin Microbiol Infect. 2017 Sep 29;:

Authors: Bhimji A, Bhaskaran A, Singer LG, Kumar D, Humar A, Pavan R, Lipton J, Kuruvilla J, Schuh A, Yee K, Minden MD, Schimmer A, Rotstein C, Keshavjee S, Mazzulli T, Husain S

Abstract
OBJECTIVE: Exhaled breath condensate (EBC) is a noninvasive means of sampling the airways that has shown significant promise in the diagnosis of many disorders. There have been no reports of its utility for the detection of galactomannan (GM), a component of the cell wall of Aspergillus. The suitability of EBC for the detection of GM for the diagnosis of invasive aspergillosis (IA) using the Platelia(®)Aspergillus enzyme-linked immunosorbent assay (ELISA) was investigated.
METHODS: Prospective, cross-sectional study of lung transplant recipient and hematological malignancy patients at a university center. EBC samples were compared with concomitant BAL samples among lung transplant recipients and healthy controls. EBC was collected over 10 min using a refrigerated condenser according to the European Respiratory Society/American Thoracic Society recommendations, with the BAL performed immediately thereafter.
RESULTS: A total of 476 EBC specimens with 444 matched BAL specimens collected from lung transplant recipients (n=197) or hematological malignancy patients (n=133) were examined. Both diluted and neat EBC optical density (OD) values [0.0830; IQR 0.0680-0.1040 and 0.1130; IQR 0.0940-0.1383] respectively, from all patients regardless of clinical syndrome were significantly higher than OD values in healthy control EBCs [0.0508; IQR 0.0597-0.0652; p<0.0001]. However, the OD index values did not correlate with the diagnosis of IA (44 samples were associated with IA). Furthermore, no significant correlation was found between EBC GM and the matched BAL specimen.
CONCLUSION: Galactomannan is detectable in exhaled breath condensate, however no correlation between OD index values and IA were noted in lung transplant recipients.

PMID: 28970160 [PubMed - as supplied by publisher]

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