Mesenchymal Stem Cell Transplantation Has a Regenerative Effect in Ischemic Myocardium: An Experimental Rat Model Evaluated by SPECT-CT Assessment.

Translational perspective: Ischemic heart disease remains a major medical problem with high mortality rates. Beside the great efforts devoted to research worldwide and the use of numerous experimental models, an absolute understanding of myocardial infarction and tissue loss has not yet been achieved. Furthermore, the regeneration of myocardial tissue and the improvement of myocardial activity after ischemia is one of the major areas of interest in the medical (and especially cardiovascular) community. In a novel experimental rat model, the beneficial effect of mesenchymal stem cell transplantation (MSCT) in a surgically induced ischemic myocardium was documented. From a clinical perspective, this work supports the surgical administration of MSCT in the infarcted area during coronary artery bypass surgery. AIMS: The regeneration of myocardial tissue and the improvement of myocardial activity after ischemia is one of the major areas of interest in cardiovascular research. We developed a novel experimental rat model and used it to examine the effect of mesenchymal stem cell transplantation (MSCT) on myocardial ischemia evaluated by SPECT-CT and immunohistochemistry. METHODS AND RESULTS: An open thoracotomy took place for forty adult female Wistar rats with (n = 30) or without (n = 10) surgical ligation of the left anterior descending coronary artery (LAD) in order to cause myocardial ischemia. Myocardial viability was evaluated via SPECT/CT 7 days before surgery, as well as at 7 and 14 days post-surgery. At day 0, 15 animals received homologous stem cells injected at the ischemic myocardium area. A SPECT/CT evaluation showed decreased activity of the myocardial cells in the left ventricle one week post-infarction. Regeneration of the ischemic myocardium fifteen days post-infarction was recorded only in animals subjected to stem cell transplantation. These findings were also confirmed by histology and immunohistochemical analysis, with the significantly higher expression of GATA4 and Nkx2.5. CONCLUSIONS: The positive effect of mesenchymal stem cell transplantation in the ischemic myocardium was recorded. The application of SPECT-CT allowed a clear evaluation of both the quality and quantity of the living myocardium post-infarction, leading to a new approach in the research of cardiovascular diseases. From a clinical perspective, MSCT may be beneficial when accompanied by myocardial revascularization procedures.

Are Extensive Open Lung Resections for Elderly Patients with Lung Cancer Justified?

BACKGROUND: Older patients with malignancies are more comorbid than younger ones and are usually undertreated only because of their age. The aim of this study is to investigate the safety of open anatomical lung resections for lung cancer in elderly patients. METHODS: We retrospectively analyzed all patients who underwent lung resection for lung cancer in our institution and categorized them into two groups: the elderly group (≥70 years old) and the control (<70). RESULTS: In total, 135 patients were included in the elderly group and 375 in the control. Elderly patients were more frequently diagnosed with squamous cell carcinoma (59.3% vs. 51.5%, p = 0.037), higher differentiated tumors (12.6% vs. 6.4%, p = 0.014), and at an earlier stage (stage I: 55.6% for elderly vs. 36.6%, p = 0.002). Elderly patients were more vulnerable to postoperative pneumonia (3.7% vs. 0.8%, p = 0.034), lung atelectasis (7.4% vs. 2.9%, p = 0.040), and pleural empyema (3.2% vs. 0%, p = 0.042), however, with no increased 30-day-mortality (5.2% for elderly vs. 2.7%, p = 0.168). Survival was comparable in both groups (43.4 vs. 45.3 months, p = 0.579). CONCLUSIONS: Elderly patients should not be excluded from open major lung resections as the survival benefit is not reduced in selected patients.

A Novel Experimental Rat Model for the In Vivo Assessment of Myocardial Ischemia Based on Single Photon Emission Computed Tomography.

BACKGROUND/AIM: Myocardial infarction, an acute medical situation with a high mortality rate worldwide, has been extensively studied in modern cardiovascular research, using different experimental models. However, a deep understanding of myocardial activity loss has not been fully investigated. We have developed a novel experimental rat model for noninvasive assessment of myocardial ischemia based on single photon emission computed tomography (SPECT/CT), in order to further understand and evaluate myocardial activity before and after surgical induction of myocardial ischemia. MATERIALS AND METHODS: Thirty adult female Wistar rats underwent open thoracotomy with (n=20) or without (n=10) surgical ligation of the left anterior descending coronary artery (LAD). The myocardial ischemia was confirmed with ECG and myocardial viability was evaluated via SPECT/CT at 7 days before as well as at 7 and 14 days post-surgery, after which animals were sacrificed and myocardial ischemic injury was further assessed histologically. RESULTS: All animals were evaluated with anatomical and functional criteria based on the SPECT/CT imaging results. A successful surgical technique causing ischemia and loss of myocardial function in all animals undergoing a LAD ligation was established. Furthermore, evaluation of the viable myocardium with SPECT/CT confirmed the reduction of functional myocardial cells of the left ventricle post-infarction, which was also documented histologically. CONCLUSION: Using our technique, the validity of this animal model to induce and evaluate myocardial ischemia was demonstrated. Our choice to apply SPECT-CT qualitative and quantitative evaluation of myocardial function leads to a new approach in experimentation with an anticipated significant impact in the ongoing cardiovascular laboratory research.

The Coadministration of Levosimendan and Exenatide Offers a Significant Cardioprotective Effect to Isolated Rat Hearts against Ischemia/Reperfusion Injury.

(1) Background: The present study aims to investigate the effect of administration of Levosimendan and Exenatide in various concentrations, as well as of the coadministration of those agents in an ischemia-reperfusion injury isolated heart model. (2) Methods: After 30 min of perfusion, the hearts underwent a 30 min period of regional ischemia followed by a 120 min period of reperfusion. All animals were randomly divided into 12 experimental groups of nine animals in each group: (1) Control, (2) Sham, (3) Digox (Negative control, Digoxin 1.67 µg/min), (4) Levo 1 (Levosimendan 0.01 µg/min), (5) Levo 2 (Levosimendan 0.03 µg/mL), (6) Levo 3 (Levosimendan 0.1 µg/min), (7) Levo 4 (Levosimendan 0.3 µg/min), (8) Levo 5 (Levosimendan 1 µg/min), (9) Exen 1 (Exenatide 0.001 µg/min), (10) Exen 2 (Exenatide 0.01 µg/min), (11) Exen 3 (Exenatide 0.1 µg/min) and (12) Combi (Levosimendan 0.1 µg/mL + Exenatide 0.001 µg/min). The hemodynamic parameters were recorded throughout the experiment. Arrhythmias and coronary flow were also evaluated. After every experiment the heart was suitably prepared and infarct size was measured. Markers of myocardial injury were also measured. Finally, oxidative stress was evaluated measuring reactive oxygen species. (3) Results: A dose-dependent improvement of the haemodynamic response was observed after the administration of both Levosimendan and Exenatide. The coadministration of both agents presented an even greater effect, improving the haemodynamic parameters further than the two agents separately. Levosimendan offered an increase of the coronary flow and both agents offered a reduction of arrhythmias. A dose-dependent reduction of the size of myocardial infarction and myocardial injury was observed after administration of Levosimendan and Exenatide. The coadministration of both agents offered a further improving the above parameters. Levosimendan also offered a significant reduction of oxidative stress. (4) Conclusions: The administration of Levosimendan and Exenatide offers a significant benefit by improving the haemodynamic response, increasing the coronary flow and reducing the occurrence of arrhythmias, the size of myocardial injury and myocardial oxidative stress in isolated rat hearts.

Antegrade Endograft Deployment with Supra-Aortic Debranching to Treat Arch and Descending Thoracic Aortic Lesions. A Single-Center Experience.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is a widely used procedure that has drastically changed the management of thoracic aortic diseases. We assess the effectiveness of supra-aortic debranching during antegrade TEVAR procedures with a retrospective analysis of our clinical experience. METHODS: Between December 2005 and April 2017, 55 patients underwent 64 TEVAR procedures. Among them, there were 8 male patients, mean age 72, who underwent hybrid antegrade stent-graft deployment. Particularly, for degenerative aneurysms of the aortic arch, 3 patients for aneurysm of descending thoracic aorta 3, for post-traumatic pseudoaneurysm 1, and for penetrating aortic ulcer 1 which had resulted in an aortoesophageal fistula. Proximal landing zones were Z0:1, Z1:3 and Z2:4. Type I hybrid aortic arch repair was performed in 1 case, carotid-carotid bypass in 2, carotid-subclavian in 5 and aorto-carotid in 1. RESULTS: The 30-day postoperative mortality was 12.5%. One patient suffered a temporary right hemiplegia which resolved after left aorto-carotid bypass. No endoleaks were observed postoperatively and in follow-up period. In the long term and a mean follow-up of 4.9 years, there were no deaths related to the stent-graft implantation or to revascularization procedures. Regarding the aortic arch rerouting procedure, there were no pseudoaneurysm or other anastomotic events. CONCLUSIONS: Antegrade delivery of the endograft, combined with hybrid and revascularization procedures of the supra-aortic vessels is a safe treatment modality, in complex hostile anatomies. However, further improvements are recommended due to the presence of neurologic complications and reinterventions.

Genetic Variations of CD40 and LTßR Genes Are Associated With Increased Susceptibility and Clinical Outcome of Non-Small-Cell Carcinoma Patients.

BACKGROUND: Immune system-related receptors CD40 (tumor necrosis factor receptor superfamily member 5), BAFFR (tumor necrosis factor receptor superfamily member 13C), and LTßR (tumor necrosis factor receptor superfamily member 3) play a pivotal role in non-small-cell lung cancer (NSCLC). To further evaluate their role in NSCLC, CD40 rs1883832 (T>C), BAFFR rs7290134 (A>G), and LTßR rs10849448 (A>G) single-nucleotide polymorphisms (SNPs) were investigated regarding their impact in risk and clinical outcome of NSCLC patients. METHODS: The three selected SNPs were evaluated in 229 NSCLC patients and 299 healthy controls, while CD40, BAFFR, and LTßR protein expression was assessed by immunohistochemistry in 96 tumor specimens from NSCLC patients. RESULTS: In total, CD40 rs1883832 was associated with NSCLC risk, with the T allele, after adjusting for cofactors, being related to increased risk (p = 0.007; OR 1.701). Moreover, the CT genotype was associated with increased risk (p = 0.024; OR 1.606) and poorer 5-year overall survival (OS) after adjusting for cofactors (p = 0.001, HR 1.829), while CC was associated with higher CD40 expression in tumorous cells (p = 0.040) and in stromal cells (p = 0.036). In addition, AA homozygotes for the LTßR rs10849448 had increased risk for NSCLC in multivariate analysis (p = 0.008; OR, 2.106) and higher LTßR membranous expression (p = 0.035). Although BAFFR rs7290134 was associated with BAFFR membranous expression (p = 0.039), BAFFR rs7290134 was not associated with neither the disease risk nor the prognosis of NSCLC patients. CONCLUSIONS: In conclusion, CD40 rs1883832 and LTßR rs10849448 seem to be associated with increased risk for NSCLC, while CD40 rs1883832 is also associated with OS of patients with NSCLC.

Antegrade Hybrid Chimney TEVAR Endograft in a Patient with Blunt Aortic Injury: A Challenging Case with Technical Success but Unfavorable Result.

Thoracic Endovascular Aortic Repair (TEVAR) has modified aortic medicine, particularly in patients with traumatic aortic injury (TAI). Conventional repair of TAI in the aortic arch is technically demanding as it requires cardiopulmonary bypass and deep hypothermic arrest with still a significant number of complications. Despite recent improvements in endovascular techniques, many patients have been excluded from endovascular repair due to unfavorable anatomy. To increase the feasibility of endovascular repair, adjunctive open extra-anatomical bypasses may be required to provide an adequate proximal landing zone. Several methods, for instance, chimney technique, hybrid technique, and fenestrated or branched stent-grafts, have been proposed as options to preserve the supra-aortic branches, each with its own advantages and disadvantages. We herein present a patient with complex anatomical features and blunt aortic injury, who underwent antegrade chimney stent-graft deployment through the ascending aorta, not otherwise amenable to standard retrograde delivery because of severe peripheral artery disease. The remarkable aspect, in this case, is that both stents were placed antegrade, through the ascending aorta.

Contribution of miRNAs, tRNAs and tRFs to Aberrant Signaling and Translation Deregulation in Lung Cancer.

Transcriptomics profiles of miRNAs, tRNAs or tRFs are used as biomarkers, after separate examination of several cancer cell lines, blood samples or biopsies. However, the possible contribution of all three profiles on oncogenic signaling and translation as a net regulatory effect, is under investigation. The present analysis of miRNAs and tRFs from lung cancer biopsies indicated putative targets, which belong to gene networks involved in cell proliferation, transcription and translation regulation. In addition, we observed differential expression of specific tRNAs along with several tRNA-related genes with possible involvement in carcinogenesis. Transfection of lung adenocarcinoma cells with two identified tRFs and subsequent NGS analysis indicated gene targets that mediate signaling and translation regulation. Broader analysis of all major signaling and translation factors in several biopsy specimens revealed a crosstalk between the PI3K/AKT and MAPK pathways and downstream activation of eIF4E and eEF2. Subsequent polysome profile analysis and 48S pre-initiation reconstitution experiments showed increased global translation rates and indicated that aberrant expression patterns of translation initiation factors could contribute to elevated protein synthesis. Overall, our results outline the modulatory effects that possibly correlate the expression of important regulatory non-coding RNAs with aberrant signaling and translation deregulation in lung cancer.

Life-threatening antineutrophil cytoplasmic antibody-associated vasculitis after influenza A H1N1 infection requiring veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: Antineutrophil cytoplasmic autoantibody-associated vasculitis is an immune-mediated necrotizing vasculitis, affecting small- and medium-sized vessels. CASE REPORT: A 22-year-old female patient with free medical history presented with life-threatening pulmonary hemorrhage due to antineutrophil cytoplasmic autoantibody-associated vasculitis, temporarily associated with influenza A H1N1 infection. Due to rapidly worsening respiratory failure, despite conventional management, veno-venous peripheral extracorporeal membrane oxygenation was initiated and continued for 26 days, with subsequent renal replacement therapy. DISCUSSION: We present a case of severe antineutrophil cytoplasmic autoantibody-associated pulmonary vasculitis, managed with veno-venous extracorporeal membrane oxygenation at the initial phase. Despite the significant challenges raised with the use of extracorporeal membrane oxygenation in pulmonary hemorrhage cases, extracorporeal membrane oxygenation may have a significant impact on outcome in this setting, by providing adequate time for a successful immunosuppressive treatment.

Healthcare professionals' knowledge on cardiopulmonary resuscitation correlated with return of spontaneous circulation rates after in-hospital cardiac arrests: A multicentric study between university hospitals in 12 European countries.

BACKGROUND: In-hospital cardiac arrest is a major cause of death in European countries, and survival of patients remains low ranging from 20% to 25%. AIMS: The purpose of this study was to assess healthcare professionals' knowledge on cardiopulmonary resuscitation among university hospitals in 12 European countries and correlate it with the return of spontaneous circulation rates of their patients after in-hospital cardiac arrest. METHODS AND RESULTS: A total of 570 healthcare professionals from cardiology, anaesthesiology and intensive care medicine departments of European university hospitals in Italy, Poland, Hungary, Belgium, Spain, Slovakia, Germany, Finland, The Netherlands, Switzerland, France and Greece completed a questionnaire. The questionnaire consisted of 12 questions based on epidemiology data and cardiopulmonary resuscitation training and 26 multiple choice questions on cardiopulmonary resuscitation knowledge. Hospitals in Switzerland scored highest on basic life support (P=0.005) while Belgium hospitals scored highest on advanced life support (P<0.001) and total score in cardiopulmonary resuscitation knowledge (P=0.01). The Swiss hospitals scored highest in cardiopulmonary resuscitation training (P<0.001). Correlation between cardiopulmonary resuscitation knowledge and return of spontaneous circulation rates of patients with in-hospital cardiac arrest demonstrated that each additional correct answer on the advanced life support score results in a further increase in return of spontaneous circulation rates (odds ratio 3.94; 95% confidence interval 2.78 to 5.57; P<0.001). CONCLUSION: Differences in knowledge about resuscitation and course attendance were found between university hospitals in 12 European countries. Education in cardiopulmonary resuscitation is considered to be vital for patients' return of spontaneous circulation rates after in-hospital cardiac arrest. A higher level of knowledge in advanced life support results in higher return of spontaneous circulation rates.

Expression Of Intracellular Components of the NF-κB Alternative Pathway (NF-κB2, RelB, NIK and Bcl3) is Associated With Clinical Outcome of NSCLC Patients.

A growing number of studies has shed light on the role of the NF-κΒ in non-small-cell lung cancer (NSCLC). To address the significance of major effectors of the NF-κΒ alternative pathway, we investigated the relationship between NF-κΒ2, RelB, NIK and Bcl3 expression (mRNA and protein) and the clinical outcome of NSCLC patients. NF-κΒ2, RelB, NIK and Bcl3 protein expression levels were assessed by immunohistochemistry in tissue samples from 151 NSCLC patients who had curative resection. mRNA levels were also evaluated in 69 patients using quantitative real-time PCR. Although all studied proteins were overexpressed in NSCLC (P < 0.001 for all), only RelB mRNA levels were strongly increased in cancerous specimens compared to tumor-adjacent non-neoplastic tissues (P = 0.009). Moreover, NF-κB2, RelB and Bcl3 expression was associated with overall survival (OS). In particular, cytoplasmic and mRNA expression of RelB was related to 5-year OS (P = 0.014 and P = 0.006, respectively). Multivariate analysis also showed that Bcl3 expression (nuclear and cytoplasmic) was associated with increased 5-year OS (P = 0.002 and P = 0.036, respectively). In addition, higher Bcl3 mRNA levels were associated with inferior OS in stages I & II and improved OS in stages III and IV after 5-year follow-up (P = 0.004 and P = 0.001, respectively). Furthermore, stage I patients with lower NF-κB2 mRNA levels had better 5-year survival in univariate and multivariate analysis (P = 0.031 and P = 0.028, respectively). Interestingly, RelB expression (cytoplasmic and mRNA) was inversely associated with relapse rates (P = 0.027 and P = 0.015, respectively), while low NIK cytoplasmic expression was associated with lower relapse rates (P = 0.019). Cytoplasmic NIK expression as well as NF-κB2/ Bcl3 detection was associated with lymph node infiltration (P = 0.039 and P = 0.014, respectively). The present study confirms the deregulation of the NF-κB alternative pathway in NSCLC and also demonstrates the importance of this pathway in prognosis, recurrence and infiltration of regional lymph nodes.

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTßR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients.

An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell activating factor receptor), RANK (Receptor activator of NF-κB) and LTßR (lymphotoxin ß receptor) receptors, which activate the alternative pathway of NF-κB, in NSCLC. Evaluation of CD40, BAFFR, RANK and LTßR expression was performed based on the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, while protein expression was assessed by immunohistochemistry in specimens from 119 operated NSCLC patients. CD40 gene overexpression was correlated with improved five-year overall survival (OS) (p < 0.001), while increased BAFFR and LTßR mRNA levels were associated with worse OS in patients with adenocarcinomas (p < 0.001 and p < 0.001, respectively). Similarly, patients with adenocarcinomas exhibited a negative correlation between membranous BAFFR protein expression in carcinoma cells and three- and five-year survival (p = 0.021; HR, 4.977 and p = 0.030; HR, 3.358, respectively) as well as between BAFFR protein overexpression in cancer-associated fibroblasts (CAFs) and two-year survival (p = 0.036; HR, 1.983). Patients with increased LTßR nuclear protein staining or stage II patients with lower cytoplasmic LTßR protein expression had worse five-year OS (p = 0.039 and p = 0.008, respectively). Moreover, CD40 protein expression in tumor infiltrating lymphocytes (TILs) and CAFs was positively associated with metastatic spread while BAFFR protein expression in CAFs was negatively associated with bone metastasis (p = 0.041). Our data suggests that CD40, BAFFR, RANK and LTßR play an important role in NSCLC and further supports the role of NF-κB alternative pathway in NSCLC.

Sclerosing Mediastinitis Causing Unilateral Pulmonary Edema Due to Left Atrial and Pulmonary Venous Compression. A Case Report and Literature Review.

Sclerosing mediastinitis (SM), previously named chronic fibrosing mediastinitis, is an inflammatory process that in its end-stage results to sclerosis around the mediastinal structures. SM is quite rare and has been correlated with inflammatory and autoimmune diseases, as well as malignancy. SM may either present in a mild form, with minor symptoms and a benign course or in a more aggressive form with severe pulmonary hypertension and subsequent higher morbidity and mortality. The diagnosis of SM may be difficult and quite challenging, as symptoms depend on the mediastinal structure that is mainly involved; quite often the superior vena cava. However, practically any mediastinal structure may be involved by the fibrotic process, such as the central airways, as well as the pulmonary arteries and veins, leading to obstruction or total occlusion. The latter may be impossible to undergo proper surgical excision of the lesion, and is considered to be a real challenge to the surgeon. We herein report a case of SM that presented with arterial and venous compression. The imaging appearance was that of unilateral pulmonary edema, associated with lung collapse. The case is supplemented by a non-systematic review of the relevant literature.

Sclerosing mediastinitis causing unilateral pulmonary edema due to left atrial and pulmonary venous compression. a case report and literature review

Abstract Sclerosing mediastinitis (SM), previously named chronic fibrosing mediastinitis, is an inflammatory process that in its end-stage results to sclerosis around the mediastinal structures. SM is quite rare and has been correlated with inflammatory and autoimmune diseases, as well as malignancy. SM may either present in a mild form, with minor symptoms and a benign course or in a more aggressive form with severe pulmonary hypertension and subsequent higher morbidity and mortality. The diagnosis of SM may be difficult and quite challenging, as symptoms depend on the mediastinal structure that is mainly involved; quite often the superior vena cava. However, practically any mediastinal structure may be involved by the fibrotic process, such as the central airways, as well as the pulmonary arteries and veins, leading to obstruction or total occlusion. The latter may be impossible to undergo proper surgical excision of the lesion, and is considered to be a real challenge to the surgeon. We herein report a case of SM that presented with arterial and venous compression. The imaging appearance was that of unilateral pulmonary edema, associated with lung collapse. The case is supplemented by a non-systematic review of the relevant literature.

A rare case of giant cell lung carcinoma with intracardiac extension via the pulmonary vein and thrombus formation.

A 61-year-old man presented with dyspnea, left thoracic pain and productive cough. Chest computed tomography demonstrated a solid mass of the left upper lobe, 2.9 × 1.8 cm2 in size, which had irregular borders and appeared to infiltrate and totally occlude the upper left pulmonary vein extending up to the left atrium (LA) with thrombus formation. The patient underwent median sternotomy and left pneumonectomy, combined with LA thrombus resection under cardiopulmonary bypass (CPB) with bicaval cannulation. The LA was partially resected and the intracavitary thrombus was completely removed. The surgical margins were free of tumor cells. Episodes of embolism were not observed during surgery. The patient was successfully weaned from CPB. The postoperative course was uncomplicated. Pathological examination of the resected specimen revealed giant cell carcinoma.

NF-kB2 Genetic Variations are Significantly Associated with Non-Small Cell Lung Cancer Risk and Overall Survival.

During the last decade, a growing number of publications implicate NF-kB2 in NSCLC pathogenesis. Here, we investigated the clinical relevance of NF-kB2 single nucleotide polymorphisms (SNPs) rs7897947, rs11574852 and rs12769316 in NSCLC and their association with NF-kB2 protein and mRNA levels. Our data show that TT (rs7897947T >G) and AA (rs12769316G >A) genotypes were strongly associated with an increased risk for NSCLC (P = 0.019 and P = 0.003, respectively). Additionally, in multivariate analysis, TT (rs7897947T >G) homozygosity was associated with worse 2- and 3-year survival rates (P = 0.030 and P = 0.028, respectively), especially among patients with stages III/IV, who had worse 2, 3 and 5-year survival (P = 0.001, P = 0.022 and P = 0.035, respectively). In chemotherapy-treated patients, TT (rs12769316G >A) homozygosity was also associated with worse 2- and 3-year survival compared to G allele carriers (P = 0.006 and P = 0.014, respectively). Furthermore, rs12769316 was correlated with survival outcome of stage I and II patients (P = 0.031 and P = 0.006, respectively). Interestingly, amongst the patients who developed metastases, A allele carriers had better 5-year survival (P = 0.020). In addition, rs12769316 was associated with NF-kB2 protein (P = 0.001) and mRNA expression (P = 0.017) as well as with tumor maximum diameter (P = 0.025). Overall, this study suggests that rs7897947 and rs12769316 are involved in NSCLC susceptibility, in treatment response and in clinical outcome.

Combined Treatment With Exenatide and Cyclosporine A or Parstatin 1-26 Results in Enhanced Reduction of Infarct Size in a Rabbit Model.

Exenatide and cyclosporine A have been shown to moderately protect against myocardial reperfusion injury leading to reduction of infarct size in patients. Our objective was to investigate whether the combined treatment with exenatide (glucagon-like peptide 1 receptor agonist) and cyclosporine A or parstatin 1-26 (inhibitors of mitochondrial permeability transition pore and/or inflammation) is more beneficial than either agent alone. Rabbits underwent 40 minutes of ischemia and 120 minutes of reperfusion. Intravenous bolus administration of exenatide or cyclosporine A, 10 minutes before reperfusion, reduced infarct size by 38% (P < 0.05) and 40% (P < 0.05), and cardiac troponin I (cTnI) plasma levels by 48% (P < 0.05) and 36% (P < 0.05), respectively, compared with control. The combined administration of both agents resulted in an additive decrease of infarct size by 55% (P < 0.05) and cTnI release by 61% (P < 0.05). Also, combined treatment of exenatide and parstatin 1-26 enhanced infarct size reduction (62%, P < 0.05), compared with monotherapies (41% for parstatin 1-26, P < 0.05; 43% for exenatide, P < 0.05). In contrast, the combined administration of parstatin 1-26 and cyclosporine A canceled out the cardioprotective effects observed by monotherapies. These results suggest that, for the therapy of myocardial reperfusion injury the combined administration of exenatide and cyclosporine A or parstatin 1-26 is more effective than monotherapies and may provide advantageous clinical outcome.