The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks. NF-κB activation is a central event leading to the activation of these networks. The rol...

NF-κB activation as a pathological mechanism of septic shock and inflammation

Video-assisted thoracoscopic surgery (VATS) has gradually been implemented in thoracic surgery, and the VATS approach has now been extended to technically challenging procedures, such as segmentectomy. The definition of VATS segmentectomy is changing over time, and the repertoire of segmentectomy is getting wider with increasing reports on atypical segmentectomy. VATS segmentectomy bears surgical, oncological, and technical advantages; however, there are still areas of controversy, particularly regarding oncological outcomes. The indication of VATS segmentectomy is diverse and is used for treating lung cancer, metastatic lung tumors, or a variety of nonmalignant diseases. It is particularly valuable for the lung-sparing resection of deeply located small nodules or repeated surgery for multiple lung lesions. VATS segmentectomy requires a thorough analysis of segmental anatomy and a tailored preoperative planning with the assessment of surgical margins. Technical challenges include intraoperative navigation, methods to identify and dissect the intersegmental plane, and the prevention of air leakage. This review will discuss the present state of VATS segmentectomy, with a focus on past studies, current indications and techniques, and future view.

VATS segmentectomy: past, present, and future

Our recent findings suggest that bacteriophages (phages) may not only eliminate bacteria, but also modulate immune functions. In this communication, we demonstrate that phages may strongly inhibit human T-cell activation and proliferation as well as activation of the nuclear transcription factor NF-kappaB in response to a viral pathogen. Phage administration in vivo can diminish cellular infiltration of allogeneic skin allografts. Thus, phage treatment should be considered in antibiotic-resistant posttransplantation infections. Furthermore, phages could find a broader application in clinical transplantation.

Bacteriophages and transplantation tolerance.

In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.). Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity. Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-γ, CXCR3/CCR5 ligand, IEF genes, TNF-α, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed.

/pdf/gene-expression-profiling-in-acute-allograft-rejection-59t65wnp8r.pdf

Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis

Nuclear factor (NF)-κB is regarded as one of the most important transcription factors and plays an essential role in the transcriptional activation of pro-inflammatory cytokines, cell proliferation and survival. NF-κB can be activated via two distinct NF-κB signal transduction pathways, the so-called canonical and non-canonical pathways, and has been demonstrated to play a key role in a wide range of inflammatory diseases and various types of cancer. Much effort has been put in strategies to inhibit NF-κB activation, for example by the development of pharmacological compounds that selectively inhibit NF-κB activity and therefore would be beneficial for immunotherapy of transplantation, autoimmune and allergic diseases, as well as an adjuvant approach in patients treated with chemotherapy for cancer. Gene therapy targeting NF-κB is a promising new strategy with the potential of long-term effects and has been explored in a wide variety of diseases, ranging from cancer to transplantation medicine and autoimmune diseases. In this review we discuss recent progress made in the development of NF-κB targeted gene therapy and the evolution towards clinical application.

/pdf/gene-therapy-targeting-nuclear-factor-kappab-towards-43x5xl6k30.pdf

Gene therapy targeting nuclear factor-kappaB: towards clinical application in inflammatory diseases and cancer

Objective: Increased production of nitric oxide (NO) is known to be a marker of lung allograft rejection and lung injury. NO production is up-regulated directly or indirectly by nuclear factor-kappa B (NF-kB), a transcriptional factor of inflammatory cytokines and iNOS. We attempted to determine whether transfection of an NF-kB decoy into allografts could reduce NO production and ameliorate acute lung injury during allograft rejection. Methods: Left lung transplantation was performed in pairs of Brown Norway (RT1 n ) and Lewis (RT 1 ) rats. In Group NF (nZ6), the allografts were flushed with 20 ml of PBS solution containing a hemagglutinating virus of Japan (HVJ) liposome-ODN complex as an NF-kB decoy and preserved for 60 min at 4 8C. A scramble decoy was used in the positive control (Group S, nZ5) and simple PBS solution in the negative control (Group C, nZ5). Five days after transplantation without use of immuno-suppressants, exhaled NO, gas exchange, and graft histological rejection score were determined. Results: The exhaled NO level was significantly reduced in Group NF as compared with Group S (445G162 vs 1305G123 ppb, P!0.02), while improvements in PaO2 (197G28 vs. 60G18 mmHg, P!0.02) and rejection score (1.8G0.3 vs. 2.5G0.4) were also observed. There were no differences in these parameters between Groups S and C. Conclusions: Inhibition of NF-kB activation in the allograft by ODN decoy transfection into the donor lung ameliorated lung injury during acute allograft rejection. Our results imply a possible therapeutic target for the inflammation process in lung transplantation clinical settings. q 2004 Elsevier B.V. All rights reserved.

/pdf/attenuation-of-lung-injury-in-allograft-rejection-using-nf-23q42d8vyh.pdf

Attenuation of lung injury in allograft rejection using NF-κB decoy transfection—novel strategy for use in lung transplantation

We present two cases of desmoplastic malignant mesothelioma (DMM) with pathological, immunohistochemical, and ultrastructural features Each patient showed rapid progress and died within 1 year from appearance of the initial symptoms Macroscopically, both showed a thickened pleura replaced by a tumor that encased the lung Microscopic results of each showed that the tumors consisted of a dense fibrous area, with mild nuclear irregularities and hyperchromatism In case 1, the tumor had invaded the diaphragm, chest wall, and cardiac sac; the mass in case 2 invaded the lung and diaphragm, and distal metastases were seen in the thoracic vertebrae, meninges, and liver Ultrastructural findings in case 1 showed a few short blunt microvilli on the cell surfaces DMM is occasionally difficult to distinguish from fibrous pleurisy and solitary fibrous tumor Immunohistochemical examinations of the present cases showed the expression of cytokeratin and vimentin, and focal positive stainings of antihuman mesothelial cell antibody (HBME-1) in both, whereas CD34 and bcl2 were negative Solitary fibrous tumor was excluded Therefore, pathological, ultrastructural, and immunohistochemical findings led us a diagnosis of DMM in each case The Ki-67 labeling index (Ki-67 LI) of cases 1 and 2 was 255 and 155, respectively, both high, which suggested malignancy Widespread immunohistological panels of malignant mesothelioma were not evaluated; Immunohistological markers commonly used for the diagnosis of malignant mesothelioma were not evaluated; however, the high ki-67 LI results and positive HBME-1 staining were helpful factors for the diagnoses of DMM

Desmoplastic malignant mesothelioma: two cases and a literature review

Objective: A novel hemagglutinating virus of Japan (HVJ)-liposome-mediated gene transfer system has been shown to have benefits of a high efficiency of transfection and low immunogenicity. The aims of this study were to determine the effect of re-transfection of the HVJliposome system via the airway, and to quantify the distribution of gene expression between transtracheal and transplantation approaches. Methods: b-Galactosidase (b-gal) plasmid DNA was introduced into lung tissues using the HVJ-liposome method. Two groups of Sprague– Dawley (SD) rats received intratracheal instillation of 10 mg of the b-gal gene, once on Day 0 in 1 group (Group Tb-1, nZ4) and 3 times on Days 0–2 in another (Group Tb-3, nZ4). In a third group of SD rats (Group Tx, nZ5), an orthotopic left lung transplantation was performed after the donor lung was flushed with an HVJ-liposome complex solution and preserved for 1 h. Gene expression and distribution in lung tissue was then quantified by counting the X-gal stained cells. Results: Both the transtracheal and transplantation approaches resulted in low levels of transfection in the vascular endothelial cells (0.2G0.1 and 4.0G1.8%), respectively, but a moderate degree of transfection to the airway (11.0G7.1 and 28.0G20.7%) and alveolar cells (3.0G1.8 and 6.0G3.6%). Three repetitive injections via the airway increased gene expression in airway epithelial cells of 41.0G12.0% compared with the single administration of 11.0G4.3%. Conclusions: Our results suggest that the repeated transtracheal gene transfection using HVJ-liposome may have benefits for treatment of problems after lung transplantation. In addition, gene transfer using a flushing solution during harvest may provide an opportunity for gene manipulation in the setting of lung transplantation. q 2005 Elsevier B.V. All rights reserved.

Application of HVJ-liposome mediated gene transfer in lung transplantation—distribution and transfection efficiency in the lung

Background/aim We investigated the relationship between solid component size (SS), carcinoembryonic antigen (CEA), and standardized uptake value (SUVmax) as continuous variables and postoperative clustered circulating tumor cell (C-CTC) detection in patients with pulmonary adenocarcinoma who underwent surgery. Patients and methods C-CTC detection was the main evaluation item, which was analyzed using the receiver operating characteristic curve to calculate areas under the curves (AUCs) for the variables. Additionally, the two-year recurrence-free survival rates (2Y-RFSRs) were analyzed. Results Among the 84 patients examined, SS, CEA, and SUVmax had AUCs>0.7, and were independent. Their thresholds were 2.1 cm, 7.5 ng/ml, and 2.9, respectively. The 2Y-RFSR were significantly better in the non-C-CTC group (n=58) and in the group of patients without high levels of these predictors (n=32). Conclusion SS, CEA level, and SUVmax predicted postoperative CTC detection in pulmonary adenocarcinoma patients.

Clustered Circulating Tumor Cells in Lung Adenocarcinoma: Implications of Test Results of Continuous Variables.

A case of metachronous multiple occurrence of lung cancer with three pathological types

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