The role of Src & ERK1/2 kinases in inspiratory resistive breathing induced acute lung injury and inflammation.

Background: Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with large negative intrathoracic pressures, due to strenuous contractions of the inspiratory muscles. IRB is shown to induce lung injury in previously healthy animals. Src is a multifunctional kinase that is activated in the lung by mechanical stress.

Inspiratory resistive breathing induces MMP-9 and MMP-12 expression in the lung.

Inspiratory resistive breathing (IRB) is characterized by large negative intrathoracic pressures and was shown to induce pulmonary inflammation in previously healthy rats. Matrix metalloproteinases (MMP)-9 and -12 are induced by inflammation and mechanical stress in the lung. We hypothesized that IRB induces MMP-9 and -12 in the lung.

Nitric oxide regulates cytokine induction in the diaphragm in response to inspiratory resistive breathing.

Resistive breathing (encountered in chronic obstructive pulmonary disease and asthma) results in cytokine upregulation and decreased nitric oxide (NO) levels in the strenuously contracting diaphragm. NO can regulate gene expression. We hypothesized that endogenously produced NO downregulates cytokine production triggered by strenuous diaphragmatic contraction.

MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress.

Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied.

Inspiratory resistive breathing induces acute lung injury.

Rationale: Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation.

Objectives: To determine the effects of resistive breathing on the healthy lung.

Nitric oxide stimulates interleukin-6 production in skeletal myotubes.

Strenuous exercise leads to the up-regulation of interleukin-6 (IL-6) production and enhanced nitric oxide (NO) release within the contracting skeletal muscles. In this study, we investigated whether NO regulates IL-6 production in C2C12 myotubes. These cells exhibited a concentration-dependent increase in IL-6 production upon stimulation with NO donors (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate), (Z)-1-[N-(3-aminopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA-NONOate), and sodium nitroprusside (SNP).

First diagnosis of factor XI deficiency in a patient with subarachnoid haemorrhage.

Aneurismal subarachnoid haemorrhage (SAH) is a devastating event affecting patients at a fairly young age and accounting for significant morbidity and mortality. Although there is progress concerning diagnostic methods and treatment, this case report might add interesting data to the current understanding of this disease and its clinical management with respect to circumstantial deficiency of the coagulation factor XI (FXI). In this report, we present a unique case of aneurismal SAH in a patient with underlying coagulation FXI deficiency which was incidentally identified after patient's admission, as routine blood tests revealed increased activated partial thromboplastin time.

Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.

DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis.

p53-dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions.

Most normal somatic cells enter a state called replicative senescence after a certain number of divisions, characterized by irreversible growth arrest. Moreover, they express a pronounced inflammatory phenotype that could contribute to the aging process and the development of age-related pathologies. Among the molecules involved in the inflammatory response that are overexpressed in senescent cells and aged tissues is intercellular adhesion molecule-1 (ICAM-1).

Association between polymorphisms in the Toll-like receptor 4, CD14, and CARD15/NOD2 and inflammatory bowel disease in the Greek population.

Aim: Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with a significant genetic background. Apart from CARD15/NOD2 gene, evidence is accumulating that molecules related to the innate immune response such as CD14 or Toll-like receptor 4 (TLR4), are involved in their pathogenesis. In further exploring the genetic background of these diseases, we investigated the variations in the CARD15/NOD2 gene (Arg702Trp, Gly908Arg and Leu1007fsinsC), and polymorphisms in the TLR4 gene (Asp299Gly and Thr399Ile) as well as in the promoter of the CD14 gene (T/C at position -159) in Greek patients with CD and UC.

Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks.

The mechanisms by which eukaryotic cells sense DNA double-strand breaks (DSBs) in order to initiate checkpoint responses are poorly understood. 53BP1 is a conserved checkpoint protein with properties of a DNA DSB sensor. Here, we solved the structure of the domain of 53BP1 that recruits it to sites of DSBs.

E2F-1 transcription factor immunoexpression is inversely associated with tumor growth in colon adenocarcinomas.

E2F-1 is an intriguing transcription factor that accumulates the integrated signal of the G1-S transition regulators. Its role in cell fate, as depicted from in vivo models and a few studies on human tissues, is a matter of debate, since it confers a tissue-specific oncogenic or tumor suppressor behavior. In the present work, in an attempt to shed light on the role of E2F-1 in colon cancer, we examined E2F-1 expression in a series of 45 colon carcinomas and we further correlated it with tumor kinetics.

Association of NOD2/CARD15 variants with Crohn's disease in a Greek population.

Objective: Single nucleotide polymorphisms in the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease (CD), but whether this susceptibility extends to all ethnic groups and geographic areas remains unknown. The aim of the present study was to evaluate the NOD2/CARD15 mutations in Greek patients with CD.

Methods: Individuals were genotyped for three NOD2/CARD15 mutations: R702W, G908R and L1007fsinsC.

Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1.

Replication licensing ensures once per cell cycle replication and is essential for genome stability. Overexpression of two key licensing factors, Cdc6 and Cdt1, leads to overreplication and chromosomal instability (CIN) in lower eukaryotes and recently in human cell lines. In this report, we analyzed hCdt1, hCdc6, and hGeminin, the hCdt1 inhibitor expression, in a series of non-small-cell lung carcinomas, and investigated for putative relations with G(1)/S phase regulators, tumor kinetics, and ploidy.

The proinflammatory phenotype of senescent cells: the p53-mediated ICAM-1 expression.

Senescent cells are characterized by the activation of the tumor suppressor protein p53 and consequently their inability to proliferate. However, their phenotype is not restricted to the exhaustion of their replicative potential, as they also exhibit a proinflammatory phenotype, which could possibly contribute to the aging process. Intercellular adhesion molecule-1 (ICAM-1) is one of the molecules involved in inflammatory response that is overexpressed in senescent cells and aged tissues.

Electron microscopy evidence that cytoplasmic localization of the p16(INK4A) "nuclear" cyclin-dependent kinase inhibitor (CKI) in tumor cells is specific and not an artifact. A study in non-small cell lung carcinomas.

It is well established that p16(INK4A) protein acts as a cell cycle inhibitor in the nucleus. Therefore, cytoplasmic localization of p16 (INK4A) usually is disregarded by investigators as nonspecific. Three recent studies reported findings that differ from the current view concerning p16(INK4A) immunohistochemical localization.

Distinct expression patterns of the transcription factor E2F-1 in relation to tumour growth parameters in common human carcinomas.

E2F-1 is a pivotal transcription factor that integrates signals from a variety of G1/S phase regulators and modulates diverse cellular functions, such as DNA synthesis, repair, mitosis, and apoptosis. Its role in cellular proliferation and apoptosis, as depicted from experimental models and limited reports in human malignancies, remains a matter of debate. Recently, in non-small cell lung cancer, it was observed that E2F-1 overexpression was associated with tumour growth, implying an 'oncogenic' effect.

Comparative evaluation of PCR assays for the robust molecular detection of Mycobacterium avium subsp. paratuberculosis.

Mycobacterium avium subsp. paratuberculosis (MAP) can cause a very serious, often-fatal disease, namely paratuberculosis, in several animal species, especially ruminants. Recently, it has also been implicated in the pathogenesis of Infectious Bowel Disease of man.

Inactivating mutations targeting the chfr mitotic checkpoint gene in human lung cancer.

A hallmark of cancer is inactivation of cell cycle checkpoints. However, very few mutations targeting mitotic checkpoint genes have been described, and in those instances, a wild-type copy of the gene was retained. chfr is a mitotic checkpoint gene that functions in early prophase delaying chromosome condensation in response to microtubule poisons.

Interferon-a2b reduces neo-microvascular density in the 'normal' urothelium adjacent to the tumor after transurethral resection of superficial bladder carcinoma.

Background: As angiogenesis represents one of the hallmarks of cancer we investigated whether intravesically administered interferon-a (IFN-a2b) reduces neo-angiogenesis in the 'normal' urothelium adjacent to the tumor in patients with superficial bladder carcinoma after complete transurethral resection (TUR) of the tumor.

Patients And Methods: In the present study 47 patients after TUR of the tumor were examined. 10 patients (group A) received no further treatment (control group); 37 patients (group B) received intravesical treatment with IFN-a2b.

p53 activates ICAM-1 (CD54) expression in an NF-kappaB-independent manner.

Intercellular adhesion molecule-1 (ICAM-1) is a crucial receptor in the cell-cell interaction, a process central to the reaction to all forms of injury. Its expression is upregulated in response to a variety of inflammatory/immune mediators, including cellular stresses. The NF-kappaB signalling pathway is known to be important for activation of ICAM-1 transcription.

The complement inhibitor CD59 and the lymphocyte function-associated antigen-3 (LFA-3, CD58) genes possess functional binding sites for the p53 tumor suppressor protein.

p53 is an oncosuppressor protein, which acts via transcriptional and non-transcriptional mechanisms. The transcriptional function of p53 is mediated by specific responsive elements. In the present study we found active responsive elements, specific for the p53 within the 5'flanking region and within the first intron of the gene encoding for the CD59 membrane inhibitor of reactive lysis, and within the first intron of the gene encoding for the CD58 membrane protein (LFA-3).

Proliferation, but not apoptosis, is associated with distinct beta-catenin expression patterns in non-small-cell lung carcinomas: relationship with adenomatous polyposis coli and G(1)-to S-phase cell-cycle regulators.

beta-catenin (beta-cat) is a versatile component of homotypic cell adhesion and signaling. Its subcellular localization and cytoplasmic levels are tightly regulated by the adenomatous polyposis coli (APC) protein. Mutations in beta-cat (exon 3) or APC (MCR) result in beta-cat aberrant overexpression that is associated with its nuclear accumulation and improper gene activation.

Transcription factor E2F-1 acts as a growth-promoting factor and is associated with adverse prognosis in non-small cell lung carcinomas.

Numerous upstream stimulatory and inhibitory signals converge to the pRb/E2F pathway, which governs cell-cycle progression, but the information concerning alterations of E2F-1 in primary malignancies is very limited. Several in vitro studies report that E2F-1 can act either as an oncoprotein or as a tumour suppressor protein. In view of this dichotomy in its functions and its critical role in cell cycle control, this study examined the following four aspects of E2F-1 in a panel of 87 non-small cell lung carcinomas (NSCLCs), previously analysed for defects in the pRb-p53-MDM2 network: firstly, the status of E2F-1 at the protein, mRNA and DNA levels; secondly, its relationship with the kinetic parameters and genomic instability of the tumours; thirdly, its association with the status of its transcriptional co-activator CBP, downstream target PCNA and main cell cycle regulatory and E2F-1-interacting molecules pRb, p53 and MDM2; and fourthly, its impact on clinical outcome.