Brain metastases are a common complication of non-small-cell lung cancer (NSCLC). The role of chemotherapy in the treatment of brain metastases has not been clearly defined. Emerging case reports of ...patients with recurrent NSCLC treated as part of the Expanded Access Programme reveal that gefitinib ("Iressa", ZD1839) has clinical activity in some patients with brain metastases. Here, we describe a number of case studies documenting the response of patients with brain metastases to treatment with gefitinib. Many of these patients had quality-of-life benefits with improvement of neurological and systemic symptoms; some had a partial response of their brain metastases and even complete responses have been seen in a few patients. One case report also describes a durable long-term response with concurrent treatment with gefitinib and radiotherapy. Such results call for larger trials designed to evaluate and define the role of gefitinib in the treatment of brain metastases in NSCLC patients, either as a single agent or in combination with radiation therapy.
Lower extremity artery disease (LEAD) is an underestimated chronic vascular disease caused by the formation of atherosclerotic plaques in the lower limb arteries. The pathological processes ...underlying this disease are regulated by many various factors, including microRNAs (miRNAs). miRNAs constitute a pool of small, non-coding RNAs with a gene expression modulatory function. In the presented study, differentially expressed miRNAs were identified in peripheral blood mononuclear cells from 18 patients with LEAD compared to 10 healthy volunteers using OpenArray RT-qPCR. Sixteen miRNAs were significantly differentially expressed in the LEAD group. Four out of them, hsa-miR-138-5p, -34a-3p, -34a-5p, and -766-3p, were consistent with a previous next-generation sequencing study. The in silico analysis performed for these four miRNAs showed associations with vascular smooth muscle cells differentiation, inflammation, and apoptosis, potentially resulting from modulation of genes involved in cell cycle, cellular adhesion, and Notch signaling. The presented study expands our knowledge on the role of miRNA in the pathology of LEAD, providing potential candidates for biomarkers of this disease.
Butyrate, a short chain fatty acid produced in the colon, induces apoptosis in cancer cell lines by a sequential process involving inhibition of histone deacetylase, de novo protein synthesis and ...activation of DEVD-caspase, a major effector of apoptotic DNA fragmentation and membrane blebbing. We now show, in LIM 1215 colorectal cancer cells, that butyrate, in addition to activating DEVD-caspase and inducing apoptosis, also increases expression and cleavage of the universal cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and leads to hypo-phosphorylation of retinoblastoma protein. Accompanying these molecular changes was a progressive loss of G(0)/G(1) and S phase cells. Expression of p21 had similar kinetics to that of the essential protein required for DEVD-caspase activation, indicating parallel effects of butyrate on anti-apoptotic and pro-apoptotic mechanisms. LIM 1215 cells, which were resistant to butyrate-induced apoptosis, were selected by three cycles of exposure to butyrate and removal of floating apoptotic cells. These cells showed markedly enhanced p21 expression and were in cell cycle arrest as determined by flow cytometry. On the other hand, subsequent culture of these cells for 2-3 days in the absence of butyrate resulted in down-regulation of p21 and restoration of sensitivity to apoptosis by butyrate. Western blots of butyrate-treated cells undergoing apoptosis consistently demonstrated a 15 kDa band (p15) that was not present in control cultures. This band became apparent immediately after the onset of DEVD-caspase activation, was enriched in the floating apoptotic cell population when compared with the adherent, non-apoptotic cells and was absent in butyrate-resistant cells lacking DEVD-caspase activity. Peptide caspase inhibitors partially blocked appearance of p15. Here we show, for the first time, that p21 is a target of effector caspases in colorectal cancer cells and that the resistance to butyrate-induced apoptosis is characterized by failure of p21 cleavage.
The role of inflammasomes in chronic inflammation has been the subject of intense research in recent years. Chronic rhinosinusitis (CRS), a persistent inflammatory disease, continues to be ...investigated hoping that a clearer pathophysiologic description will guide discovery of future treatment modalities. This study investigates the role of inflammasome complexes in CRS patients with Staphylococcus aureus biofilm infection, a key culprit associated with disease severity and recalcitrance.
Sinonasal tissue samples were collected from CRS patients with (P+) and without (P-) polyps and controls. S. aureus biofilm status was obtained using fluorescence in situ hybridization and classified as biofilm positive (B+) or negative (B-). RNA was analysed using a Human Inflammasome PCR array, profiling the expression of 84 genes involved in inflammasome function.
Sixteen samples were obtained: 5 B+P+, 5 B-P- and 6 controls. Comparing B+P+ vs. controls showed the greatest number of differentially expressed genes. In particular, Absent in Melanoma 2 (AIM2) was consistently and significantly up-regulated in the B+P+ vs. B-P- and controls. In contrast, when comparing the B-P- vs. controls, no genes showed significant changes.
Our results indicate the involvement of inflammasome complexes and their signalling pathways in CRS patients with polyps and S. aureus biofilms. In particular, AIM2, activated by intracellular double-stranded DNA, is up-regulated in this group, implying that S. aureus may play a role in intracellular triggering of the inflammasome response. Studies with further patient stratification and assessing corresponding protein expression are needed to further characterize the role of inflammasomes in CRS.
We used an intracellular zinc-specific fluorophore, Zinquin, in conjunction with fluorescence video image analysis, to reveal labile zinc in pancreatic islet cells, which concentrate this metal for ...use in synthesis, storage, and secretion of insulin. Zinquin vividly demonstrated zinc in the islet cell secretory granules, which formed a brightly labeled crescent in the cytoplasm between one side of the nucleus and the plasma membrane. Lower but still appreciable amounts of zinc were detected in the remaining cytoplasm, but there was little labeling in the nucleus. Fluorescence intensity varied among islet cells, suggesting differences in zinc content. Their average fluorescence intensity greatly surpassed that of the surrounding pancreatic acinar cells in frozen sections of pancreas and in all other types of cell studied, including lymphocytes, neutrophils, fibroblasts, and erythrocytes. Less labile zinc was detected in cells of the mouse insulinoma cell line NIT-1, regardless of whether they were maintained in long-term culture in the presence or absence of exogenous extracellular zinc. Exposure of islet or insulinoma cells to a high concentration of glucose or other secretagogue decreased the content of labile zinc. Zinquin should be a useful probe for revealing changes in zinc homeostasis in islet B-cells that may be important in their dysfunction and death during diabetes.
The first clinical case of canine angiostrongylosis from Slovakia, previously infection-free country, is described. 18-month old male Bernese mountain dog living in south-eastern part of Slovakia ...showed poor health condition characterized by weight loss, irritating cough, dispnoe, intense salivation, vomiting and bilateral scleral bleeding. Two times even the acute physical collapse occurred. Blood analysis was provided and revealed increase of total protein, eosinophilia, monocytosis, and mild thrombocytopenia. Anaemia characterized by reduced number of erythrocytes and reduced levels of haemoglobin, packed cell volume and iron was also diagnosed. Larvoscopic Baermann technique revealed the presence of Angiostrongylus first stage larvae. Infected dog excreted larvae in high numbers - in 10 g of the faecal material more than 800 larvae were counted. DNA analysis using PCR confirmed the presence of Angiostrongylus vasorum species. The first clinical case of angiostrongylosis has evidenced that the new life-threatening parasitic disease of dogs has spread to the territory of Slovakia. A serious effort is therefore inevitable to increase the professional awareness and knowledge on diagnosis, treatment and prevention.
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