Her-2/neu (ErbB2) oncogene, the second member of the epidermal growth factor receptor (EGFR) family, encodes a transmembrane tyrosine kinase receptor in Her-2-positive tumors. Accumulating evidences demonstrate that signaling networks activated by EGFR and transcription factor NFjB are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF-jB activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominantnegative mutant IjB (MCF-7/ErbB2/mIjB) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF-jB activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF-jB regulation, basal and IR-induced Akt, a kinase downstream of ErbB2, was activated in MCF-7/ ErbB2 cells and inhibited by Herceptin. To identify specific genes affected by ErbB2-mediated NF-jB activation, a group of IR-responsive elements Cyclin B1, Cyclin D1, Bcl-2, Bcl/XL, BAD and BAX were evaluated. Basal levels of prosurvival elements Cyclin B1, Cyclin D1, Bcl-2 and Bcl/XL but not apoptotic BAD and BAX were upregulated in MCF-7/ErbB2 cells with striking enhancements in Bcl-2 and Bcl/XL. IR further induced Cyclin B1 and Cyclin D1 expression that was reduced by Herceptin. Bcl-2 kept a high steady level after Herceptin þ IR treatment and, in contrast to control MCF-7/Vector cells, Bcl/XL was inhibited in MCF-7/ErbB2 cells by Herceptin þ IR treatment. However, all four prosurvival proteins were downregulated by inhibition of NF-jB in MCF-7/ErbB2/mIjB cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF-jB response to IR, and that a specific prosurvival network downstream of NF-jB is triggered by treatments using anti-ErbB2 antibody combined with radiation.
Alcoholic liver disease (ALD) encompasses hepatic steatosis, which may progress to alcoholic hepatitis, fibrosis, and cirrhosis. It remains a leading cause of morbidity and mortality in the US and worldwide. The severity of liver disease correlates with plasma levels of bacterial products in patients, and experimental ALD depends on the level of gut derived bacterial products in rodents. Since intestinal decontamination and deficiency of bacterial product receptors or their downstream signaling molecules protect from alcohol-induced liver disease, bacterial translocation (BT), qualitative, and quantitative changes of the enteric microbiome are considered as being of fundamental importance in the pathogenesis of ALD. Recent enhancements in diagnostic technologies provide a better insight into these shifts. This review highlights vital events in ALD such as BT, the importance of Toll-like receptor (TLR) signaling, intestinal bacterial overgrowth (IBO), and changes in the intestinal microbiome. Furthermore, a treatment trial section of patients reviews possible future options of therapy for ALD modifying the enteric microbiome.
Introduction Most trials evaluating the efficacy of atrial fibrillation ablation report follow-up periods of 1–2 years. Long term results (> 5 years) following segmental pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) are largely unreported. Objective To evaluate the long-term efficacy of segmental PVI for the treatment of symptomatic, medically refractory, PAF. Methods Patients with paroxysmal atrial fibrillation who underwent pulmonary vein isolation at the University of California, San Diego Medical Center were evaluated retrospectively to determine the outcome of the index procedure. Of one hundred and eighteen segmental pulmonary vein isolation procedures preformed at UCSD Medical Center between January 1, 2002 and August 31, 2003, seventy-one patients who had long-term follow-up data were included. The five year outcomes were determined by last clinic encounter and telephone encounter at or after five years from the index procedure. Patients had routine clinic visits with EKGs and underwent cardiac monitoring for any complaints of symptoms suggestive of recurrent arrhythmia. Results Seventy-one patients (60±10 years, 56 male) were followed for > 5 years. After one procedure, with 12 months of follow up, sixty-one (86%) of patients were free from symptomatic atrial fibrillation (AF). After 24 months, fifty-six (79%) of patients remained free of AF. At the end of a follow up period of 63±5 months, only forty patients (56%) remained free from symptomatic atrial fibrillation after one procedure. In sixteen patients (22.5%), atrial fibrillation recurred after the second year post-ablation, with four patients recurring during the third year, four patients during the fourth year, and eight patients having their first recurrence of atrial fibrillation greater than 48 months after their index ablation procedure. Thirty-one patients underwent more than one ablation procedure (average 1.9±0.9 procedures per patient). After multiple procedures, sixty patients (84%) were arrhythmia free off medication at 63±5 months after their initial procedure. In patients who underwent more than one ablation procedure, the mean duration of follow up after the last ablation procedure was 7.5±2.1 months. Conclusions Overall five-year outcomes after segmental PVI for PAF are consistent with previously reported shorter term follow-up (≤ 2 years); however, late recurrences (>2 years) after a successful initial ablation procedure are not infrequent, and repeat ablation procedures are often required to maintain freedom from symptomatic arrhythmias. Continued long-term follow-up of patients with PAF after initially successful ablation may be warranted, especially in those patients in whom anticoagulation is discontinued.
Background: To understand the evolution of animals it is essential to have taxon sampling across a representative spread of the animal kingdom. With the recent rearrangement of most of the Bilateria into three major clades (Ecdysozoa, Lophotrochozoa and Deuterostomia) it has become clear that the Lophotrochozoa are relatively poorly represented in our knowledge of animal development, compared to the Ecdysozoa and Deuterostomia. We aim to contribute towards redressing this balance with data on the development of the muscular, nervous and ciliary systems of the annelid Pomatoceros lamarckii (Serpulidae). We compare our data with other lophotrochozoans.
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