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Background To investigate a prognostic role of gross tumor volume (GTV) changes on survival outcomes following concurrent chemoradiotherapy (CCRT) in stage III non-small-cell lung cancer (NSCLC) patients. Methods We enrolled 191 patients with stage III NSCLC from 2001 to 2009 undergoing definitive CCRT. The GTV of 157 patients was delineated at the planning CT prior to CCRT and with a follow-up CT 1 month after CCRT. We assessed the volumetric parameters of pre-treatment GTV (GTVpre) post-treatment GTV (GTVpost), and volume reduction ratio of GTV (VRR). The primary endpoint was overall survival (OS) and secondary endpoints were progressionfree survival (PFS) and locoregional progression-free survival (LRPFS). The best cut-off value was defined as that which exhibited the maximum difference between the two groups. Results The median follow-up duration was 52.7 months in surviving patients. Median survival, 3- year OS, PFS and LRPFS rates were 25.5 months, 36.4%, 23.0%, and 45.0%, respectively. The selected cut-off values were 50 cm3 for GTVpre , 20 cm3 for GTVpost , and 50% for VRR. The smaller GTVpre and GTVpost values were associated with better OS (p < 0.001 and p = 0.015) and PFS (p = 0.001 and p = 0.004), respectively, upon univariate analysis. The higher VRR of > 50% was associated with a trend toward poorer OS (p = 0.004) and PFS (p = 0.054). Upon multivariate analysis, smaller GTVpre indicated significantly improved OS (p = 0.001), PFS (p = 0.013) and LRPFS (p = 0.002), while smaller GTVpost was marginally significant for PFS (p = 0.086). Higher VRR was associated with a trend toward poorer OS (p = 0.075). Conclusions In patients with stage III NSCLC undergoing definitive CCRT, GTVpre was an independent prognostic factor of survival. Notably, improved outcome was not correlated with higher VRR after short-term follow-up with CT alone. [ABSTRACT FROM AUTHOR]

Most vestibular schwannoma is hypovascular with well known poor tumor staining in cerebral angiography. However, hypervascular vestibular schwannoma might be observed as a rare subtype with increased risk of bleeding during surgery. Multimodal imaging features which represent hypervascularity of the tumor can be observed in hypervascular vestibular schwannoma. Here we report a case of hypervascular vestibular schwannoma with brief literature review. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether triple negative (TN) early stage breast cancers have poorer survival rates compared with other molecular types. Materials and Methods: Between August 2000 and July 2006, patients diagnosed with stage I, II early stage breast cancers, in whom all three markers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor [HER]-2) were available and treated with modified radical mastectomy or breast conserving surgery followed by radiotherapy, were retrospectively reviewed. Results: Of 446 patients, 94 (21.1%) were classified as TN, 57 (12.8%) as HER-2 type, and 295 (66.1%) as luminal. TN was more frequently associated with young patients younger than 35 years old (p = 0.002), higher histologic grade (p < 0.0001), and nuclear (p < 0.0001). The median follow-up period was 78 months (range, 4 to 130 months). There were 9 local relapses (2.0%), 15 nodal (3.4%), 40 distant metastases (9.0%), and 33 deaths (7.4%) for all patients. The rates of 5-year OS, DFS, LFS, and DMFS for all patients were 95.5%, 89.9%, 95.4%, and 91.7%, respectively. There were no significant differences in OS, DFS, LFS, and DMFS between triple negative and other subtypes (p > 0.05). Conclusion: We found that patients with TN early stage breast cancers had no difference in survival rates compared with other molecular subtypes. Prospective study in homogeneous treatment group will need for a prognosis of TN early stage breast cancer. [ABSTRACT FROM AUTHOR]

To investigate the relationship between the linker length and the catalytic activities of metal-decorated CNTs, three samples were prepared with different linker molecules, viz.NaSH, HSCH2CH2SH, and C2H2N2S3. The structures of the prepared samples were characterized using transmission electron microscopy (TEM), powder X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The analysis of the TEM images and XRD patterns showed that the Pd nanoparticles strongly adhered to the outside of the CNTs, with average particle sizes of ∼3 nm, ∼5 nm, and ∼6 nm for samples A, B and C, respectively. The XPS spectra revealed that the Pd species on the Pd-decorated CNTs consisted of Pd0, Pd2+and Pd4+. The oxidized Pd species were formed by the interaction of the electron-donor Pd0atoms with the electrophilic neighboring protons (H+) during the sample preparation. The oxidized Pd species become more abundant with increasing linker length, causing a decrease of their catalytic activities in organic and electrocatalytic reactions. Nevertheless, all of the samples exhibited higher activity in organic and electrocatalytic reactions than that of the reference systems. [ABSTRACT FROM AUTHOR]

OBJECTIVE--The adipocyte-derived secretory protein adiponectin has been widely studied and shown to have potent insulin-sensitizing, antiapoptotic, and anti-inflammatory properties. While its biosynthesis is well understood, its fate, once in circulation, is less well established. RESEARCH DESIGN AND METHODS--Here, we examine the half-life of adiponectin in circulation by tracking fluorescently labeled recombinant adiponectin in the circulation, following it to its final destination in the hepatocyte. RESULTS--Despite its abundant presence in plasma, adiponectin is cleared rapidly with a half-life of ∼75 min. A more bioactive version carrying a mutation at cysteine 39 is cleared within minutes. Even though steady-state levels of adiponectin differ between male and female mice, we failed to detect any differences in clearance rates, suggesting that differences in plasma are mostly due to differential production rates. In a metabolically challenged state (high-fat diet exposure or in an ob/ob background), adiponectin levels are reduced in plasma and clearance is significantly prolonged, reflecting a dramatic drop in adiponectin production levels. CONCLUSIONS--Combined, these results show a surprisingly rapid turnover of adiponectin with multiple fat pads contributing to the plasma levels of adiponectin and clearance mediated primarily by the liver. It is surprising that despite high-level production and rapid clearance, plasma levels of adiponectin remain remarkably constant. Diabetes 58:1961-1970, 2009 [ABSTRACT FROM AUTHOR]

Adverse influences of organic contaminants on electronic devices have been studied and the results are reported. Contamination of silicon wafers by organic compounds during their manufacturing processes has been clearly demonstrated by a few surface analytical techniques. Silicon wafers were intentionally contaminated by one of the major contaminants, bis(2-ethylhexyl) phthalate; its incorporation into the silicon oxide layer during the thermal oxidation of silicon and its influences on device performances have been evaluated in detail by monitoring the breakdown voltages. During thermal oxidation of the contaminated silicon surface, the atomized carbon species produced from the pyrolysis of organic contaminants help grow the oxide thicker, expand the silicon oxide lattice, and degrade the silicon oxide, which was shown by transmission electron microscopy and secondary ion mass spectroscopy, and finally exert adverse influences on the device performance. [ABSTRACT FROM AUTHOR]

Whereas NF-κB has potent antiapoptotic function in most cell types, it was reported that in pancreatic β cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of β cell NF-κB in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of IκBα in pancreatic β cells (RIP-mlκBα mice). β cells of these mice were more susceptible to killing by TNF-α plus IFN-γ but more resistant to IL-1β plus IFN-γ titan normal β cells. Similar results were obtained with β cells lacking IκB kinase β, a protein kinase required for NF-κB activation. Inhibition of β cell NF-κB accelerated the development of autoimmune diabetes in nonobese diabetic mice but had no effect on glucose tolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4+ T cells was accelerated in RIP-mlκBα/nonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-κB is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-κB in IL-1β-stimulated β cells. [ABSTRACT FROM AUTHOR]

Objectives: To examine the molecular mechanisms involved in the -lactam resistance of multidrug-resistant Proteus mirabilis isolates that showed an unusual synergy between imipenem and ceftazidime in a Korean hospital.Methods: Over an 11?month period, a total of 12 P. mirabilis isolates showing resistance to ampicillin, gentamicin, ceftazidime, cefotaxime, cefuroxime, cefalothin, cefepime, piperacillin, trimethoprim/sulfamethoxazole and ciprofloxacin, were recovered from the sputum and urine specimens of nine patients who were hospitalized in the neurosurgery ward. The extended-spectrum -lactamases were screened with a double disc synergy test using ceftazidime, cefotaxime, aztreonam, cefepime and clavulanate. The ESBL types were determined by PCR using specific primers for blaTEM-1, blaSHV-1, blaCTX-M-1, blaCTX-M-2, blaCTX-M-8, blaCTX-M-9, blaPER-1, blaGES-1, blaVEB-1, blaOXA-10 and blaOXA-13 followed by sequencing. All the isolates underwent molecular typing by PFGE. The transferability was examined by conjugation.Results and conclusions: All the isolates showed a marked synergy between the extended-spectrum cephalosporins and clavulanate together with an unusual synergy between cefoxitin and the cephalosporins (cefalothin, cefuroxime, ceftazidime, cefotaxime) and between imipenem, and ceftazidime and cefotaxime. Isoelectric focusing of the crude bacterial extracts showed a -lactamase band with a pI value of 5.4, which was inhibited by clavulanate. PCR and sequencing identified the gene to be blaVEB-1. In addition, the aadB gene was detected, conferring aminoglycoside resistance. The resistance was not transferred by conjugation. The outbreak was of a clonal origin as shown by PFGE demonstrating an identical banding pattern. This is the first report of VEB-1-producing Enterobacteriaceae in Korea. [ABSTRACT FROM AUTHOR]

Presents a study on the resistance of mitochondrial DNA-deficient cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Role of mitochondrial function in TRAIL-induced apoptosis; Morphological changes of mitochondria after TRAIL treatment; Effect of mitochondrial DNA depletion on cytochrome c translocation.

Human soluble Fas ligand (sFasL) has an apoptotic activity in contrast to murine sFasL. The physiological function of human sFasL is not known, while the pathological consequence of sFasL overproduction has been reported. To understand the physiological function of (human) sFasL, murine and human lymphocytes were treated with sFasL. sFasL treatment significantly decreased CD45RB lo "memory" CD4+ lymphocyte fraction and increased propidium iodide (PI)+ apoptotic CD45RB lo CD4+ lymphocytes among murine peripheral lymphocytes. However, sFasL treatment neither decreased CD45RO+ "memory" CD4+ lymphocyte fraction nor increased PI+ CD45RO+CD4+ lymphocytes among human peripheral lymphocytes, suggesting that the deletion of memory cells by sFasL had already occurred in vivo . Patients with systemic lupus erythematosus had sFasL-susceptible "memory" cell fraction suggesting an incomplete deletion of such "memory" cells. These results suggest that the physiological function of human sFasL is to delete the potentially auto-reactive "memory" lymphocytes, which complements membrance FasL (mFasL)-mediated deletion of auto-reactive cells in human beings but not in mice. [ABSTRACT FROM AUTHOR]

PPARγ agonists are anti-hyperglycemia agents acting primarily through the adipocyte. Upon activation, PPARγ stimulates adipocyte differentiation, regulates the expression of genes involved in lipid metabolism and storage, and increases the expression and secretion of the adipokine adiponectin. Mice expressing the adiponectin transgene or injected with exogenous adiponectin protein have improved metabolic profiles characterized by increased hepatic insulin sensitivity reminiscent of PPARγagonist treatment. In fact, recent studies with adiponectin null mice have demonstrated that adiponectin partially mediates the anti-hyperglycemic action of PPARγ agonists. Here, we have injected C57B1/6J male mice with adiponectin protein (2µg/g each, 10am and 6pm on day 1, 10am on day 2) or treated them with a PPARγ full agonist (COOH, 10mpk or 30mpk by oral gavage daily for 7 days) and profiled their liver and adipose transcriptomes. In liver, an adiponectin-dependent PPARγ agonist signature was identified that included a number of genes regulated by adiponectin protein injection. Notably, adiponectin injection elicited a robust down-regulation of immunoregulatory genes (eg. Cc12, Cc13). In white adipose tissue (WAT), PPARγagonists produced a large signature which was adiponectin-independent thus demonstrating that the peptide does not generally mediate the major activities of such ligands at their primary site of action (eg. Acadvl, Acaa2). Nevertheless, we identified a common PPARγ/adiponectin WAT signature that was significantly enriched for down-regulated immunoregulatory genes, possibly due, at least in part, to the reversal of macrophage infiltration as has been associated with the insulin resistant state (eg. CD68, CD14). [ABSTRACT FROM AUTHOR]

: Objectives We investigated the occurrence and mechanism of amikacin resistance and its association with various β-lactamase genes in Pseudomonas aeruginosa isolates. : Methods Of the total 250 consecutive, non-duplicated isolates of P. aeruginosa, 55 isolates showed amikacin resistance. PCR amplification of genes for aminoglycoside (AG)-modifying enzymes [aac(3)-I, aac(3)-II/VI, aac(3)-III/IV, aac(6′)-I, aac(6′)-II, ant(2″)-I, ant(4′)-II and aph(3′)-VI], 16S rRNA methylases (rmtA, rmtB, rmtC and armA) and class 1 integrons was performed. In addition, we analysed the association of AG resistance genes with various β-lactamase genes. : Results and conclusions In Korea, the amikacin resistance rate in P. aeruginosa was high (22%), and it varied among provinces (3.8% to 40%). Four types of AG-modifying enzyme genes [aph(3′)-VI, ant(2″)-I, aac(6′)-I and aac(3)-II/VI] were found in 48 isolates. Thirty-six strains harboured two or more types of enzymes, of which a combination of aph(3′)-VI and ant(2″)-I was the most frequent (24/36 isolates, 66.7%). None harboured aac(3)-I, aac(3)-III/IV, aac(6′)-II, ant(4′)-II, rmtA, rmtB, rmtC or armA. Forty-two isolates co-harboured β-lactamase genes (mostly blaOXA-10). A class 1 integron was detected in all but one, and all the ant(2″)-I and 26/29 blaOXA-10 were found in it. In contrast, aph(3′)-VI was not found to be associated with the class 1 integron. Considering the possibility of co-selection and dissemination, constant monitoring of resistance evolution is necessary. [ABSTRACT FROM AUTHOR]

The contribution of adiponectin to insulin's indirect effects on hepatic glucose production (HGP) is unclear, as is the mechanism by which insulin regulates adiponectin action. We previously characterized insulin receptor (Insr) transgenic/knockout mice (referred to as L1). These mice express Insr in liver, brain and β cells only. L1 mice are resistant to insulin inhibition of HGP, indicating that insulin's indirect effects on HGP are predominant in this model. The combination of defective insulin inhibition of HGP and adipose Insr deficiency makes L1 mice an excellent model to examine how adipose insulin resistance affects adiponectin production and its contribution to insulin's indirect effects on HGP. We have shown that L1 mice have a 140% increase in circulating adiponectin, while levels of leptin, resistin and other inflammatory cytokines are similar to WT. The correlation between hyperadiponectinemia and hyperinsulinemia in L1 mice is suggestive of a state of "adiponectin resistance". Indeed, adiponectin treatment lowered plasma glucose levels and caused phosphorylation of hepatic AMPK in control mice, but failed to do so in L1 mice. In contrast, basal AMPK phosphorylation levels were elevated in L1 mouse liver compared to WT, likely due to chronic hyperadiponectinemia. We did not observe changes in mRNA levels of adiponectin receptors (AdipoR) 1 and 2. These data suggest that adiponectin contributes to insulin's indirect effects on HGP, while insulin signaling regulates adiponectin sensitivity. We therefore propose that impaired insulin signaling in adipose tissue results in increased adiponectin levels, which in turn enhances systemic insulin sensitivity primarily by increasing insulin's indirect effects on HGP. In summary, our data establish a model of adiponectin resistance and provide evidence for an important role of adiponectin in insulin's indirect effects on HGP regulation. [ABSTRACT FROM AUTHOR]

Adiponectin is a secretory protein abundantly secreted from adipocytes. It assembles into a number of different higher-order complexes. Adipocytes maintain tight control over circulating plasma levels, suggesting the existence of a complex, highly regulated biosynthetic pathway. However, the critical mediators of adiponectin maturation within the secretory pathway have not been elucidated. Previously, we found that a significant portion of de novo-synthesized adiponectin is not secreted and retained in adipocytes. Here, we show that there is an abundant pool of properly folded adiponectin in the secretory pathway that is retained through thiol-mediated retention, as judged by the release of adiponectin in response to treatment of adipocytes with reducing agents. Adiponectin is covalently bound to the ER chaperone ERp44. An adiponectin mutant lacking cysteine 39 fails to stably interact with ERp44, demonstrating that this residue is the primary site mediating the covalent interaction. Another ER chaperone, Ero1-Lα, plays a critical role in the release of adiponectin from ERp44. Levels of both of these proteins are highly regulated in adipocytes and are influenced by the metabolic state of the cell. While less critical for the secretion of trimers, these chaperones play a major role in the assembly of higher-order adiponectin complexes. Our data highlight the importance of posttranslational events controlling adiponectin levels and the release of adiponectin from adipocytes. One mechanism for increasing circulating levels of specific adiponectin complexes by peroxisome proliferator-activated receptor gamma agonists may be selective upregulation of rate-limiting chaperones. [ABSTRACT FROM AUTHOR]

Compromised immunoregulation contributes to obesity and complications in metabolic pathogenesis. Here, we demonstrate that the nuclear factor of activated T cell (NFAT) group of transcription factors contributes to glucose and insulin homeostasis. Expression of two members of the NFAT family (NFATc2 and NFATc4) is induced upon adipogenesis and in obese mice. Mice with the Nfatc2-/- Nfatc4-/- compound disruption exhibit defects in fat accumulation and are lean. Nfatc2-/- Nfatc4-/- mice are also protected from diet-induced obesity. Ablation of NFATc2 and NFATc4 increases insulin sensitivity, in part, by sustained activation of the insulin signaling pathway. Nfatc2-/- Nfatc4-/- mice also exhibit an altered adipokine profile, with reduced resistin and leptin levels. Mechanistically, NFAT is recruited to the transcription loci and regulates resistin gene expression upon insulin stimulation. Together, these results establish a role for NFAT in glucose/insulin homeostasis and expand the repertoire of NFAT function to metabolic pathogenesis and adipokine gene transcription. [ABSTRACT FROM AUTHOR]

OBJECTIVES This study examined the association between lack of compensation for COVID-19-related overtime work (LCCOW) and burnout among emergency medical service (EMS) providers in Seoul, Korea. METHODS We conducted a cross-sectional survey of 693 EMS providers in Seoul, Korea. Participants were classified into 3 groups according to their experience of coronavirus disease 2019 (COVID-19)-related overtime work and LCCOW: (1) “did not experience,” (2) “experienced and was compensated,” and (3) “experienced and was not compensated.” Burnout was measured using the Korean version of the Copenhagen Burnout Inventory, which has 3 subdomains: personal burnout (PB), work-related burnout (WRB), and citizen-related burnout (CRB). Multiple linear regression was applied to examine whether LCCOW was associated with burnout after adjusting for potential confounders. RESULTS In total, 74.2% of participants experienced COVID-19-related overtime work, and 14.6% of those who worked overtime experienced LCCOW. COVID-19-related overtime work showed a statistically non-significant association with burnout. However, the association differed by LCCOW. Compared to the “did not experience” group, the “experienced and was not compensated” group was associated with PB (β=10.519; 95% confidence interval [CI], 3.455 to 17.584), WRB (β=10.339; 95% CI, 3.398 to 17.280), and CRB (β=12.290; 95% CI, 6.900 to 17.680), whereas no association was observed for the “experienced and was compensated” group. Furthermore, an analysis restricted to EMS providers who worked overtime due to COVID-19 showed that LCCOW was associated with PB (β=7.970; 95% CI, 1.064 to 14.876), WRB (β=7.276; 95% CI, 0.270 to 14.283), and CRB (β=10.000; 95% CI, 3.435 to 16.565). CONCLUSIONS This study suggests that LCCOW could be critical in worsening burnout among EMS providers who worked overtime due to COVID-19.

We have shown that mitochondrial DNA-depleted (ρ0) SK-Hep1 hepatoma cells are resistant to apoptosis, contrary to previous papers reporting normal apoptotic susceptibility of ρ0 cells. We studied the changes of gene expression in SK-Hep1 ρ0 cells. DNA chip analysis showed that MnSOD expression was profoundly increased in ρ0 cells. O2... contents increased during pO cell derivation but became normalized after establishment of ρ0 phenotypes, suggesting that MnSOD induction is an adaptive process to increased O2.... ρ0 cells were resistant to menadione, paraquat, or doxorubicin, and O2... contents after treatment with them were lower in ρ0 cells compared with parental cells because of MnSOD overexpression. Expression levels and activity of glutathione peroxidases were also increased in ρ0 cells, rendering them resistant to exogenous H2O2. ρ0 cells were resistant to p53, and intracellular ROS contents after p53 expression were lower compared with parental cells. Other types of ρ0 cells also showed increased MnSOD expression and resistance against ROS. Heme oxygenase-1 expression was increased in ρ0 cells, and a heme oxygenase-1 inhibitor decreased the induction of MnSOD in ρ0 cells and their resistance against ROS donors. These results indicate that ρ0 cells are resistant to cell death contrary to previous reports and suggest that an adaptive increase in the expression of antioxidant enzymes renders cancer cells or aged cells with frequent mitochondrial DNA mutations to resist against oxidative stress, host anti-cancer surveillance, or chemotherapeutic agents, conferring survival advantage on them. [ABSTRACT FROM AUTHOR]

Insulin resistance, hyperlipidemia, and cardiovascular complications are common dysregulations of metabolic syndrome. Transplant patients treated with immunosuppressant drugs such as cyclosporine A (CsA), an inhibitor of calcineurin phosphatase, frequently develop similar metabolic complications. Although calcineurin is known to mediate insulin sensitivity by regulating β-cell growth and adipokine gene transcription, its role in lipid homeostasis is poorly understood. Here, we examined lipid homeostasis in mice lacking calcineurin Aβ (CnAβ-/-). We show that mice lacking calcineurin Aβ are hyperlipidemic and develop age-dependent insulin resistance. Hyperlipidemia found in CnAβ-/- mice is, in part, due to increased lipolysis in adipose tissues, a process mediated by β-adrenergic G-protein-coupled receptor signaling pathways. CnAβ-/- mice also exhibit additional pathophysiological phenotypes caused by the potentiated GPCR signaling pathways. A cell autonomous mechanism with sustained cAMP/PKA activation is found in CnAβ-/- mice or upon CsA treatment to inhibit calcineurin. Increased PKA activation and cAMP accumulation in CnAβ-/- mice, however, are sensitive to phosphodiesterase inhibitor. Indeed, we show that calcineurin regulates degradation of phosphodiesterase 3B, in addition to phosphodiesterase 4D. These results establish a role for calcineurin in lipid homeostasis. These data also indicate that potentiated cAMP signaling pathway may provide an alternative molecular pathogenesis for the metabolic complications elicited by CsA in transplant patients. [ABSTRACT FROM AUTHOR]