bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia
Authors: Kavanagh E , Rodhe J , Burguillos M A , Venero J L , Joseph B 
Published: December 2014

AbstractThe activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders.
Heme oxygenase-1 protects against Alzheimer’s amyloid-β1-42-induced toxicity via carbon monoxide production
Authors: Hettiarachchi N , Dallas M , Al-Owais M , Griffiths H , Hooper N , Scragg J , Boyle J , Peers C 
Published: December 2014

AbstractHeme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer’s disease, catabolises heme to biliverdin, Fe2+ and carbon monoxide (CO). CO can protect neurones from oxidative stress-induced apoptosis by inhibiting Kv2.1 channels, which mediates cellular K+ efflux as an early step in the apoptotic cascade. Since apoptosis contributes to the neuronal loss associated with amyloid β peptide (Aβ) toxicity in AD, we investigated the protective effects of HO-1 and CO against Aβ1-42 toxicity in SH-SY5Y cells, employing cells stably transfected with empty vector or expressing the cellular prion protein, PrPc, and rat primary hippocampal neurons. Aβ1-42 (containing protofibrils) caused a concentration-dependent decrease in cell viability, attributable at least in part to induction of apoptosis, with the PrPc-expressing cells showing greater susceptibility to Aβ1-42 toxicity. Pharmacological induction or genetic over-expression of HO-1 significantly ameliorated the effects of Aβ1-42. The CO-donor CORM-2 protected cells against Aβ1-42 toxicity in a concentration-dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-Aβ1-42 treatment suggesting that K+ channel activity is unaffected in these cells. Instead, Aβ toxicity was reduced by the L-type Ca2+ channel blocker nifedipine, and by the CaMKKII inhibitor, STO-609. Aβ also activated the downstream kinase, AMP-dependent protein kinase (AMPK). CO prevented this activation of AMPK. Our findings indicate that HO-1 protects against Aβ toxicity via production of CO. Protection does not arise from inhibition of apoptosis-associated K+ efflux, but rather by inhibition of AMPK activation, which has been recently implicated in the toxic effects of Aβ. These data provide a novel, beneficial effect of CO which adds to its growing potential as a therapeutic agent.
XIAP-targeting drugs re-sensitize PIK3CA-mutated colorectal cancer cells for death receptor-induced apoptosis
Authors: Ehrenschwender M , Bittner S , Seibold K , Wajant H 
Published: December 2014

AbstractMutations in the oncogenic PIK3CA gene are found in 10–20% of colorectal cancers (CRCs) and are associated with poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic TRAIL death receptor antibodies emerged as promising anti-neoplastic therapeutics, but to date failed to prove their capability in the clinical setting as especially primary tumors exhibit high rates of TRAIL resistance. In our study, we investigated the molecular mechanisms underlying TRAIL resistance in CRC cells with a mutant PIK3CA (PIK3CA-mut) gene. We show that inhibition of the constitutively active phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway only partially overcame TRAIL resistance in PIK3CA-mut-protected HCT116 cells, although synergistic effects of TRAIL plus PI3K, Akt or cyclin-dependent kinase (CDK) inhibitors could be noted. In sharp contrast, TRAIL triggered full-blown cell death induction in HCT116 PIK3CA-mut cells treated with proteasome inhibitors such as bortezomib and MG132. At the molecular level, resistance of HCT116 PIK3CA-mut cells against TRAIL was reflected by impaired caspase-3 activation and we provide evidence for a crucial involvement of the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) therein. Drugs interfering with the activity and/or the expression of XIAP, such as the second mitochondria-derived activator of caspase mimetic BV6 and mithramycin-A, completely restored TRAIL sensitivity in PIK3CA-mut-protected HCT116 cells independent of a functional mitochondrial cell death pathway. Importantly, proteasome inhibitors and XIAP-targeting agents also sensitized other CRC cell lines with mutated PIK3CA for TRAIL-induced cell death. Together, our data suggest that proteasome- or XIAP-targeting drugs offer a novel therapeutic approach to overcome TRAIL resistance in PIK3CA-mutated CRC.
Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2
Authors: Simmini Salvatore , Bialecka Monika , Huch Meritxell , Kester Lennart , van de Wetering Marc , Sato Toshiro , Beck Felix , van Oudenaarden Alexander , Clevers Hans , Deschamps Jacqueline 
Published: December 2014

AbstractThe endodermal lining of the adult gastro-intestinal tract harbours stem cells that are responsible for the day-to-day regeneration of the epithelium. Stem cells residing in the pyloric glands of the stomach and in the small intestinal crypts differ in their differentiation programme and in the gene repertoire that they express. Both types of stem cells have been shown to grow from single cells into 3D structures (organoids) in vitro. We show that single adult Lgr5-positive stem cells, isolated from small intestinal organoids, require Cdx2 to maintain their intestinal identity and are converted cell-autonomously into pyloric stem cells in the absence of this transcription factor. Clonal descendants of Cdx2null small intestinal stem cells enter the gastric differentiation program instead of producing intestinal derivatives. We show that the intestinal genetic programme is critically dependent on the single transcription factor encoding gene Cdx2.
Influence of MoO3(110) Crystalline Plane on Its Self-Charging Photoelectrochemical Properties
Authors: Lou Shi Nee , Yap Nicholas , Scott Jason , Amal Rose , Ng Yun Hau 
Published: December 2014

AbstractNanocrystalline molybdenum oxide (α-MoO3) thin films with iso-oriented crystalline layers were synthesised by the anodisation of Mo foils. Upon band-gap excitation using light illumination, α-MoO3 generates excited electrons for reductive reactions and stores some of the excited electrons in its layered crystalline structure via alkali cation intercalation. These stored electrons can be subsequently discharged from α-MoO3 to allow reductive reactions to continue to occur under non-illuminated conditions. The modulation of water concentrations in the organic/aqueous anodisation electrolytes readily produces α-MoO3 crystals with high degree of (kk0) crystallographic orientation. Moreover, these (kk0)-oriented MoO3 crystals exhibit well-developed {hk0} and {0k0} crystal facets. In this paper, we show the benefits of producing α-MoO3 thin films with defined crystal facets and an iso-oriented layered structure for in situ storing of excited charges. α-MoO3 crystals with dominant (kk0) planes can achieve fast charging and a strong balance between charge release for immediate exploitation under illuminated conditions and charge storage for subsequent utilisation in dark. In comparison, α-MoO3 crystals with dominant (0k0) planes show a preference for excited charge storage.
Evolutionary Importance of the Intramolecular Pathways of Hydrolysis of Phosphate Ester Mixed Anhydrides with Amino Acids and Peptides
Authors: Liu Ziwei , Beaufils Damien , Rossi Jean-Christophe , Pascal Robert 
Published: December 2014

AbstractAminoacyl adenylates (aa-AMPs) constitute essential intermediates of protein biosynthesis. Their polymerization in aqueous solution has often been claimed as a potential route to abiotic peptides in spite of a highly efficient CO2-promoted pathway of hydrolysis. Here we investigate the efficiency and relevance of this frequently overlooked pathway from model amino acid phosphate mixed anhydrides including aa-AMPs. Its predominance was demonstrated at CO2 concentrations matching that of physiological fluids or that of the present-day ocean, making a direct polymerization pathway unlikely. By contrast, the occurrence of the CO2-promoted pathway was observed to increase the efficiency of peptide bond formation owing to the high reactivity of the N-carboxyanhydride (NCA) intermediate. Even considering CO2 concentrations in early Earth liquid environments equivalent to present levels, mixed anhydrides would have polymerized predominantly through NCAs. The issue of a potential involvement of NCAs as biochemical metabolites could even be raised. The formation of peptide–phosphate mixed anhydrides from 5(4H)-oxazolones (transiently formed through prebiotically relevant peptide activation pathways) was also observed as well as the occurrence of the reverse cyclization process in the reactions of these mixed anhydrides. These processes constitute the core of a reaction network that could potentially have evolved towards the emergence of translation.
Modelling of dual three‐phase permanent magnet brushless machine and drive using matrix and tensor approach
Authors: Luo Zhanqiang , Liang Deliang , Ding Wen 
Published: December 2014

The advent of electrically powered actuation system (EPAS) promises improved reliability, controllability and efficiency as well as reduced maintenance in high‐power applications that have historically been serviced by hydraulic systems. Dual three‐phase permanent magnet brushless machine (DTPPMBLM) is the key subsystem in EPAS. The strong mutual coupling and nonlinearity of DTPPMBLM as well as its drive make it very difficult to obtain a comprehensive mathematical model. This paper proposes a new method to modelling the DTPPMBLM and drive based on the matrix and tensor approach (MTA). The magnetic equivalent circuit (MEC) is used to model the magnetic field of DTPPMBLM. The switching mode of the converter is analysed and modelled theoretically, based on which the DTPPMBLM and drive is coupled with MTA. Then, the MTA and two dimensional finite element analysis (2D‐FEA) model are used to simulate the various steady‐state and transient performances of the 2 × 1.8 kW DTPPMBLM. Comparison of the simulation results verifies the feasibility of MTA. The results suggest that MTA may be an efficient approach for the DTPPMBLM and drive. The experimental results are reported to show that the modelling scheme has good estimation performance under different operation conditions of the DTPPMBLM.
Exophiala angulospora Causes Systemic Mycosis in Atlantic Halibut: a Case Report
Authors: Overy David P. , Groman David , Giles Jan , Duffy Stephanie , Rommens Mellisa , Johnson Gerald 
Published: December 2014

Abstract
Filamentous black yeasts from the genus Exophiala are ubiquitous, opportunistic pathogens causing both superficial and systemic mycoses in warm- and cold-blooded animals. Infections by black yeasts have been reported relatively frequently in a variety of captive and farmed freshwater and marine fishes. In November 2012, moribund and recently dead, farm-raised Atlantic Halibut Hippoglossus hippoglossus were necropsied to determine the cause of death. Histopathology revealed that three of seven fish were affected by a combination of an ascending trans-ductual granulomatous mycotic nephritis, necrotizing histiocytic encephalitis, and in one fish the addition of a fibrogranulomatous submucosal branchitis. Microbial cultures of kidney using selective mycotic media revealed pure growth of a black-pigmenting septated agent. Application of molecular and phenotypic taxonomy methodologies determined that all three isolates were genetically consistent with Exophiala angulospora. This is the first report of E. angulospora as the causal agent of systemic mycosis in Atlantic Halibut.
Received January 27, 2014; accepted July 23, 2014
Gene expression profiling of coelomic cells and discovery of immune-related genes in the earthworm, Eisenia andrei, using expressed sequence tags
Authors: Tak Eun Sik , Cho Sung-Jin , Park Soon Cheol 
Published: December 2014

Abstract
The coelomic cells of the earthworm consist of leukocytes, chlorogocytes, and coelomocytes, which play an important role in innate immunity reactions. To gain insight into the expression profiles of coelomic cells of the earthworm, Eisenia andrei, we analyzed 1151 expressed sequence tags (ESTs) derived from the cDNA library of the coelomic cells. Among the 1151 ESTs analyzed, 493 ESTs (42.8%) showed a significant similarity to known genes and represented 164 unique genes, of which 93 ESTs were singletons and 71 ESTs manifested as two or more ESTs. From the 164 unique genes sequenced, we found 24 immune-related and cell defense genes. Furthermore, real-time PCR analysis showed that levels of lysenin-related proteins mRNA in coelomic cells of E. andrei were upregulated after the injection of Bacillus subtilis bacteria. This EST data-set would provide a valuable resource for future researches of earthworm immune system.
Contingency Management Facilitates the Use of Postexposure Prophylaxis Among Stimulant-Using Men Who Have Sex With Men
Authors: Landovitz Raphael J. , Fletcher Jesse B. , Shoptaw Steven , Reback Cathy J. 
Published: December 2014

Abstract
Background.  Stimulant-using men who have sex with men (MSM) are at high risk of human immunodeficiency virus (HIV) acquisition. Contingency Management (CM) is a robust substance abuse intervention that provides voucher-based incentives for stimulant-use abstinence.
Methods.  We conducted a randomized controlled trial of CM with postexposure prophylaxis (PEP) among stimulant-using MSM. Participants were randomized to CM or a noncontingent “yoked” control (NCYC) intervention and observed prospectively. Generalized linear models were used to estimate the effect of CM on PEP course completion, medication adherence, stimulant use, and sexual risk behaviors.
Results.  At a single site in Los Angeles, 140 MSM were randomized to CM (n = 70) or NCYC (n = 70). Participants were 37% Caucasian, 37% African American, and 18% Latino. Mean age was 36.8 (standard deviation = 10.2) years. Forty participants (29%) initiated PEP after a high-risk sexual exposure, with a mean exposure-to-PEP time of 32.9 hours. PEP course completion was greater in the CM group vs the NCYC group (adjusted odds ratio [AOR] 7.2; 95% confidence interval {CI}, 1.1–47.9), with a trend towards improved medication adherence in the CM group (AOR, 4.3; 95% CI, 0.9–21.9).
Conclusions.  CM facilitated reduced stimulant use and increased rates of PEP course completion, and we observed a trend toward improved adherence. Participants in the CM group reported greater reductions in stimulant use and fewer acts of condomless anal intercourse than the control group. This novel application of CM indicated the usefulness of combining a CM intervention with PEP to produce a synergistic HIV prevention strategy that may reduce substance use and sexual risk behaviors while improving PEP parameters.
Spinal Peroxynitrite Contributes to Remifentanil-induced Postoperative Hyperalgesia via Enhancement of Divalent Metal Transporter 1 without Iron-responsive Element–mediated Iron Accumulation in Rats
Authors: Shu Rui-Chen , Zhang Lin-Lin , Wang Chun-Yan , Li Nan , Wang Hai-Yun , Xie Ke-Liang , Yu Yong-Hao , Wang Guo-Lin 
Published: December 2014

AbstractAbstract
Spinal cord levels of 3-nitrotyrosine, a biomarker for peroxynitrite production, were elevated after remifentanil infusion in rats. The administration of hydrogen-rich saline both reduced peroxynitrite production and reduced hyperalgesia after remifentanil infusion.

Background:
Hyperalgesia is one of the negative consequences following intraoperative analgesia with remifentanil. Peroxynitrite is a critical determinant in nociceptive process. Peroxynitrite inactivates iron-sulfur cluster that results in mitochondrial dysfunction and the release of iron, leading to mitochondrial iron accumulation. Iron accumulation mediated by divalent metal transporter 1 (DMT1) plays a key role in N-methyl-d-aspartate neurotoxicity. This study aims to determine whether peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via DMT1-mediated iron accumulation.

Methods:
Behavior testing was performed in rat model at different time points. Three-nitrotyrosine, nitrated manganese superoxide dismutase, and DMT1 with/without iron-responsive element [DMT1(+)IRE and DMT1(-)IRE] in spinal cord were detected by Western blot and immunohistochemistry. Spinal iron concentration was measured using the Perl stain and atomic absorption spectrophotometer. Hydrogen-rich saline imparting selectivity for peroxynitrite decomposition and iron chelator was applied in mechanistic study on the roles of peroxynitrite and iron, as well as the prevention of hyperalgesia.

Results:
Remifentanil induced thermal and mechanical hyperalgesia at postoperative 48 h. Compared with control, there were higher levels of 3-nitrotyrosine (mean ± SD, hyperalgesia vs. control, 1.22 ± 0.18 vs. 0.25 ± 0.05, n = 4), nitrated manganese superoxide dismutase (1.01 ± 0.1 vs. 0.19 ± 0.03, n = 4), DMT1(-)IRE (1.42 ± 0.19 vs. 0.33 ± 0.06, n = 4), and iron concentration (12.87 ± 1.14 vs. 5.26 ± 0.61 μg/g, n = 6) in remifentanil-induced postoperative hyperalgesia, while DMT1(+)IRE was unaffected. Eliminating peroxynitrite with hydrogen-rich saline protected against hyperalgesia and attenuated DMT1(-)IRE overexpression and iron accumulation. Iron chelator prevented hyperalgesia in a dose-dependent manner.

Conclusions:
Our study identifies that spinal peroxynitrite activates DMT1(-)IRE, leading to abnormal iron accumulation in remifentanil-induced postoperative hyperalgesia, while providing the rationale for the development of molecular hydrogen and “iron-targeted” therapies.
The Prognostic Significance of Facial Nerve Involvement in Carcinomas of the Parotid Gland
Authors: Terakedis Breanne E. , Hunt Jason P. , Buchmann Luke O. , Avizonis Vilija N. , Anker Christopher J. , Hitchcock Ying J. 
Published: December 2014

Importance and Background:Facial nerve (FN) palsy and perineural invasion (PNI) are adverse features in carcinomas of the parotid gland. FN sacrifice at the time of surgery is associated with significant morbidity. The role of adjuvant radiotherapy in patients with high-risk features, including FN involvement, remains unclear.Objective:Analyze the disease-free survival (DFS) and overall survival (OS) and the impact of tumor characteristics, including FN involvement, for patients treated with surgical resection for carcinoma of the parotid gland.Design:This is a retrospective chart review.Setting:University of Utah and Intermountain Healthcare, Utah.Participants:A total of 129 patients who were treated with primary surgery for nonmetastatic primary malignancies of the parotid gland from 1988 to 2006.Interventions:Parotidectomy with or without adjuvant therapy.Main Outcome(s) and Measures:Kaplan-Meier analysis was used to obtain 5-year estimates of DFS and OS. Recurrence risk factors, particularly the impact of FN involvement, were analyzed.Results:Five-year DFS and OS rates were 79% and 78%, respectively. Thirty-two (28%) patients developed recurrent disease. Disease recurrence occurred in 64% of patients with both FN palsy and PNI, in 43% with FN palsy without PNI, in 27% with only PNI, and in 16% without either feature.Conclusions and Relevance:FN involvement, particularly FN palsy, is a predictor of increased risk of recurrence and death. Radiotherapy cannot substitute for FN sacrifice in high-risk patients.
Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies
Authors: Jalal Shadia I. , Hanna Nasser , Zon Robin , Masters Gregory A. , Borghaei Hossein , Koneru Karuna , Badve Sunil , Prasad Nagendra , Somaiah Neeta , Wu Jingwei , Yu Zhangsheng , Einhorn Lawrence 
Published: December 2014

Objectives:
Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC.

Materials and Methods:
The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m2 on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m2 with increments of 5 mg/m2 per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response.

Results:
Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m2, AMR 30 mg/m2) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response.

Conclusions:
AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.