Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1).

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Harlan, Benjamin A; Pehar, Mariana; Sharma, Deep R; Beeson, Gyda; Beeson, Craig C; Vargas, Marcelo R

2016-05-13

Nicotinamide adenine dinucleotide (NAD(+)) participates in redox reactions and NAD(+)-dependent signaling pathways. Although the redox reactions are critical for efficient mitochondrial metabolism, they are not accompanied by any net consumption of the nucleotide. On the contrary, NAD(+)-dependent signaling processes lead to its degradation. Three distinct families of enzymes consume NAD(+) as substrate: poly(ADP-ribose) polymerases, ADP-ribosyl cyclases (CD38 and CD157), and sirtuins (SIRT1-7). Because all of the above enzymes generate nicotinamide as a byproduct, mammalian cells have evolved an NAD(+) salvage pathway capable of resynthesizing NAD(+) from nicotinamide. Overexpression of the rate-limiting enzyme in this pathway, nicotinamide phosphoribosyltransferase, increases total and mitochondrial NAD(+) levels in astrocytes. Moreover, targeting nicotinamide phosphoribosyltransferase to the mitochondria also enhances NAD(+) salvage pathway in astrocytes. Supplementation with the NAD(+) precursors nicotinamide mononucleotide and nicotinamide riboside also increases NAD(+) levels in astrocytes. Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Superoxide dismutase 1 (SOD1) mutations account for up to 20% of familial ALS and 1-2% of apparently sporadic ALS cases. Primary astrocytes isolated from mutant human superoxide dismutase 1-overexpressing mice as well as human post-mortem ALS spinal cord-derived astrocytes induce motor neuron death in co-culture. Increasing total and mitochondrial NAD(+) content in ALS astrocytes increases oxidative stress resistance and reverts their toxicity toward co-cultured motor neurons. Taken together, our results suggest that enhancing the NAD(+) salvage pathway in astrocytes could be a potential therapeutic target to prevent astrocyte-mediated motor neuron death in ALS. © 2016 by The American Society for Biochemistry and Molecular

Muscle type-specific responses to NAD+ salvage biosynthesis promote muscle function in Caenorhabditis elegans.

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Vrablik, Tracy L; Wang, Wenqing; Upadhyay, Awani; Hanna-Rose, Wendy

2011-01-15

Salvage biosynthesis of nicotinamide adenine dinucleotide (NAD(+)) from nicotinamide (NAM) lowers NAM levels and replenishes the critical molecule NAD(+) after it is hydrolyzed. This pathway is emerging as a regulator of multiple biological processes. Here we probe the contribution of the NAM-NAD(+) salvage pathway to muscle development and function using Caenorhabditis elegans. C. elegans males with mutations in the nicotinamidase pnc-1, which catalyzes the first step of this NAD(+) salvage pathway, cannot mate due to a spicule muscle defect. Multiple muscle types are impaired in the hermaphrodites, including body wall muscles, pharyngeal muscles and vulval muscles. An active NAD(+) salvage pathway is required for optimal function of each muscle cell type. However, we found surprising muscle-cell-type specificity in terms of both the timing and relative sensitivity to perturbation of NAD(+) production or NAM levels. Active NAD(+) biosynthesis during development is critical for function of the male spicule protractor muscles during adulthood, but these muscles can surprisingly do without salvage biosynthesis in adulthood under the conditions examined. The body wall muscles require ongoing NAD(+) salvage biosynthesis both during development and adulthood for maximum function. The vulval muscles do not function in the presence of elevated NAM concentrations, but NAM supplementation is only slightly deleterious to body wall muscles during development or upon acute application in adults. Thus, the pathway plays distinct roles in different tissues. As NAM-NAD(+) biosynthesis also impacts muscle differentiation in vertebrates, we propose that similar complexities may be found among vertebrate muscle cell types. Copyright © 2010 Elsevier Inc. All rights reserved.

Synthesizing and salvaging NAD: lessons learned from Chlamydomonas reinhardtii.

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Huawen Lin

2010-09-01

Full Text Available The essential coenzyme nicotinamide adenine dinucleotide (NAD+ plays important roles in metabolic reactions and cell regulation in all organisms. Bacteria, fungi, plants, and animals use different pathways to synthesize NAD+. Our molecular and genetic data demonstrate that in the unicellular green alga Chlamydomonas NAD+ is synthesized from aspartate (de novo synthesis, as in plants, or nicotinamide, as in mammals (salvage synthesis. The de novo pathway requires five different enzymes: L-aspartate oxidase (ASO, quinolinate synthetase (QS, quinolate phosphoribosyltransferase (QPT, nicotinate/nicotinamide mononucleotide adenylyltransferase (NMNAT, and NAD+ synthetase (NS. Sequence similarity searches, gene isolation and sequencing of mutant loci indicate that mutations in each enzyme result in a nicotinamide-requiring mutant phenotype in the previously isolated nic mutants. We rescued the mutant phenotype by the introduction of BAC DNA (nic2-1 and nic13-1 or plasmids with cloned genes (nic1-1 and nic15-1 into the mutants. NMNAT, which is also in the de novo pathway, and nicotinamide phosphoribosyltransferase (NAMPT constitute the nicotinamide-dependent salvage pathway. A mutation in NAMPT (npt1-1 has no obvious growth defect and is not nicotinamide-dependent. However, double mutant strains with the npt1-1 mutation and any of the nic mutations are inviable. When the de novo pathway is inactive, the salvage pathway is essential to Chlamydomonas for the synthesis of NAD+. A homolog of the human SIRT6-like gene, SRT2, is upregulated in the NS mutant, which shows a longer vegetative life span than wild-type cells. Our results suggest that Chlamydomonas is an excellent model system to study NAD+ metabolism and cell longevity.

Live-cell microscopy reveals small molecule inhibitor effects on MAPK pathway dynamics.

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Daniel J Anderson

Full Text Available Oncogenic mutations in the mitogen activated protein kinase (MAPK pathway are prevalent in human tumors, making this pathway a target of drug development efforts. Recently, ATP-competitive Raf inhibitors were shown to cause MAPK pathway activation via Raf kinase priming in wild-type BRaf cells and tumors, highlighting the need for a thorough understanding of signaling in the context of small molecule kinase inhibitors. Here, we present critical improvements in cell-line engineering and image analysis coupled with automated image acquisition that allow for the simultaneous identification of cellular localization of multiple MAPK pathway components (KRas, CRaf, Mek1 and Erk2. We use these assays in a systematic study of the effect of small molecule inhibitors across the MAPK cascade either as single agents or in combination. Both Raf inhibitor priming as well as the release from negative feedback induced by Mek and Erk inhibitors cause translocation of CRaf to the plasma membrane via mechanisms that are additive in pathway activation. Analysis of Erk activation and sub-cellular localization upon inhibitor treatments reveals differential inhibition and activation with the Raf inhibitors AZD628 and GDC0879 respectively. Since both single agent and combination studies of Raf and Mek inhibitors are currently in the clinic, our assays provide valuable insight into their effects on MAPK signaling in live cells.

The evolutionary portrait of metazoan NAD salvage.

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Carneiro, João; Duarte-Pereira, Sara; Azevedo, Luísa; Castro, L Filipe C; Aguiar, Paulo; Moreira, Irina S; Amorim, António; Silva, Raquel M

2013-01-01

Nicotinamide Adenine Dinucleotide (NAD) levels are essential for cellular homeostasis and survival. Main sources of intracellular NAD are the salvage pathways from nicotinamide, where Nicotinamide phosphoribosyltransferases (NAMPTs) and Nicotinamidases (PNCs) have a key role. NAMPTs and PNCs are important in aging, infection and disease conditions such as diabetes and cancer. These enzymes have been considered redundant since either one or the other exists in each individual genome. The co-occurrence of NAMPT and PNC was only recently detected in invertebrates though no structural or functional characterization exists for them. Here, using expression and evolutionary analysis combined with homology modeling and protein-ligand docking, we show that both genes are expressed simultaneously in key species of major invertebrate branches and emphasize sequence and structural conservation patterns in metazoan NAMPT and PNC homologues. The results anticipate that NAMPTs and PNCs are simultaneously active, raising the possibility that NAD salvage pathways are not redundant as both are maintained to fulfill the requirement for NAD production in some species.

New function for Escherichia coli xanthosine phophorylase (xapA): genetic and biochemical evidences on its participation in NAD+ salvage from nicotinamide

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2014-01-01

Background In an effort to reconstitute the NAD+ synthetic pathway in Escherichia coli (E. coli), we produced a set of gene knockout mutants with deficiencies in previously well-defined NAD+de novo and salvage pathways. Unexpectedly, the mutant deficient in NAD+de novo and salvage pathway I could grow in M9/nicotinamide medium, which was contradictory to the proposed classic NAD+ metabolism of E. coli. Such E. coli mutagenesis assay suggested the presence of an undefined machinery to feed nicotinamide into the NAD+ biosynthesis. We wanted to verify whether xanthosine phophorylase (xapA) contributed to a new NAD+ salvage pathway from nicotinamide. Results Additional knockout of xapA further slowed down the bacterial growth in M9/nicotinamide medium, whereas the complementation of xapA restored the growth phenotype. To further validate the new function of xapA, we cloned and expressed E. coli xapA as a recombinant soluble protein. Biochemical assay confirmed that xapA was capable of using nicotinamide as a substrate for nicotinamide riboside formation. Conclusions Both the genetic and biochemical evidences indicated that xapA could convert nicotinamide to nicotinamide riboside in E. coli, albeit with relatively weak activity, indicating that xapA may contribute to a second NAD+ salvage pathway from nicotinamide. We speculate that this xapA-mediated NAD+ salvage pathway might be significant in some bacteria lacking NAD+de novo and NAD+ salvage pathway I or II, to not only use nicotinamide riboside, but also nicotinamide as precursors to synthesize NAD+. However, this speculation needs to be experimentally tested. PMID:24506841

Developmental defects in zebrafish for classification of EGF pathway inhibitors

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Pruvot, Benoist; Curé, Yoann; Djiotsa, Joachim; Voncken, Audrey; Muller, Marc, E-mail: m.muller@ulg.ac.be

2014-01-15

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems. - Highlights: • We analyze the functions of Egf signaling on zebrafish development. • Genetic blocking of Egf expression causes cartilage, myelin and circulatory defects. • Chemical inhibition of Egf receptor function causes similar defects. • Developmental defects can reveal the specificity of Egf pathway inhibitors.

Developmental defects in zebrafish for classification of EGF pathway inhibitors

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Pruvot, Benoist; Curé, Yoann; Djiotsa, Joachim; Voncken, Audrey; Muller, Marc

2014-01-01

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems. - Highlights: • We analyze the functions of Egf signaling on zebrafish development. • Genetic blocking of Egf expression causes cartilage, myelin and circulatory defects. • Chemical inhibition of Egf receptor function causes similar defects. • Developmental defects can reveal the specificity of Egf pathway inhibitors

The evolutionary portrait of metazoan NAD salvage.

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João Carneiro

Full Text Available Nicotinamide Adenine Dinucleotide (NAD levels are essential for cellular homeostasis and survival. Main sources of intracellular NAD are the salvage pathways from nicotinamide, where Nicotinamide phosphoribosyltransferases (NAMPTs and Nicotinamidases (PNCs have a key role. NAMPTs and PNCs are important in aging, infection and disease conditions such as diabetes and cancer. These enzymes have been considered redundant since either one or the other exists in each individual genome. The co-occurrence of NAMPT and PNC was only recently detected in invertebrates though no structural or functional characterization exists for them. Here, using expression and evolutionary analysis combined with homology modeling and protein-ligand docking, we show that both genes are expressed simultaneously in key species of major invertebrate branches and emphasize sequence and structural conservation patterns in metazoan NAMPT and PNC homologues. The results anticipate that NAMPTs and PNCs are simultaneously active, raising the possibility that NAD salvage pathways are not redundant as both are maintained to fulfill the requirement for NAD production in some species.

Timber salvage economics

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Jeffrey P. Prestemon; Thomas P. Holmes

2008-01-01

Timber salvage is commonly done following natural disturbances, to recover some value from damaged forests. Decision making about salvage, however, is affected by ownership objectives, the nature of the damage agent, site factors, and the strength of the local timber market. For profit-maximizing landowners, salvage decisions must balance the cost of harvesting...

Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway

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Schwarzenberg, Johannes [David Geffen School of Medicine, University of California, Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Division, Los Angeles, CA (United States); Medical University of Vienna, Department of Pediatrics, Vienna (Austria); Radu, Caius G.; Tran, Andrew Q.; Phelps, Michael E.; Satyamurthy, Nagichettiar [David Geffen School of Medicine, University of California, Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, Los Angeles, CA (United States); Benz, Matthias; Fueger, Barbara; Czernin, Johannes; Schiepers, Christiaan [David Geffen School of Medicine, University of California, Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Division, Los Angeles, CA (United States); Witte, Owen N. [David Geffen School of Medicine, University of California, Howard Hughes Medical Institute and Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA (United States)

2011-04-15

Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway involved in the production and maintenance of a balanced pool of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis. dCK phosphorylates and therefore activates nucleoside analogs such as cytarabine, gemcitabine, decitabine, cladribine, and clofarabine that are used routinely in cancer therapy. Imaging probes that target dCK might allow stratifying patients into likely responders and nonresponders with dCK-dependent prodrugs. Here we present the biodistribution and radiation dosimetry of three fluorinated dCK substrates, {sup 18}F-FAC, L-{sup 18}F-FAC, and L-{sup 18}F-FMAC, developed for positron emission tomography (PET) imaging of dCK activity in vivo. PET studies were performed in nine healthy human volunteers, three for each probe. After a transmission scan, the radiopharmaceutical was injected intravenously and three sequential emission scans acquired from the base of the skull to mid-thigh. Regions of interest encompassing visible organs were drawn on the first PET scan and copied to the subsequent scans. Activity in target organs was determined and absorbed dose estimated with OLINDA/EXM. The standardized uptake value was calculated for various organs at different times. Renal excretion was common to all three probes. Bone marrow had higher uptake for L-{sup 18}F-FAC and L-{sup 18}F-FMAC than {sup 18}F-FAC. Prominent liver uptake was seen in L-{sup 18}F-FMAC and L-{sup 18}F-FAC, whereas splenic activity was highest for {sup 18}F-FAC. Muscle uptake was also highest for {sup 18}F-FAC. The critical organ was the bladder wall for all three probes. The effective dose was 0.00524, 0.00755, and 0.00910 mSv/MBq for {sup 18}F-FAC, L-{sup 18}F-FAC, and L-{sup 18}F-FMAC, respectively. The biodistribution of {sup 18}F-FAC, L-{sup 18}F-FAC, and L-{sup 18}F-FMAC in humans reveals similarities and differences. Differences may be explained by different probe

Salvage robotic radical prostatectomy

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Samuel D Kaffenberger

2014-01-01

Full Text Available Failure of non-surgical primary treatment for localized prostate cancer is a common occurrence, with rates of disease recurrence ranging from 20% to 60%. In a large proportion of patients, disease recurrence is clinically localized and therefore potentially curable. Unfortunately, due to the complex and potentially morbid nature of salvage treatment, radical salvage surgery is uncommonly performed. In an attempt to decrease the morbidity of salvage therapy without sacrificing oncologic efficacy, a number of experienced centers have utilized robotic assistance to perform minimally invasive salvage radical prostatectomy. Herein, we critically evaluate the existing literature on salvage robotic radical prostatectomy with a focus on patient selection, perioperative complications and functional and early oncologic outcomes. These results are compared with contemporary and historical open salvage radical prostatectomy series and supplemented with insights we have gained from our experience with salvage robotic radical prostatectomy. The body of evidence by which conclusions regarding the efficacy and safety of robotic salvage radical prostatectomy can be drawn comprises fewer than 200 patients with limited follow-up. Preliminary results are promising and some outcomes have been favorable when compared with contemporary open salvage prostatectomy series. Advantages of the robotic platform in the performance of salvage radical prostatectomy include decreased blood loss, short length of stay and improved visualization. Greater experience is required to confirm the long-term oncologic efficacy and functional outcomes as well as the generalizability of results achieved at experienced centers.

Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors.

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Andersen, Jannik N; Sathyanarayanan, Sriram; Di Bacco, Alessandra; Chi, An; Zhang, Theresa; Chen, Albert H; Dolinski, Brian; Kraus, Manfred; Roberts, Brian; Arthur, William; Klinghoffer, Rich A; Gargano, Diana; Li, Lixia; Feldman, Igor; Lynch, Bethany; Rush, John; Hendrickson, Ronald C; Blume-Jensen, Peter; Paweletz, Cloud P

2010-08-04

Although we have made great progress in understanding the complex genetic alterations that underlie human cancer, it has proven difficult to identify which molecularly targeted therapeutics will benefit which patients. Drug-specific modulation of oncogenic signaling pathways in specific patient subpopulations can predict responsiveness to targeted therapy. Here, we report a pathway-based phosphoprofiling approach to identify and quantify clinically relevant, drug-specific biomarkers for phosphatidylinositol 3-kinase (PI3K) pathway inhibitors that target AKT, phosphoinositide-dependent kinase 1 (PDK1), and PI3K-mammalian target of rapamycin (mTOR). We quantified 375 nonredundant PI3K pathway-relevant phosphopeptides, all containing AKT, PDK1, or mitogen-activated protein kinase substrate recognition motifs. Of these phosphopeptides, 71 were drug-regulated, 11 of them by all three inhibitors. Drug-modulated phosphoproteins were enriched for involvement in cytoskeletal reorganization (filamin, stathmin, dynamin, PAK4, and PTPN14), vesicle transport (LARP1, VPS13D, and SLC20A1), and protein translation (S6RP and PRAS40). We then generated phosphospecific antibodies against selected, drug-regulated phosphorylation sites that would be suitable as biomarker tools for PI3K pathway inhibitors. As proof of concept, we show clinical translation feasibility for an antibody against phospho-PRAS40(Thr246). Evaluation of binding of this antibody in human cancer cell lines, a PTEN (phosphatase and tensin homolog deleted from chromosome 10)-deficient mouse prostate tumor model, and triple-negative breast tumor tissues showed that phospho-PRAS40(Thr246) positively correlates with PI3K pathway activation and predicts AKT inhibitor sensitivity. In contrast to phosphorylation of AKT(Thr308), the phospho-PRAS40(Thr246) epitope is highly stable in tissue samples and thus is ideal for immunohistochemistry. In summary, our study illustrates a rational approach for discovery of drug

The NAD+ metabolism of Leishmania, notably the enzyme nicotinamidase involved in NAD+ salvage, offers prospects for development of anti-parasite chemotherapy.

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Michels, Paul A M; Avilán, Luisana

2011-10-01

NAD+ plays multiple, essential roles in the cell. As a cofactor in many redox reactions it is key in the cellular energy metabolism and as a substrate it participates in many reactions leading to a variety of covalent modifications of enzymes with major roles in regulation of expression and metabolism. Cells may have the ability to produce this metabolite either via alternative de novo synthesis pathways and/or by different salvage pathways. In this issue of Molecular Microbiology, Gazanion et al. (2011) demonstrate that Leishmania species can only rely on the salvage of NAD+ building blocks. One of the enzymes involved, nicotinamidase, is absent from human cells. The enzyme is important for growth of Leishmania infantum and essential for establishing an infection. The crystal structure of the parasite protein has been solved and shows prospects for design of inhibitors to be used as leads for development of new drugs. Indeed, NAD+ metabolism is currently being considered as a promising drug target in various diseases and the vulnerability of Leishmania for interference of this metabolism has been proved in previous work by the same group, by showing that administration of NAD+ precursors has detrimental effect on the pathogenic, amastigote stage of this parasite. © 2011 Blackwell Publishing Ltd.

Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death

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Ozaki, Kei-ichi; Minoda, Ai; Kishikawa, Futaba; Kohno, Michiaki

2006-01-01

Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway is associated with the neoplastic phenotype of a large number of human tumor cells. Although specific blockade of the ERK pathway by treating such tumor cells with potent mitogen-activated protein kinase/ERK kinase (MEK) inhibitors completely suppresses their proliferation, it by itself shows only a modest effect on the induction of apoptotic cell death. However, these MEK inhibitors markedly enhance the efficacy of histone deacetylase (HDAC) inhibitors to induce apoptotic cell death: such an enhanced cell death is observed only in tumor cells in which the ERK pathway is constitutively activated. Co-administration of MEK inhibitor markedly sensitizes tumor cells to HDAC inhibitor-induced generation of reactive oxygen species, which appears to mediate the enhanced cell death induced by the combination of these agents. These results suggest that the combination of MEK inhibitors and HDAC inhibitors provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway is constitutively activated

In Silico Investigation of Flavonoids as Potential Trypanosomal Nucleoside Hydrolase Inhibitors

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Christina Hung Hung Ha

2015-01-01

Full Text Available Human African Trypanosomiasis is endemic to 37 countries of sub-Saharan Africa. It is caused by two related species of Trypanosoma brucei. Current therapies suffer from resistance and public accessibility of expensive medicines. Finding safer and effective therapies of natural origin is being extensively explored worldwide. Pentamidine is the only available therapy for inhibiting the P2 adenosine transporter involved in the purine salvage pathway of the trypanosomatids. The objective of the present study is to use computational studies for the investigation of the probable trypanocidal mechanism of flavonoids. Docking experiments were carried out on eight flavonoids of varying level of hydroxylation, namely, flavone, 5-hydroxyflavone, 7-hydroxyflavone, chrysin, apigenin, kaempferol, fisetin, and quercetin. Using AutoDock 4.2, these compounds were tested for their affinity towards inosine-adenosine-guanosine nucleoside hydrolase and the inosine-guanosine nucleoside hydrolase, the major enzymes of the purine salvage pathway. Our results showed that all of the eight tested flavonoids showed high affinities for both hydrolases (lowest free binding energy ranging from −10.23 to −7.14 kcal/mol. These compounds, especially the hydroxylated derivatives, could be further studied as potential inhibitors of the nucleoside hydrolases.

Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice.

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Neelakantan, Harshini; Vance, Virginia; Wetzel, Michael D; Wang, Hua-Yu Leo; McHardy, Stanton F; Finnerty, Celeste C; Hommel, Jonathan D; Watowich, Stanley J

2018-01-01

There is a critical need for new mechanism-of-action drugs that reduce the burden of obesity and associated chronic metabolic comorbidities. A potentially novel target to treat obesity and type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in cellular metabolism and energy homeostasis. To validate NNMT as an anti-obesity drug target, we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors. Membrane permeability of NNMT inhibitors was characterized using parallel artificial membrane permeability and Caco-2 cell assays. Selectivity was tested against structurally-related methyltransferases and nicotinamide adenine dinucleotide (NAD + ) salvage pathway enzymes. Effects of NNMT inhibitors on lipogenesis and intracellular levels of metabolites, including NNMT reaction product 1-methylnicotianamide (1-MNA) were evaluated in cultured adipocytes. Effects of a potent NNMT inhibitor on obesity measures and plasma lipid were assessed in diet-induced obese mice fed a high-fat diet. Methylquinolinium scaffolds with primary amine substitutions displayed high permeability from passive and active transport across membranes. Importantly, methylquinolinium analogues displayed high selectivity, not inhibiting related SAM-dependent methyltransferases or enzymes in the NAD + salvage pathway. NNMT inhibitors reduced intracellular 1-MNA, increased intracellular NAD + and S-(5'-adenosyl)-l-methionine (SAM), and suppressed lipogenesis in adipocytes. Treatment of diet-induced obese mice systemically with a potent NNMT inhibitor significantly reduced body weight and white adipose mass, decreased adipocyte size, and lowered plasma total cholesterol levels. Notably, administration of NNMT inhibitors did not impact total food intake nor produce any observable adverse effects. These results support development of small molecule NNMT inhibitors as therapeutics to

The Stringent Response Induced by Phosphate Limitation Promotes Purine Salvage in Agrobacterium fabrum.

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Sivapragasam, Smitha; Deochand, Dinesh K; Meariman, Jacob K; Grove, Anne

2017-10-31

Agrobacterium fabrum induces tumor growth in susceptible plant species. The upregulation of virulence genes that occurs when the bacterium senses plant-derived compounds is enhanced by acidic pH and limiting inorganic phosphate. Nutrient starvation may also trigger the stringent response, and purine salvage is among the pathways expected to be favored under such conditions. We show here that phosphate limitation induces the stringent response, as evidenced by production of (p)ppGpp, and that the xdhCSML operon encoding the purine salvage enzyme xanthine dehydrogenase is upregulated ∼15-fold. The xdhCSML operon is under control of the TetR family transcription factor XdhR; direct binding of ppGpp to XdhR attenuates DNA binding, and the enhanced xdhCSML expression correlates with increased cellular levels of (p)ppGpp. Xanthine dehydrogenase may also divert purines away from salvage pathways to form urate, the ligand for the transcription factor PecS, which in the plant pathogen Dickeya dadantii is a key regulator of virulence gene expression. However, urate levels remain low under conditions that produce increased levels of xdhCSML expression, and neither acidic pH nor limiting phosphate results in induction of genes under control of PecS. Instead, expression of such genes is induced only by externally supplemented urate. Taken together, our data indicate that purine salvage is favored during the stringent response induced by phosphate starvation, suggesting that control of this pathway may constitute a novel approach to modulating virulence. Because bacterial purine catabolism appears to be unaffected, as evidenced by the absence of urate accumulation, we further propose that the PecS regulon is induced by only host-derived urate.

Optimal timing of salvage radiotherapy for biochemical recurrence after radical prostatectomy: is ultra-early salvage radiotherapy beneficial?

International Nuclear Information System (INIS)

Taguchi, Satoru; Shiraishi, Kenshiro; Fukuhara, Hiroshi; Nakagawa, Keiichi; Morikawa, Teppei; Naito, Akihiro; Kakutani, Shigenori; Takeshima, Yuta; Miyazaki, Hideyo; Nakagawa, Tohru; Fujimura, Tetsuya; Kume, Haruki; Homma, Yukio

2016-01-01

The optimal timing of salvage radiotherapy for biochemical recurrence after radical prostatectomy is controversial. In particular, the prognostic significance of salvage radiotherapy delivered before a current definition of biochemical recurrence, i.e. ultra-early salvage radiotherapy, is unclear. We reviewed 76 patients with pT2-3N0M0 prostate cancer who underwent salvage radiotherapy for post-prostatectomy biochemical recurrence at the following three timings: ultra-early salvage radiotherapy (n = 20) delivered before meeting a current definition of biochemical recurrence (two consecutive prostate-specific antigen [PSA] values ≥0.2 ng/mL); early salvage radiotherapy (n = 40) delivered after meeting the definition but before PSA reached 0.5 ng/mL; and delayed salvage radiotherapy (n = 16) delivered after PSA reached 0.5 ng/mL. The primary endpoint was failure of salvage radiotherapy, defined as a PSA value ≥0.2 ng/mL. The log-rank test and Cox proportional hazards model were used for univariate and multivariate analyses, respectively. During the follow-up period (median: 70 months), four of 20 (20 %), nine of 40 (23 %) and seven of 16 (44 %) patients failed biochemically in the ultra-early, early and delayed salvage radiotherapy groups, respectively. On univariate analyses, the outcome of delayed salvage radiotherapy was worse than the others, while there was no significant difference between ultra-early and early groups. Multivariate analysis demonstrated the presence of Gleason pattern 5, perineural invasion and delayed salvage radiotherapy as independent predictors of poorer survival. No survival benefit of ultra-early salvage radiotherapy was demonstrated, whereas delayed salvage radiotherapy was associated with worse outcome as reported in previous studies. Our results may support the current recommendations that salvage radiotherapy should be undertaken after two consecutive PSA values ≥0.2 ng/mL and before reaching 0.5 ng/mL

Windthrow and salvage logging in an old-growth hemlock-northern hardwoods forest

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Lang, K.D.; Schulte, L.A.; Guntenspergen, G.R.

2009-01-01

Although the initial response to salvage (also known as, post-disturbance or sanitary) logging is known to vary among system components, little is known about longer term forest recovery. We examine forest overstory, understory, soil, and microtopographic response 25 years after a 1977 severe wind disturbance on the Flambeau River State Forest in Wisconsin, USA, a portion of which was salvage logged. Within this former old-growth hemlock-northern hardwoods forest, tree dominance has shifted from Eastern hemlock (Tsuga canadensis) to broad-leaf deciduous species (Ulmus americana, Acer saccharum, Tilia americana, Populus tremuloides, and Betula alleghaniensis) in both the salvaged and unsalvaged areas. While the biological legacies of pre-disturbance seedlings, saplings, and mature trees were initially more abundant in the unsalvaged area, regeneration through root suckers and stump sprouts was common in both areas. After 25 years, tree basal area, sapling density, shrub layer density, and seedling cover had converged between unsalvaged and salvaged areas. In contrast, understory herb communities differed between salvaged and unsalvaged forest, with salvaged forest containing significantly higher understory herb richness and cover, and greater dominance of species benefiting from disturbance, especially Solidago species. Soil bulk density, pH, organic carbon content, and organic nitrogen content were also significantly higher in the salvaged area. The structural legacy of tip-up microtopography remains more pronounced in the unsalvaged area, with significantly taller tip-up mounds and deeper pits. Mosses and some forest herbs, including Athyrium filix-femina and Hydrophyllum virginianum, showed strong positive responses to this tip-up microrelief, highlighting the importance of these structural legacies for understory biodiversity. In sum, although the pathways of recovery differed, this forest appeared to be as resilient to the compound disturbances of windthrow

SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis.

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Ferreira, Viviana P; Fazito Vale, Vladimir; Pangburn, Michael K; Abdeladhim, Maha; Mendes-Sousa, Antonio Ferreira; Coutinho-Abreu, Iliano V; Rasouli, Manoochehr; Brandt, Elizabeth A; Meneses, Claudio; Lima, Kolyvan Ferreira; Nascimento Araújo, Ricardo; Pereira, Marcos Horácio; Kotsyfakis, Michalis; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, Jose M C; Gontijo, Nelder F; Collin, Nicolas; Valenzuela, Jesus G

2016-01-13

Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases.

Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma.

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Terra Vleeshouwer-Neumann

Full Text Available Embryonal rhabdomyosarcoma (ERMS is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients.

SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis

OpenAIRE

Viviana P. Ferreira; Vladimir Fazito Vale; Michael K. Pangburn; Maha Abdeladhim; Antonio Ferreira Mendes-Sousa; Iliano V. Coutinho-Abreu; Manoochehr Rasouli; Elizabeth A. Brandt; Claudio Meneses; Kolyvan Ferreira Lima; Ricardo Nascimento Araújo; Marcos Horácio Pereira; Michalis Kotsyfakis; Fabiano Oliveira; Shaden Kamhawi

2016-01-01

Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the sa...

Response of HIV positive patients to the long-term salvage therapy by lopinavir/ritonavir

Czech Academy of Sciences Publication Activity Database

Prejdová, Jana; Machala, L.; Staňková, M.; Linka, M.; Brůčková, M.; Vandasová, J.; Konvalinka, Jan

2005-01-01

Roč. 33, č. 4 (2005), 319-323 ISSN 1386-6532 R&D Projects: GA MZd(CZ) NI6339 Grant - others:5th Framework(XE) QLK2-CT-2001-02360 Institutional research plan: CEZ:AV0Z4055905 Keywords : protease inhibitor * salvage therapy * resistance development Subject RIV: CE - Biochemistry Impact factor: 2.623, year: 2005

Airway necrosis after salvage esophagectomy

International Nuclear Information System (INIS)

Tanaka, Norimitsu; Hokamura, Nobukazu; Tachimori, Yuji

2010-01-01

Salvage esophagectomy is the sole curative intent treatment for patients with persistent or recurrent locoregional disease after definitive chemoradiotherapy (CRT) for esophageal carcinoma. However, salvage esophagectomy is a very high-risk operation, and airway necrosis is a fatal complication. Between 1997 and 2007, 49 patients with thoracic esophageal cancer underwent salvage esophagectomy after definitive CRT. We retrospectively compared patients with and without airway necrosis, and investigated operative procedures related to airway necrosis. Airway necrosis occurred in five patients (10.2%), of four patients (80%) died during their hospitalization. Airway necrosis seemed to be closely related to operative procedures, such as resection of bronchial artery and cervical and subcarinal lymph node dissection. Bronchogastric fistula following necrosis of gastric conduit occured in 2 patients reconstructed through posterior mediastinal route. Airway necrosis is a highly lethal complication after salvage esophagectomy. It is important in salvage esophagectomy to take airway blood supply into consideration sufficiently and to reconstruct through retrosternal route to prevent bronchogastric fistula. (author)

Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors

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Turker Mitchell S

2009-12-01

Full Text Available Abstract Background The Fanconi anemia (FA pathway is a multigene DNA damage response network implicated in the repair of DNA lesions that arise during replication or after exogenous DNA damage. The FA pathway displays synthetic lethal relationship with certain DNA repair genes such as ATM (Ataxia Telangectasia Mutated that are frequently mutated in tumors. Thus, inhibition of FANCD2 monoubiquitylation (FANCD2-Ub, a key step in the FA pathway, might target tumor cells defective in ATM through synthetic lethal interaction. Curcumin was previously identified as a weak inhibitor of FANCD2-Ub. The aim of this study is to identify derivatives of curcumin with better activity and specificity. Results Using a replication-free assay in Xenopus extracts, we screened monoketone analogs of curcumin for inhibition of FANCD2-Ub and identified analog EF24 as a strong inhibitor. Mechanistic studies suggest that EF24 targets the FA pathway through inhibition of the NF-kB pathway kinase IKK. In HeLa cells, nanomolar concentrations of EF24 inhibited hydroxyurea (HU-induced FANCD2-Ub and foci in a cell-cycle independent manner. Survival assays revealed that EF24 specifically sensitizes FA-competent cells to the DNA crosslinking agent mitomycin C (MMC. In addition, in contrast with curcumin, ATM-deficient cells are twofold more sensitive to EF24 than matched wild-type cells, consistent with a synthetic lethal effect between FA pathway inhibition and ATM deficiency. An independent screen identified 4H-TTD, a compound structurally related to EF24 that displays similar activity in egg extracts and in cells. Conclusions These results suggest that monoketone analogs of curcumin are potent inhibitors of the FA pathway and constitute a promising new class of targeted anticancer compounds.

Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors.

Science.gov (United States)

Krishnamurthy, Nithya; Kurzrock, Razelle

2018-01-01

The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog. Copyright © 2017 Elsevier Ltd. All rights reserved.

25 CFR 700.99 - Salvage value.

Science.gov (United States)

2010-04-01

... 25 Indians 2 2010-04-01 2010-04-01 false Salvage value. 700.99 Section 700.99 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES General Policies and Instructions Definitions § 700.99 Salvage value. Salvage value means the probable sale price of an...

Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD+ biosynthesis pathway and NAMPT mutation.

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Guo, Jun; Lam, Lloyd T; Longenecker, Kenton L; Bui, Mai H; Idler, Kenneth B; Glaser, Keith B; Wilsbacher, Julie L; Tse, Chris; Pappano, William N; Huang, Tzu-Hsuan

2017-09-23

Cancer cells have an unusually high requirement for the central and intermediary metabolite nicotinamide adenine dinucleotide (NAD + ), and NAD + depletion ultimately results in cell death. The rate limiting step within the NAD + salvage pathway required for converting nicotinamide to NAD + is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). Targeting NAMPT has been investigated as an anti-cancer strategy, and several highly selective small molecule inhibitors have been found to potently inhibit NAMPT in cancer cells, resulting in NAD + depletion and cytotoxicity. To identify mechanisms that could cause resistance to NAMPT inhibitor treatment, we generated a human fibrosarcoma cell line refractory to the highly potent and selective NAMPT small molecule inhibitor, GMX1778. We uncovered novel and unexpected mechanisms of resistance including significantly increased expression of quinolinate phosphoribosyl transferase (QPRT), a key enzyme in the de novo NAD + synthesis pathway. Additionally, exome sequencing of the NAMPT gene in the resistant cells identified a single heterozygous point mutation that was not present in the parental cell line. The combination of upregulation of the NAD + de novo synthesis pathway through QPRT over-expression and NAMPT mutation confers resistance to GMX1778, but the cells are only partially resistant to next-generation NAMPT inhibitors. The resistance mechanisms uncovered herein provide a potential avenue to continue exploration of next generation NAMPT inhibitors to treat neoplasms in the clinic. Copyright © 2017 Elsevier Inc. All rights reserved.

Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity

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Wynn Michelle L

2011-10-01

Full Text Available Abstract Background It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone. Results We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn "on" an otherwise "off" parallel cascade when two cascades share an upstream activator. Conclusions A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective

Role of salvage esophagectomy after definitive chemoradiotherapy

International Nuclear Information System (INIS)

Tachimori, Yuji

2009-01-01

Chemoradiotherapy has become a popular definitive therapy among many patients and oncologists for potentially resectable esophageal carcinoma. Although the complete response rates are high and short-term survival is favorable after chemoradiotherapy, persistent or recurrent locoregional disease is quite frequent. Salvage surgery is the sole curative intent treatment option for this course. As experience with definitive chemoradiotherapy grows, the number of salvage surgeries may increase. Selected articles about salvage esophagectomy after definitive chemoradiotherapy for esophageal carcinoma are reviewed. The number of salvage surgeries was significantly lower than the number of expected candidates. To identify candidates for salvage surgery, patients undergoing definitive chemoradiotherapy should be followed up carefully. Salvage esophagectomy is difficult when dissecting fibrotic masses from irradiated tissues. Patients who underwent salvage esophagectomy had increased morbidity and mortality. Pulmonary complications such as pneumonia and acute respiratory distress syndrome were common. The anastomotic leak rate was significantly increased because of the effects of the radiation administered to the tissues used as conduits. The most significant factor associated with long-term survival appeared to be complete resection. However, precise evaluation of resectability before operation was difficult. Nevertheless, increased morbidity and mortality will be acceptable in exchange for potential long-term survival after salvage esophagectomy. Such treatment should be considered for carefully selected patients at specialized centers. (author)

Integrated QSAR study for inhibitors of Hedgehog Signal Pathway against multiple cell lines:a collaborative filtering method.

Science.gov (United States)

Gao, Jun; Che, Dongsheng; Zheng, Vincent W; Zhu, Ruixin; Liu, Qi

2012-07-31

The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have proposed several

GDC-0449-a potent inhibitor of the hedgehog pathway.

Science.gov (United States)

Robarge, Kirk D; Brunton, Shirley A; Castanedo, Georgette M; Cui, Yong; Dina, Michael S; Goldsmith, Richard; Gould, Stephen E; Guichert, Oivin; Gunzner, Janet L; Halladay, Jason; Jia, Wei; Khojasteh, Cyrus; Koehler, Michael F T; Kotkow, Karen; La, Hank; Lalonde, Rebecca L; Lau, Kevin; Lee, Leslie; Marshall, Derek; Marsters, James C; Murray, Lesley J; Qian, Changgeng; Rubin, Lee L; Salphati, Laurent; Stanley, Mark S; Stibbard, John H A; Sutherlin, Daniel P; Ubhayaker, Savita; Wang, Shumei; Wong, Susan; Xie, Minli

2009-10-01

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.

ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors.

Science.gov (United States)

Goetz, Eva M; Ghandi, Mahmoud; Treacy, Daniel J; Wagle, Nikhil; Garraway, Levi A

2014-12-01

The use of targeted therapeutics directed against BRAF(V600)-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAF(V600)-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor-resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents. ©2014 American Association for Cancer Research.

Characterization of an fungal l-fucokinase involved in Mortierella alpina GDP-l-fucose salvage pathway.

Science.gov (United States)

Wang, Hongchao; Zhang, Chen; Chen, Haiqin; Yang, Qin; Zhou, Xin; Gu, Zhennan; Zhang, Hao; Chen, Wei; Chen, Yong Q

2016-08-01

GDP-l-fucose functions as a biological donor for fucosyltransferases, which are required for the catalysis of l-fucose to various acceptor molecules including oligosaccharides, glycoproteins and glycolipids. Mortierella alpina is one of the highest lipid-producing fungi and can biosynthesis GDP-l-fucose in the de novo pathway. Analysis of the M. alpina genome suggests that there is a gene encoding l-fucokinase (FUK) for the conversion of fucose to l-fucose-1-phosphate in the GDP-l-fucose salvage pathway, which has never been found in fungi before. This gene was characterized to explore its role in GDP-l-fucose synthesis. The yield of GDP-l-fucose is relatively higher in lipid accumulation phase (0.096 mg per g cell) than that in cell multiplication phase (0.074 mg per g cell) of M. alpina Additionally, the transcript level of FUK is up regulated by nitrogen exhaustion when M. alpina starts to accumulate lipid, highlights the functional significance of FUK in the GDP-l-fucose biosynthesis in M. alpina Gene encoding FUK was expressed heterologously in Escherichia coli and the resulting protein was purified to homogeneity. The product of FUK reaction was analyzed by liquid chromatography and mass spectrometry. Kinetic parameters and other properties of FUK were investigated. Comparative analyses between the FUK protein and other homologous proteins were performed. To our knowledge, this study is the first to report a comprehensive characterization of FUK in a fungus. Mortierella alpina could be used as an alternative source for the production of GDP-l-fucose. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Clinical study of salvage surgery after concurrent chemoradiotherapy

International Nuclear Information System (INIS)

Shimane, Toshikazu; Nakamura, Taisuke; Shimotatara, Yuko

2013-01-01

As the use of concurrent chemoradiotherapy (CCRT) is becoming more widespread, with numerous facilities performing it to maintain function and form, the number of cases requiring salvage surgery is also increasing. We investigated the postoperative prognosis of patients who experienced complications during salvage surgery after CCRT. Subjects were 27 patients who underwent salvage surgery following CCRT at our department during the 7-year period between January 2005 and December 2011. We selected all cases of salvage surgery, comprising neck dissections, total laryngectomies, partial laryngectomies, esophageal resections, and reconstructive surgeries, for analysis. The results were favorable, with a complication rate during salvage surgery after CCRT of 14.8% and a survival rate of 77.8%. Although it is difficult to compare these complications and outcome findings with available reports on salvage surgery without CCRT, it is believed complications can arise in approximately half of the cases. Thus, surgeons should be cognizant of the potential for serious complications, which are sometimes unexpected. Different from our findings, the prognosis following salvage surgery is generally not thought to be favorable and therefore care should be taken to detect recurrence and provide treatment early in salvage surgery cases. (author)

Tissue factor pathway inhibitor for prediction of placenta-mediated adverse pregnancy outcomes in high-risk women: AngioPred study.

Directory of Open Access Journals (Sweden)

Aurélie Di Bartolomeo

Full Text Available The study aimed to evaluate if the rate of tissue factor pathway inhibitor during pregnancy and following delivery could be a predictive factor for placenta-mediated adverse pregnancy outcomes in high-risk women.This was a prospective multicentre cohort study of 200 patients at a high risk of occurrence or recurrence of placenta-mediated adverse pregnancy outcomes conducted between June 2008 and October 2010. Measurements of tissue factor pathway inhibitor resistance (normalized ratio and tissue factor pathway inhibitor activity were performed for the last 72 patients at 20, 24, 28, 32, and 36 weeks of gestation and during the postpartum period.Overall, 15 patients presented a placenta-mediated adverse pregnancy outcome. There was no difference in normalized tissue factor pathway inhibitor ratios between patients with and without placenta-mediated adverse pregnancy outcomes during pregnancy and in the post-partum period. Patients with placenta-mediated adverse pregnancy outcomes had tissue factor pathway inhibitor activity rates that were significantly higher than those in patients without at as early as 24 weeks of gestation. The same results were observed following delivery.Among high-risk women, the tissue factor pathway inhibitor activity of patients with gestational vascular complications is higher than that in other patients. Hence, these markers could augment a screening strategy that includes an analysis of angiogenic factors as well as clinical and ultrasound imaging with Doppler measurement of the uterine arteries.

Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis.

Science.gov (United States)

Pisithkul, Tippapha; Jacobson, Tyler B; O'Brien, Thomas J; Stevenson, David M; Amador-Noguez, Daniel

2015-09-01

An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using (13)C-labeled sugars and [(15)N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. Copyright © 2015, Pisithkul et al.

Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis

Science.gov (United States)

Pisithkul, Tippapha; Jacobson, Tyler B.; O'Brien, Thomas J.; Stevenson, David M.

2015-01-01

An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using 13C-labeled sugars and [15N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. PMID:26070680

Limb salvage surgery.

Science.gov (United States)

Kadam, Dinesh

2013-05-01

The threat of lower limb loss is seen commonly in severe crush injury, cancer ablation, diabetes, peripheral vascular disease and neuropathy. The primary goal of limb salvage is to restore and maintain stability and ambulation. Reconstructive strategies differ in each condition such as: Meticulous debridement and early coverage in trauma, replacing lost functional units in cancer ablation, improving vascularity in ischaemic leg and providing stable walking surface for trophic ulcer. The decision to salvage the critically injured limb is multifactorial and should be individualised along with laid down definitive indications. Early cover remains the standard of care, delayed wound coverage not necessarily affect the final outcome. Limb salvage is more cost-effective than amputations in a long run. Limb salvage is the choice of procedure over amputation in 95% of limb sarcoma without affecting the survival. Compound flaps with different tissue components, skeletal reconstruction; tendon transfer/reconstruction helps to restore function. Adjuvant radiation alters tissue characters and calls for modification in reconstructive plan. Neuropathic ulcers are wide and deep often complicated by osteomyelitis. Free flap reconstruction aids in faster healing and provides superior surface for offloading. Diabetic wounds are primarily due to neuropathy and leads to six-fold increase in ulcerations. Control of infections, aggressive debridement and vascular cover are the mainstay of management. Endovascular procedures are gaining importance and have reduced extent of surgery and increased amputation free survival period. Though the standard approach remains utilising best option in the reconstruction ladder, the recent trend shows running down the ladder of reconstruction with newer reliable local flaps and negative wound pressure therapy.

Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

Energy Technology Data Exchange (ETDEWEB)

Sakamoto, Toshiaki; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Shu-hei [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Uesato, Shin-ichi [Department of Biotechnology, Faculty of Engineering, Kansai University, Osaka 564-8680 (Japan); Watanabe, Kazushi [Proubase Technology Inc., Kanagawa 211-0063 (Japan); Tanimura, Susumu [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Koji, Takehiko [Department of Histology and Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kohno, Michiaki, E-mail: kohnom@nagasaki-u.ac.jp [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Proubase Technology Inc., Kanagawa 211-0063 (Japan); Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501 (Japan)

2013-04-19

Highlights: •Blockade of the ERK pathway enhances the anticancer efficacy of HDAC inhibitors. •MEK inhibitors sensitize human tumor xenografts to HDAC inhibitor cytotoxicity. •Such the enhanced efficacy is achieved by a transient blockade of the ERK pathway. •This drug combination provides a promising therapeutic strategy for cancer patients. -- Abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.

Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels

NARCIS (Netherlands)

Crawley, James T. B.; Goulding, David A.; Ferreira, Valérie; Severs, Nicholas J.; Lupu, Florea

2002-01-01

Tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type, serine protease inhibitor with inhibitory activity toward activated factor XI, plasma kallikrein, plasmin, certain matrix metalloproteinases, and the tissue factor:activated factor VII complex. In this study, we investigated TFPI-2

Salvage versus amputation: Utility of mangled extremity severity score in severely injured lower limbs

Directory of Open Access Journals (Sweden)

Kumar M

2007-01-01

Full Text Available Background: The purpose of the present study was to evaluate the clinical utility of Mangled extremity severity score (MESS in severely injured lower limbs. Materials and Methods: Retrospectively 25 and prospectively 36 lower limbs in 58 patients with high-energy injuries were evaluated with the use of MESS, to assist in the decision-making process for the care of patients with such injuries. Difference between the mean MESS scores for amputated and salvaged limbs was analyzed. Results: In the retrospective study 4.65 (4.65 ± 1.32 was the mean score for the salvaged limbs and 8.80 (8.8 ± 1.4 for the amputated limbs. In the prospective study 4.53 (4.53 ± 2.44 was the mean score for the salvaged limbs and 8.83 (8.83 ± 2.34 for the amputated limbs. There was a significant difference in the mean scores for salvaged and amputated limbs. Retrospective 21 (84% and prospective 29 (80.5% limbs remained in the salvage pathway six months after the injury. Conclusion: MESS could predict amputation of severely injured lower limbs, having score of equal or more than 7 with 91% sensitivity and 98% specificity. There was a significant difference in the mean MESS scores in the prospective study (n=36, 4.53 (4.53 ± 2.44 in thirty salvaged limbs (83.33% and 8.83 (8.83 ± 2.34 in six amputated limbs (16.66% with a P -value 0.002 ( P -value < 0.01. Similarly there was a significant difference in the mean MESS score in the retrospective study (n=25, 4.65 (4.65 ± 1.32 in twenty salvaged limbs (80% and 8.80 (8.8 ± 1.4 in five amputated limbs (20% with a P -value 0.00005 ( P -value < 0.01. MESS is a simple and relatively easy and readily available scoring system which can help the surgeon to decide the fate of the lower extremity with a high-energy injury.

Limb salvage surgery

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Dinesh Kadam

2013-01-01

Full Text Available The threat of lower limb loss is seen commonly in severe crush injury, cancer ablation, diabetes, peripheral vascular disease and neuropathy. The primary goal of limb salvage is to restore and maintain stability and ambulation. Reconstructive strategies differ in each condition such as: Meticulous debridement and early coverage in trauma, replacing lost functional units in cancer ablation, improving vascularity in ischaemic leg and providing stable walking surface for trophic ulcer. The decision to salvage the critically injured limb is multifactorial and should be individualised along with laid down definitive indications. Early cover remains the standard of care, delayed wound coverage not necessarily affect the final outcome. Limb salvage is more cost-effective than amputations in a long run. Limb salvage is the choice of procedure over amputation in 95% of limb sarcoma without affecting the survival. Compound flaps with different tissue components, skeletal reconstruction; tendon transfer/reconstruction helps to restore function. Adjuvant radiation alters tissue characters and calls for modification in reconstructive plan. Neuropathic ulcers are wide and deep often complicated by osteomyelitis. Free flap reconstruction aids in faster healing and provides superior surface for offloading. Diabetic wounds are primarily due to neuropathy and leads to six-fold increase in ulcerations. Control of infections, aggressive debridement and vascular cover are the mainstay of management. Endovascular procedures are gaining importance and have reduced extent of surgery and increased amputation free survival period. Though the standard approach remains utilising best option in the reconstruction ladder, the recent trend shows running down the ladder of reconstruction with newer reliable local flaps and negative wound pressure therapy.

A Comparison of Four Year Health Outcomes following Combat Amputation and Limb Salvage

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2017-01-25

pathways that address the physical and psychological healthcare needs of such patients over time. Introduction Previous studies indicated that extremity...patients, there is a need to quan- tify and compare long-term health outcomes following amputation and limb salvage. A recent study followed the...and psychological complications. Wound complications. Wound complications selected for study were those that required prolonged surveillance

Purine salvage in the apicomplexan Sarcocystis neurona, and generation of hypoxanthine-xanthine-guanine phosphoribosyltransferase-deficient clones for positive-negative selection of transgenic parasites.

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Dangoudoubiyam, Sriveny; Zhang, Zijing; Howe, Daniel K

2014-09-01

Sarcocystis neurona is an apicomplexan parasite that causes severe neurological disease in horses and marine mammals. The Apicomplexa are all obligate intracellular parasites that lack purine biosynthesis pathways and rely on the host cell for their purine requirements. Hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) and adenosine kinase (AK) are key enzymes that function in two complementary purine salvage pathways in apicomplexans. Bioinformatic searches of the S. neurona genome revealed genes encoding HXGPRT, AK and all of the major purine salvage enzymes except purine nucleoside phosphorylase. Wild-type S. neurona were able to grow in the presence of mycophenolic acid (MPA) but were inhibited by 6-thioxanthine (6-TX), suggesting that the pathways involving either HXGPRT or AK are functional in this parasite. Prior work with Toxoplasma gondii demonstrated the utility of HXGPRT as a positive-negative selection marker. To enable the use of HXGPRT in S. neurona, the SnHXGPRT gene sequence was determined and a gene-targeting plasmid was transfected into S. neurona. SnHXGPRT-deficient mutants were selected with 6-TX, and single-cell clones were obtained. These Sn∆HXG parasites were susceptible to MPA and could be complemented using the heterologous T. gondii HXGPRT gene. In summary, S. neurona possesses both purine salvage pathways described in apicomplexans, thus allowing the use of HXGPRT as a positive-negative drug selection marker in this parasite.

Local recurrence risk after previous salvage mastectomy.

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Tanabe, M; Iwase, T; Okumura, Y; Yoshida, A; Masuda, N; Nakatsukasa, K; Shien, T; Tanaka, S; Komoike, Y; Taguchi, T; Arima, N; Nishimura, R; Inaji, H; Ishitobi, M

2016-07-01

Breast-conserving surgery is a standard treatment for early breast cancer. For ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery, salvage mastectomy is the current standard surgical procedure. However, it is not rare for patients with IBTR who have received salvage mastectomy to develop local recurrence. In this study, we examined the risk factors of local recurrence after salvage mastectomy for IBTR. A total of 118 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent salvage mastectomy without irradiation for IBTR between 1989 and 2008 were included from eight institutions in Japan. The risk factors of local recurrence were assessed. The median follow-up period from salvage mastectomy for IBTR was 4.6 years. Patients with pN2 or higher on diagnosis of the primary tumor showed significantly poorer local recurrence-free survival than those with pN0 or pN1 at primary tumor (p mastectomy for IBTR. Further research and validation studies are needed. (UMIN-CTR number UMIN000008136). Copyright © 2016 Elsevier Ltd. All rights reserved.

Plasma Tissue Factor Pathway Inhibitor Levels in Angiographically Defined Coronary Artery Disease Among Saudis

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Syed Shahid Habib

2013-05-01

Full Text Available Objectives: This study was aimed to determine plasma levels of total (TFPI-T and free (TFPI-F tissue factor pathway inhibitor, plasminogen activator inhibitor-1 (PAI-1, and tissue plasminogen activator (t-PA in a cohort of Saudi patients with chronic stable angiographically defined coronary artery disease (CAD and to determine its correlation with its severity.Methods: This cross sectional study was conducted in the department of physiology and department of cardiology, College of Medicine, and King Khalid University Hospital and King Saud University, Riyadh. Sixty known cases of CAD who had undergone angiography (35 males and 25 females were selected. A control group included 39 (20 males and 19 females healthy subjects. Fasting venous blood samples were analyzed for total (TFPI-T and free (TFPI-F tissue factor pathway inhibitor, plasminogen activator inhibitor-1 (PAI-1, and tissue plasminogen activator (t-PA. Gensini scores and vessel scores were determined for assessing CAD severity.Results: There were non-significant differences between age, body mass index (BMI and Blood pressure between the controls and CAD subjects. A comparison of hemostatic markers between control and CAD patients showed significantly higher levels of Fibrinogen, PAI-1, TFPI-T and TFPI-F in CAD patients compared to control subjects. But there was no difference in plasma t-PA levels. TFPI-T had a significant positive correlation with severity of disease determined by Gensini Scores (r=0.344; p=0.006 and vessel scores (r=0.338; p=0.015.Conclusion: Plasma levels of total tissue factor pathway inhibitor are significantly related with the presence and severity of CAD. Elevated levels of TFPI-T may be considered as useful diagnostic and prognostic markers in patients with CAD.

Small molecule inhibitors of the Candida albicans budded-to-hyphal transition act through multiple signaling pathways.

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John Midkiff

Full Text Available The ability of the pathogenic yeast Candida albicans to interconvert between budded and hyphal growth states, herein termed the budded-to-hyphal transition (BHT, is important for C. albicans development and virulence. The BHT is under the control of multiple cell signaling pathways that respond to external stimuli, including nutrient availability, high temperature, and pH. Previous studies identified 21 small molecules that could inhibit the C. albicans BHT in response to carbon limitation in Spider media. However, the studies herein show that the BHT inhibitors had varying efficacies in other hyphal-inducing media, reflecting their varying abilities to block signaling pathways associated with the different media. Chemical epistasis analyses suggest that most, but not all, of the BHT inhibitors were acting through either the Efg1 or Cph1 signaling pathways. Notably, the BHT inhibitor clozapine, a FDA-approved drug used to treat atypical schizophrenia by inhibiting G-protein-coupled dopamine receptors in the brain, and several of its functional analogs were shown to act at the level of the Gpr1 G-protein-coupled receptor. These studies are the first step in determining the target and mechanism of action of these BHT inhibitors, which may have therapeutic anti-fungal utility in the future.

Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

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Gadgeel, Shirish M; Wozniak, Antoinette

2013-07-01

Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials. Copyright © 2013 Elsevier Inc. All rights reserved.

Salvage Islet Auto Transplantation After Relaparatomy.

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Balzano, Gianpaolo; Nano, Rita; Maffi, Paola; Mercalli, Alessia; Melzi, Raffaelli; Aleotti, Francesca; Gavazzi, Francesca; Berra, Cesare; De Cobelli, Francesco; Venturini, Massimo; Magistretti, Paola; Scavini, Marina; Capretti, Giovanni; Del Maschio, Alessandro; Secchi, Antonio; Zerbi, Alessandro; Falconi, Massimo; Piemonti, Lorenzo

2017-10-01

To assess feasibility, safety, and metabolic outcome of islet auto transplantation (IAT) in patients undergoing completion pancreatectomy because of sepsis or bleeding after pancreatic surgery. From November 2008 to October 2016, approximately 22 patients were candidates to salvage IAT during emergency relaparotomy because of postpancreatectomy sepsis (n = 11) or bleeding (n = 11). Feasibility, efficacy, and safety of salvage IAT were compared with those documented in a cohort of 36 patients who were candidate to simultaneous IAT during nonemergency preemptive completion pancreatectomy through the pancreaticoduodenectomy. The percentage of candidates that received the infusion of islets was significantly lower in salvage IAT than simultaneous IAT (59.1% vs 88.9%, P = 0.008), mainly because of a higher rate of inadequate islet preparations. Even if microbial contamination of islet preparation was significantly higher in candidates to salvage IAT than in those to simultaneous IAT (78.9% vs 20%, P < 0.001), there was no evidence of a higher rate of complications related to the procedure. Median follow-up was 5.45 ± 0.52 years. Four (36%) of 11 patients reached insulin independence, 6 patients (56%) had partial graft function, and 1 patient (9%) had primary graft nonfunction. At the last follow-up visit, median fasting C-peptide was 0.43 (0.19-0.93) ng/mL; median insulin requirement was 0.38 (0.04-0.5) U/kg per day, and median HbA1c was 6.6% (5.9%-8.1%). Overall mortality, in-hospital mortality, metabolic outcome, graft survival, and insulin-free survival after salvage IAT were not different from those documented after simultaneous IAT. Our data demonstrate the feasibility, efficacy, and safety of salvage IAT after relaparotomy.

A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma – the STORM trial

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Witzens-Harig, Mathias; Memmer, Marie Luise; Dreyling, Martin; Hess, Georg

2013-01-01

The current standard treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL) primarily consists of intensified salvage therapy and, if the disease is chemo-sensitive, high dose therapy followed with autologous stem cell transplantation. In the rituximab era however, this treatment approach has shown only limited benefit. In particular, patients relapsing after rituximab-containing primary treatment have an adverse prognosis, especially if this occurs within the first year after therapy or if the disease is primarily refractory. Therefore there is an ultimate need for improved salvage treatment approaches. The STORM study is a prospective, multicentre phase I/II study to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to the standard therapy rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. The primary objective of the phase I of the trial is to establish the maximum tolerated dose (MTD) of temsirolimus in combination with rituximab and DHAP. The secondary objective is to demonstrate that stem cells can be mobilized during this regimen in patients scheduled to proceed to high dose therapy. In phase II, the previously established maximum tolerated dose of temsirolimus will be used. The primary objective is to evaluate the overall response rate (ORR) in patients with relapsed DLBCL. The secondary objective is to evaluate progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by an analysis of lymphoma subtypes determined by gene expression analysis (GEP). The STORM trial evaluates the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. It also might identify predictive markers for this treatment modality. ClinicalTrials.gov http

High-dose chemotherapy and auto-SCT for relapsed and refractory Hodgkin's lymphoma patients refractory to first-line salvage chemotherapy but responsive to second-line salvage chemotherapy.

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Rauf, Muhammad Shahzad; Maghfoor, Irfan; Elhassan, Tusneem Ahmed M; Akhtar, Saad

2015-01-01

Relapsed or primary refractory Hodgkin's lymphoma (HL) patients refractory to first-line salvage chemotherapy (first salvage) and unable to undergo high-dose chemotherapy (HDC) and autologous stem cell transplant (auto-SCT) have very poor outcome. Some patients are offered second-line salvage chemotherapy (second salvage), if they are responsive and may receive HDC auto-SCT. We identified 31 patients (18 males, 13 females) from 1996-2012 who received second salvage prior to auto-SCT. Median age at auto-SCT is 22 years. Patients were grouped as (1) relapsed-refractory (Rel:Ref): patients with prior complete response (CR) and on relapse found refractory to first salvage and received second salvage and (2) refractory-refractory (Ref:Ref): patients refractory to both primary treatment and first salvage and received second salvage. Median follow-up is 63 months (18-170). Disease status after second salvage prior to HDC was CR 16 %, partial response (PR) 71 % and stable disease 13 %. After HDC auto-SCT, CR:PR: progressive disease was observed in 18 (58 %): four (12 %): nine (29 %) patients, respectively. Five-year overall survival (OS) for whole group is 57 % (Rel:Ref vs. Ref:Ref, 73 % vs. 48 %, p = 0.48). Progression-free survival (PFS) for whole group is 52 % (Rel:Ref vs. Ref:Ref, 73 % vs. 40 % respectively, p = 0.11). Second-line salvage is a valid approach with no long-term side effects for those HL patients who do not respond to first-line salvage chemotherapy and they can be candidate of HDC and stem cell transplant with a high ORR, the PFS and OS in relapse-refractory and refractory-refractory group of patients.

Association Between Proton Pump Inhibitors and Metronomic Capecitabine as Salvage Treatment for Patients With Advanced Gastrointestinal Tumors: A Randomized Phase II Trial.

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Marchetti, Paolo; Milano, Annalisa; D'Antonio, Chiara; Romiti, Adriana; Falcone, Rosa; Roberto, Michela; Fais, Stefano

2016-12-01

The acidification of extracellular compartment represents a conceivable mechanism of drug resistance in malignant cells. In addition, it has been reported to drive proliferation and promote invasion and metastasis. Experimental evidence has shown that proton pump inhibitors can counteract tumor acidification and restore sensitivity to anticancer drugs. Moreover, early clinical data have supported the role of proton pump inhibitors in anticancer treatments. Metronomic capecitabine has demonstrated beneficial effects as salvage chemotherapy for heavily pretreated or frail patients with gastrointestinal cancer. The present study (EudraCT Number: 2013-001096-20) was aimed at investigating the activity and safety of high-dose rabeprazole in combination with metronomic capecitabine in patients with advanced gastrointestinal cancer refractory to standard treatment. A total of 66 patients will be randomized 1:1 to receive capecitabine 1500 mg/daily, continuously with or without rabeprazole 1.5 mg/kg twice a day, 3 days a week until disease progression, undue toxicity, or withdrawal of informed consent. The primary endpoint is progression-free survival. The secondary endpoints are clinical benefit, which reflects the proportion of patients with complete response, partial response, and stable disease, and overall survival. Progression-free and overall survival will be evaluated using a log-rank test to determine the effect of rabeprazole independently at the 2-sided α-level of 0.05. Other assessments will include the frequency and severity of adverse events and changes in laboratory parameters to measure the safety, and the pharmacokinetics of capecitabine. The results are expected in 2016. Copyright © 2016 Elsevier Inc. All rights reserved.

INDONESIAN SALVAGE LAW WITHIN THE FRAMEWORK OF CONTEMPORARY MARITIME LAW

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Dhiana Puspitawati

2015-12-01

Full Text Available Located in a strategic position, that is between two great oceans and two land masses have made Indonesia a centre of international trade and shipping. In fact, 90% of international trades are carried out through the ocean. It is therefore crucial to assure that the activities in carrying goods across the ocean are incident free. However, if accident happens, assistance from professionals to preserve items of property is desirable. In such, salvage law emerged. This paper discusses comprehensively Indonesian salvage law within the framework of contemporary maritime law. While Indonesian maritime law is mostly based on its national law on the carriage of goods by the sea, in fact, the development of maritime law is highly affected by international practices which are largely based on international conventions and regulations. This research finds that while Indonesian salvage law can be found in Book II Chapter VII article 545-568k Wetboek Van Koophandel or known as Kitab Undang-undang Hukum Dagang (KUHD, which focused narrowly on the value of salved property as the primary measures of success, yet Indonesian salvage law has not been developed in accordance with current international salvage law, which adopted a broader and more balanced approached in both commercial and environmental aspects. Although it is believed that such approached is “culturally unrecognized” in Indonesia, this research argued that since Indonesian waters are part of international waters, all process by waters including salvage should confirm the relevant international practices and regulations. While Indonesia has taken out salvage law from KUHD and regulates it within Act Number 17/2008 on navigation, however, such act only provides one article for salvage stating that salvage will be regulates further by Ministry Regulation. Untill this paper was written no such government regulation produced yet by Indonesia. Since Indonesian waters is the centre of international

Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation.

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Sabine Kuettel

2011-05-01

Full Text Available BACKGROUND: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP utilizing adenosine triphosphate (ATP as the preferred phosphoryl donor. METHODS AND FINDINGS: Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK: the structure of TbrAK in complex with the bisubstrate inhibitor P(1,P(5-di(adenosine-5'-pentaphosphate (AP5A at 1.55 Å, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl-2H-pyrazol-3-yl]morpholine (compound 1 at 2.8 Å resolution. CONCLUSIONS: The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK.

DPP4 inhibitors promote biological functions of human endothelial progenitor cells by targeting the SDF-1/CXCR4 signaling pathway

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Liu Feng

2016-01-01

Full Text Available Dipeptidyl peptidase 4 (DPP4 inhibitors(oral hypoglycemic agentshave beneficial effects during the early stages of diabetes. In this study, we evaluated the role of DPP4inhibitorsonthe biological functions of cultured human endothelial progenitor cells (EPCs. After treating EPCs with the DPP4 inhibitors sitagliptin and vildagliptin, we examined the mRNA expression of DPP4, vascular endothelial growth factor (VEGF,VEGF receptor 2 (VEGFR-2,endothelial nitric oxide synthase (eNOS, caspase-3,stromal cell-derived factor-1 (SDF-1, chemokine (C-X-C motif receptor 4 (CXCR4 were measured by RT-PCR. The protein expression of SDF-1 and CXCR4 was determined by Western blot; cell proliferation was tested by the MTT method, and DPP4 activity was determined by a DPP4 assay. Our results revealed that DPP4 expression and activity were inhibited following the treatment with various doses of DPP4 inhibitors. Cell proliferation and the expression of VEGF, VEGFR-2andeNOS were up regulated, while cell apoptosis was inhibited by DPP4 inhibitors in a dose-dependent manner. DPP4 inhibitors activated the SDF-1/CXCR4 signaling pathway, shown by the elevated expression of SDF-1/CXCR4. This further proved that after the SDF-1/CXCR4 signaling pathway was blocked by its inhibitor ADM3100, the effects of DPP4 inhibitors on the proliferation and apoptosis, and the expression of VEGF, VEGFR-2and eNOS of EPCs were significantly reduced. These findings suggest that DPP4 inhibitors promote the biological functions of human EPCs by up regulating the SDF-1/CXCR4 signaling pathway.

Novel bioassay for the discovery of inhibitors of the 2-C-methyl-D-erythritol 4-phosphate (MEP and terpenoid pathways leading to carotenoid biosynthesis.

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Natália Corniani

Full Text Available The 2-C-methyl-D-erythritol 4-phosphate (MEP pathway leads to the synthesis of isopentenyl diphosphate in plastids. It is a major branch point providing precursors for the synthesis of carotenoids, tocopherols, plastoquinone and the phytyl chain of chlorophylls, as well as the hormones abscisic acid and gibberellins. Consequently, disruption of this pathway is harmful to plants. We developed an in vivo bioassay that can measure the carbon flow through the carotenoid pathway. Leaf cuttings are incubated in the presence of a phytoene desaturase inhibitor to induce phytoene accumulation. Any compound reducing the level of phytoene accumulation is likely to interfere with either one of the steps in the MEP pathway or the synthesis of geranylgeranyl diphosphate. This concept was tested with known inhibitors of steps of the MEP pathway. The specificity of this in vivo bioassay was also verified by testing representative herbicides known to target processes outside of the MEP and carotenoid pathways. This assay enables the rapid screen of new inhibitors of enzymes preceding the synthesis of phytoene, though there are some limitations related to the non-specific effect of some inhibitors on this assay.

Cell salvage as part of a blood conservation strategy in anaesthesia.

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Ashworth, A; Klein, A A

2010-10-01

The use of intraoperative cell salvage and autologous blood transfusion has become an important method of blood conservation. The main aim of autologous transfusion is to reduce the need for allogeneic blood transfusion and its associated complications. Allogeneic blood transfusion has been associated with increased risk of tumour recurrence, postoperative infection, acute lung injury, perioperative myocardial infarction, postoperative low-output cardiac failure, and increased mortality. We have reviewed the current evidence for cell salvage in modern surgical practice and examined the controversial issues, such as the use of cell salvage in obstetrics, and in patients with malignancy, or intra-abdominal or systemic sepsis. Cell salvage has been demonstrated to be safe and effective at reducing allogeneic blood transfusion requirements in adult elective surgery, with stronger evidence in cardiac and orthopaedic surgery. Prolonged use of cell salvage with large-volume autotransfusion may be associated with dilution of clotting factors and thrombocytopenia, and regular laboratory or near-patient monitoring is required, along with appropriate blood product use. Cell salvage should be considered in all cases where significant blood loss (>1000 ml) is expected or possible, where patients refuse allogeneic blood products or they are anaemic. The use of cell salvage in combination with a leucocyte depletion filter appears to be safe in obstetrics and cases of malignancy; however, further trials are required before definitive guidance may be provided. The only absolute contraindication to the use of cell salvage and autologous blood transfusion is patient refusal.

Prevention of Bronchial Hyperplasia by EGFR Pathway Inhibitors in an Organotypic Culture Model

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Lee, Jangsoon; Ryu, Seung-Hee; Kang, Shin Myung; Chung, Wen-Cheng; Gold, Kathryn Ann; Kim, Edward S.; Hittelman, Walter N.; Hong, Waun Ki; Koo, Ja Seok

2011-01-01

Lung cancer is the leading cause of cancer-related mortality worldwide. Early detection or prevention strategies are urgently needed to increase survival. Hyperplasia is the first morphologic change that occurs in the bronchial epithelium during lung cancer development, followed by squamous metaplasia, dysplasia, carcinoma in situ, and invasive tumor. The current study was designed to determine the molecular mechanisms that control bronchial epithelium hyperplasia. Using primary normal human tracheobronchial epithelial (NHTBE) cells cultured using the 3-dimensional organotypic method, we found that the epidermal growth factor receptor (EGFR) ligands EGF, transforming growth factor-alpha, and amphiregulin induced hyperplasia, as determined by cell proliferation and multilayered epithelium formation. We also found that EGF induced increased cyclin D1 expression, which plays a critical role in bronchial hyperplasia; this overexpression was mediated by activating the mitogen-activated protein kinase pathway but not the phosphoinositide 3-kinase/Akt signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, and U0126, a MEK inhibitor, completely inhibited EGF-induced hyperplasia. Furthermore, a promoter analysis revealed that the activator protein-1 transcription factor regulates EGF-induced cyclin D1 overexpression. Activator protein-1 depletion using siRNA targeting its c-Jun component completely abrogated EGF-induced cyclin D1 expression. In conclusion, we demonstrated that bronchial hyperplasia can be modeled in vitro using primary NHTBE cells maintained in a 3-dimensional (3-D) organotypic culture. EGFR and MEK inhibitors completely blocked EGF-induced bronchial hyperplasia, suggesting that they have a chemopreventive role. PMID:21505178

Metabolic engineering of Escherichia coli to produce 2'-fucosyllactose via salvage pathway of guanosine 5'-diphosphate (GDP)-l-fucose.

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Chin, Young-Wook; Seo, Nari; Kim, Jae-Han; Seo, Jin-Ho

2016-11-01

2'-Fucosyllactose (2-FL) is one of the key oligosaccharides in human milk. In the present study, the salvage guanosine 5'-diphosphate (GDP)-l-fucose biosynthetic pathway from fucose was employed in engineered Escherichia coli BL21star(DE3) for efficient production of 2-FL. Introduction of the fkp gene coding for fucokinase/GDP-l-fucose pyrophosphorylase (Fkp) from Bacteroides fragilis and the fucT2 gene encoding α-1,2-fucosyltransferase from Helicobacter pylori allows the engineered E. coli to produce 2-FL from fucose, lactose and glycerol. To enhance the lactose flux to 2-FL production, the attenuated, and deleted mutants of β-galactosidase were employed. Moreover, the 2-FL yield and productivity were further improved by deletion of the fucI-fucK gene cluster coding for fucose isomerase (FucI) and fuculose kinase (FucK). Finally, fed-batch fermentation of engineered E. coli BL21star(DE3) deleting lacZ and fucI-fucK, and expressing fkp and fucT2 resulted in 23.1 g/L of extracellular concentration of 2-FL and 0.39 g/L/h productivity. Biotechnol. Bioeng. 2016;113: 2443-2452. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

International Climate Migration: Evidence for the Climate Inhibitor Mechanism and the Agricultural Pathway.

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Nawrotzki, Raphael J; Bakhtsiyarava, Maryia

2017-05-01

Research often assumes that, in rural areas of developing countries, adverse climatic conditions increase (climate driver mechanism) rather than reduce (climate inhibitor mechanism) migration, and that the impact of climate on migration is moderated by changes in agricultural productivity (agricultural pathway). Using representative census data in combination with high-resolution climate data derived from the novel Terra Populus system, we explore the climate-migration relationship in rural Burkina Faso and Senegal. We construct four threshold-based climate measures to investigate the effect of heat waves, cold snaps, droughts and excessive precipitation on the likelihood of household-level international outmigration. Results from multi-level logit models show that excessive precipitation increases international migration from Senegal while heat waves decrease international mobility in Burkina Faso, providing evidence for the climate inhibitor mechanism. Consistent with the agricultural pathway, interaction models and results from a geographically weighted regression (GWR) reveal a conditional effect of droughts on international outmigration from Senegal, which becomes stronger in areas with high levels of groundnut production. Moreover, climate change effects show a clear seasonal pattern, with the strongest effects appearing when heat waves overlap with the growing season and when excessive precipitation occurs prior to the growing season.

Myricetin is a novel inhibitor of human inosine 5′-monophosphate dehydrogenase with anti-leukemia activity

International Nuclear Information System (INIS)

Pan, Huiling; Hu, Qian; Wang, Jingyuan; Liu, Zehui; Wu, Dang; Lu, Weiqiang; Huang, Jin

2016-01-01

Human inosine 5′-monophosphate dehydrogenase (hIMPDH) is a rate-limiting enzyme in the de novo biosynthetic pathway of purine nucleotides, playing crucial roles in cellular proliferation, differentiation, and transformation. Dysregulation of hIMPDH expression and activity have been found in a variety of human cancers including leukemia. In this study, we found that myricetin, a naturally occurring phytochemical existed in berries, wine and tea, was a novel inhibitor of human type 1 and type 2 IMPDH (hIMPDH1/2) with IC_5_0 values of 6.98 ± 0.22 μM and 4.10 ± 0.14 μM, respectively. Enzyme kinetic analysis using Lineweaver-Burk plot revealed that myricetin is a mix-type inhibitor for hIMPDH1/2. Differential scanning fluorimetry and molecular docking simulation data demonstrate that myricetin is capable of binding with hIMPDH1/2. Myricetin treatment exerts potent anti-proliferative and pro-apoptotic effects on K562 human leukemia cells in a dose-dependent manner. Importantly, cytotoxicity of myricetin on K562 cells were markedly attenuated by exogenous addition of guanosine, a salvage pathway of maintaining intracellular pool of guanine nucleotides. Taking together, these results indicate that natural product myricetin exhibits potent anti-leukemia activity by interfering with purine nucleotides biosynthetic pathway through the suppression of hIMPDH1/2 catalytic activity. - Highlights: • Myricetin, a common dietary flavonoid, is a novel inhibitor of hIMPDH1/2. • Myricetin directly binds with hIMPDH1/2 and induces cell cycle arrest and apoptosis of leukemia cells. • The cytotoxicity of myricetin on K562 cells is markedly attenuated by exogenous addition of guanosine.

Myricetin is a novel inhibitor of human inosine 5′-monophosphate dehydrogenase with anti-leukemia activity

Energy Technology Data Exchange (ETDEWEB)

Pan, Huiling; Hu, Qian; Wang, Jingyuan; Liu, Zehui; Wu, Dang [Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237 (China); Lu, Weiqiang, E-mail: wqlu@bio.ecnu.edu.cn [Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241 (China); Huang, Jin, E-mail: huangjin@ecust.edu.cn [Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237 (China)

2016-09-02

Human inosine 5′-monophosphate dehydrogenase (hIMPDH) is a rate-limiting enzyme in the de novo biosynthetic pathway of purine nucleotides, playing crucial roles in cellular proliferation, differentiation, and transformation. Dysregulation of hIMPDH expression and activity have been found in a variety of human cancers including leukemia. In this study, we found that myricetin, a naturally occurring phytochemical existed in berries, wine and tea, was a novel inhibitor of human type 1 and type 2 IMPDH (hIMPDH1/2) with IC{sub 50} values of 6.98 ± 0.22 μM and 4.10 ± 0.14 μM, respectively. Enzyme kinetic analysis using Lineweaver-Burk plot revealed that myricetin is a mix-type inhibitor for hIMPDH1/2. Differential scanning fluorimetry and molecular docking simulation data demonstrate that myricetin is capable of binding with hIMPDH1/2. Myricetin treatment exerts potent anti-proliferative and pro-apoptotic effects on K562 human leukemia cells in a dose-dependent manner. Importantly, cytotoxicity of myricetin on K562 cells were markedly attenuated by exogenous addition of guanosine, a salvage pathway of maintaining intracellular pool of guanine nucleotides. Taking together, these results indicate that natural product myricetin exhibits potent anti-leukemia activity by interfering with purine nucleotides biosynthetic pathway through the suppression of hIMPDH1/2 catalytic activity. - Highlights: • Myricetin, a common dietary flavonoid, is a novel inhibitor of hIMPDH1/2. • Myricetin directly binds with hIMPDH1/2 and induces cell cycle arrest and apoptosis of leukemia cells. • The cytotoxicity of myricetin on K562 cells is markedly attenuated by exogenous addition of guanosine.

Evaluation of WO2014207069 A1: Multitarget Hedgehog pathway inhibitors and uses thereof.

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Manetti, Fabrizio; Petricci, Elena

2016-01-01

In recent years, the involvement of the Hedgehog (Hh) signaling pathway in various human diseases and dysfunctions has been clearly demonstrated. Smoothened (Smo), one of the upstream signal transducers, has been the most druggable target of the Hh pathway. However, the emergence of resistance to Smo inhibitors and the identification of Smo-independent activation of the Hh pathway led to the need to find new chemical entities able to interfere with downstream components, such as Gli. For this purpose, two different computational approaches have been applied to a small-sized library of natural compounds. As a result, an isoflavone derivative that showed ability to inhibit both Smo and Gli1 has been identified; namely, Glabrescione B. A new synthetic approach has been planned for this compound and its derivatives. Biological evaluation demonstrated the mechanism of action and showed a promising preclinical profile.

Malignant bone tumors and limb-salvage surgery in children

International Nuclear Information System (INIS)

Meyer, James S.; Mackenzie, William

2004-01-01

Limb-salvage surgery plays a major role in the management of children with malignant bone tumors. This article provides background on the clinical presentation and imaging evaluation of children with malignant bone tumors and describes various limb-salvage procedures used in the treatment of these children. (orig.)

Clinical, virological and immunological responses in Danish HIV patients receiving raltegravir as part of a salvage regimen

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Frederik N Engsig

2010-05-01

Full Text Available Frederik N Engsig1, Jan Gerstoft1, Gitte Kronborg2, Carsten S Larsen3, Gitte Pedersen4, Anne M Audelin5, Louise B Jørgensen5, Niels Obel11Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark; 2Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark; 3Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; 4Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; 5Department of Virology, Statens Serum Institute, Copenhagen, DenmarkBackground: Raltegravir is the first integrase inhibitor approved for treatment of HIV-infected patients harboring multiresistant viruses.Methods: From a Danish population-based nationwide cohort of HIV patients we identified the individuals who initiated a salvage regimen including raltegravir and a matched cohort of HIV-infected patients initiating HAART for the first time. We compared these two cohorts for virological suppression, gain in CD4 count, and time to first change of initial regimen.Results: We identified 32 raltegravir patients and 64 HIV patients who initiated HAART for the first time in the period 1 January 2006 to 1 July 2009. The virological and immunological responses in the raltegravir patients were comparable to those seen in the control cohort. No patients in the two cohorts died and no patients terminated raltegravir treatment in the observation period. Time to first change of initial regimen was considerably shorter for HAART-naïve patients.Conclusion: We conclude that salvage regimens including raltegravir have high effectiveness in the everyday clinical setting. The effectiveness of the regimens is comparable to that observed for patients initiating HAART for the first time. The risk of change in the salvage regimens after initiation of raltegravir is low.Keywords: HIV, raltegravir, salvage regime, efficacy, matched cohort

Use of antibiotic beads to salvage infected breast implants.

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Sherif, Rami D; Ingargiola, Michael; Sanati-Mehrizy, Paymon; Torina, Philip J; Harmaty, Marco A

2017-10-01

When an implant becomes infected, implant salvage is often performed where the implant is removed, capsulectomy is performed, and a new implant is inserted. The patient is discharged with a PICC line and 6-8 weeks of intravenous (IV) antibiotics. This method has variable success and subjects the patient to long-term systemic antibiotics. In the 1960s, the use of antibiotic-impregnated beads for the treatment of chronic osteomyelitis was described. These beads deliver antibiotic directly to the site of the infection, thereby eliminating the complications of systemic IV antibiotics. This study aimed to present a case series illustrating the use of STIMULAN calcium sulfate beads loaded with vancomycin and tobramycin to increase the rate of salvage of the infected implant and forgo IV antibiotics. A retrospective analysis was performed of patients who were treated at Mount Sinai Hospital for implant infection with salvage and antibiotic beads. Twelve patients were identified, 10 of whom had breast cancer. Comorbidities included hypertension, smoking, and immunocompromised status. Infections were noted anywhere from 5 days to 8 years postoperatively. Salvage was successful in 9 out of the 12 infected implants using antibiotic bead therapy without home IV antibiotics. The use of antibiotic beads is promising for salvaging infected breast implants without IV antibiotics. Seventy-five percent of the implants were successfully salvaged. Of the three patients who had unsalvageable implants, one was infected with antibiotic-resistant Rhodococcus that was refractory to bead therapy and one was noncompliant with postoperative instructions. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Psychosocial reactions to upper extremity limb salvage: A cross-sectional study.

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Sposato, Lindsay; Yancosek, Kathleen; Lospinoso, Josh; Cancio, Jill

2017-08-09

Descriptive cross-sectional survey study. Limb salvage spares an extremity at risk for amputation after a major traumatic injury. Psychosocial recovery for individuals with lower extremity limb salvage has been discussed in the literature. However, to date, psychosocial reactions for individuals with upper extremity (UE) limb salvage have not been examined. To determine which factors may influence psychosocial adaptation to UE limb salvage. Participants (n = 30; 28 males) were adults (mean, 30.13; range, 18-61) who sustained an UE limb salvage from a traumatic event. Adaptation was measured using a modified version of the Reactions to Impairment and Disability Inventory. A linear mixed-effects regression found that worse psychosocial adaptation was associated with having less than a college degree, being less than 6 months post-injury, being older than 23 years, and having more pain. Dominant hand injuries were found to influence poor adaptation on the denial Reactions to Impairment and Disability Inventory subscale only. The results of this study indicate that there is potential for nonadaptive reactions and psychological distress with certain variables in UE limb salvage. Therapists may use these results to anticipate which clients may be at risk for poor psychosocial outcomes. This study indicates the need for early consideration to factors that affect psychological prognosis for the UE limb salvage population. However, future research is indicated to better understand the unique psychosocial challenges and needs of these individuals. 4. Copyright © 2017 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.

Ipsilateral breast tumor recurrence after breast conservation therapy: Outcomes of salvage mastectomy vs. salvage breast-conserving surgery and prognostic factors for salvage breast preservation

International Nuclear Information System (INIS)

Alpert, Tracy E.; Kuerer, Henry M.; Arthur, Douglas W.; Lannin, Donald R.; Haffty, Bruce G.

2005-01-01

Purpose: To compare outcomes of salvage mastectomy (SM) and salvage breast-conserving surgery (SBCS) and study the feasibility of SBCS. Methods and Materials: Of 2,038 patients treated with breast-conserving therapy at Yale-New Haven Hospital before 1999, 166 sustained an ipsilateral breast tumor recurrence (IBTR). Outcomes and prognostic factors of patients treated with SM or SBCS were compared. Patients were considered amenable to SBCS if the recurrence was localized on mammogram and physical examination, and had pathologic size <3 cm, confined to the biopsy site, without skin or lymphovascular invasion, and with ≤3 positive nodes. Results: Of the 146 patients definitively managed at IBTR, surgery was SM (n = 116) or SBCS (n 30). The median length of follow-up after IBTR was 13.8 years. The SM and SBCS cohorts had no significant differences, except at IBTR the SM cohort had a greater tumor size (p = 0.049). Of the SM cohort, 65.5% were considered appropriate for SBCS, and a localized relapse was predicted by estrogen-receptor positive, diploid, and detection of recurrence by mammogram. Multicentric disease correlated with BRCA1/2 mutation, estrogen-receptor negative, lymph node positive at relapse, and detection of recurrence by physical examination. Survival after IBTR was 64.5% at 10 years, with no significant difference between SM (65.7%) and SBCS (58.0%). Only 2 patients in the SBCS cohort subsequently had a second IBTR, and were salvaged with mastectomy. Conclusions: While mastectomy is considered the standard surgical salvage of IBTR, SBCS is feasible and prognostic factors are related to favorable tumor biology and early detection. Patients with BRCA1/2 germline mutations may be less appropriate for SBCS, as multicentric disease was more prevalent. Patients who underwent SBCS had comparable outcomes as those who underwent SM, but remain at continued risk for IBTR. A prospective trial evaluating repeat lumpectomy and partial breast reirradiation is

Radiotherapy salvage for Hodgkin's disease after chemotherapy failure

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Wirth, A; Corry, J; Liew, K H

1995-07-01

Purpose/Objective: The precise role of salvage radiotherapy (RT) following chemotherapy (CT) failure in patients with Hodgkin's disease (HD) remains undefined. The aims of this study are: (1) to assess the pattern of failure, failure-free and overall survival, in patients who receive salvage RT for HD after CT failure; and (2) to identify patient subsets most suitable for this treatment approach. Materials and Methods: A review of patients treated between 1978 and 1992 at the Peter MacCallum Cancer Institute identified 52 patients with relapsed/refractory HD following CT who received RT with curative intent. Eligibility for this study required either biopsy confirmation of relapse/residual disease, or else clear clinical or radiological disease progression. Patient characteristics at diagnosis: median age 26, with 32% > 40 years old; M/ F 31/21; stage I-4, II-16, III-25, IV-7. Initial CT was MOPP- 31 patients, ABVD-1, both-16. A median 6 cycles of CT was given per regimen. Prior to salvage RT, 26/52 patients had received both MOPP and ABVD, either as sequential regimens, or as alternating or hybrid protocols. The response to initial CT was: CR-30, PR/SD-18, PD-4. Duration of initial CR was < 12 months in 8/30 patients. Salvage treatment consisted of radiotherapy to all known areas of disease. Doses ranged from 3600-4000 cGy. Results: Twenty three patients (45%) achieved CR. With a median follow-up of 70 months (range 4.8-166), actuarial median failure free survival (FFS) and overall survival (OS) are 22 months and 83 months respectively. Actuarial 5 year FFS and OS are 26% and 57% respectively. Patients with CR duration > 12 months following initial CT, only one CT regimen prior to salvage RT, and anatomically limited relapse had a significantly longer FFS. These factors, and age < 40 were associated with significantly longer OS. Only 6% of patients failed solely in the irradiated volume as first site of relapse, with the total in-field relapse of 30%. Sixty

Mitigating Hillslope Erosion After Post-fire Salvage Logging Operations

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Robichaud, P. R.; Bone, E. D.; Brown, R. E.

2017-12-01

In the past decades, wildfires around the world have continued to increase in size, severity, and cost. Major concerns after wildfires are the increased runoff and erosion due to loss of the protective forest floor layer, loss of water storage, and creation of water repellent soil conditions. Salvage logging is often a post-fire forest management action to recoup the economic loss of the burned timber, yet concerns arise on the impacts of this activity on water quality. Recently, several studies have been conducted to determine the effect of salvage logging on hillslope erosion. Logging skid trails have been cited as being the cause of high erosion during and after salvage operations. We investigated the impacts of adding operational logging slash to skid trails to reduce hillslope erosion after salvage operations on the 2015 North Star Fire, Washington. We implemented well-designed rapid response approach to compare slash treatment effectiveness by monitoring sediment yield and runoff response from hillslopes with a concentrated flow (rill) experiment. Various runoff amounts are incrementally added to 4 m hillslope plots with and without slash treatments. Our initial results suggest that adding logging slash increased ground cover significantly which contributed to an order of magnitude decrease in hillslope erosion. Integrating erosion mitigation strategies into salvage logging operations should be commonplace when hillslope erosion is a concern.

An Ixodes ricinus Tick Salivary Lectin Pathway Inhibitor Protects Borrelia burgdorferi sensu lato from Human Complement

NARCIS (Netherlands)

Wagemakers, Alex; Coumou, Jeroen; Schuijt, Tim J.; Oei, Anneke; Nijhof, Ard M.; van 't Veer, Cornelis; van der Poll, Tom; Bins, Adriaan D.; Hovius, Joppe W. R.

2016-01-01

We previously identified tick salivary lectin pathway inhibitor (TSLPI) in Ixodes scapularis, a vector for Borrelia burgdorferi sensu stricto (s.s.) in North America. TSLPI is a salivary protein facilitating B. burgdorferi s.s. transmission and acquisition by inhibiting the host lectin complement

Salvage felling in the Slovak forests in the period 2004–2013

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Kunca Andrej

2015-09-01

Full Text Available Salvage felling is one of the indicators of the forest health quality and stability. Most of the European Union countries monitor forest harmful agents, which account for salvage felling, in order to see trends or functionality between factors and to be able to predict their development. The systematic evidence of forest harmful agents and volume of salvage felling in Slovakia started at the Forest Research Institute in Zvolen in 1960. The paper focuses on the occurrence of the most relevant harmful agents and volume of salvage felling in the Slovak forests over the last decade. Within the 10 years period (2004–2013 salvage felling in Slovakia reached 42.31 mil. m3 of wood, which was 53.2% of the total felling. Wind and European spruce bark beetle Ips typographus damaged 78.4% of salvage wood, i.e. they were the most important pest agents. Norway spruce (Picea abies was the most frequently damaged tree species that represented the amount of 35.6 mil. m3 of wood (81.2% of total volume of salvage felling. As Norway spruce grows mostly in mountains, these regions of Central and Northern Slovakia were most affected. At the damaged localities new forests were prevailingly established with regard to suitable ecological conditions for trees, climate change scenarios and if possible, natural regeneration has been preferred. These approaches in forest stand regeneration together with silvicultural and control measures are assumed to gradually decrease the amount of salvage felling over long term perspective.

International Climate Migration: Evidence for the Climate Inhibitor Mechanism and the Agricultural Pathway

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Nawrotzki, Raphael J.; Bakhtsiyarava, Maryia

2016-01-01

Research often assumes that, in rural areas of developing countries, adverse climatic conditions increase (climate driver mechanism) rather than reduce (climate inhibitor mechanism) migration, and that the impact of climate on migration is moderated by changes in agricultural productivity (agricultural pathway). Using representative census data in combination with high-resolution climate data derived from the novel Terra Populus system, we explore the climate-migration relationship in rural Burkina Faso and Senegal. We construct four threshold-based climate measures to investigate the effect of heat waves, cold snaps, droughts and excessive precipitation on the likelihood of household-level international outmigration. Results from multi-level logit models show that excessive precipitation increases international migration from Senegal while heat waves decrease international mobility in Burkina Faso, providing evidence for the climate inhibitor mechanism. Consistent with the agricultural pathway, interaction models and results from a geographically weighted regression (GWR) reveal a conditional effect of droughts on international outmigration from Senegal, which becomes stronger in areas with high levels of groundnut production. Moreover, climate change effects show a clear seasonal pattern, with the strongest effects appearing when heat waves overlap with the growing season and when excessive precipitation occurs prior to the growing season. PMID:28943813

Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors.

Science.gov (United States)

Naujok, Ortwin; Lentes, Jana; Diekmann, Ulf; Davenport, Claudia; Lenzen, Sigurd

2014-04-29

Small membrane-permeable molecules are now widely used during maintenance and differentiation of embryonic stem cells of different species. In particular the glycogen synthase kinase 3 (GSK3) is an interesting target, since its chemical inhibition activates the Wnt/beta-catenin pathway. In the present comparative study four GSK3 inhibitors were characterized. Cytotoxicity and potential to activate the Wnt/beta-catenin pathway were tested using the commonly used GSK3 inhibitors BIO, SB-216763, CHIR-99021, and CHIR-98014. Wnt/beta-catenin-dependent target genes were measured by quantitative PCR to confirm the Wnt-reporter assay and finally EC50-values were calculated. CHIR-99021 and SB-216763 had the lowest toxicities in mouse embryonic stem cells and CHIR-98014 and BIO the highest toxicities. Only CHIR-99021 and CHIR-98014 lead to a strong induction of the Wnt/beta-catenin pathway, whereas BIO and SB-216763 showed a minor or no increase in activation of the Wnt/beta-catenin pathway over the natural ligand Wnt3a. The data from the Wnt-reporter assay were confirmed by gene expression analysis of the TCF/LEF regulated gene T. Out of the four tested GSK3 inhibitors, only CHIR-99021 and CHIR-98014 proved to be potent pharmacological activators of the Wnt/beta-catenin signaling pathway. But only in the case of CHIR-99021 high potency was combined with very low toxicity.

The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells

Science.gov (United States)

Bach, Thomas J

2013-01-01

We have established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, based on the expression of a dexamethasone-inducible GFP fused to the carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL). By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP) pathway with known inhibitors like oxoclomazone and fosmidomycin, as well as inhibition of the protein geranylgeranyltransferase type 1 (PGGT-1), shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA) pathway with mevinolin did not affect the localization. During the present work, this test system has been used to examine the effect of newly designed inhibitors of the MEP pathway and inhibitors of sterol biosynthesis such as squalestatin, terbinafine and Ro48-8071. In addition, we also studied the impact of different post-prenylation inhibitors or those suspected to affect the transport of proteins to the plasma membrane on the localization of the geranylgeranylable fusion protein GFP-BD-CVIL. PMID:24555083

Bacterial reduction by cell salvage washing and leukocyte depletion filtration.

Science.gov (United States)

Waters, Jonathan H; Tuohy, Marion J; Hobson, Donna F; Procop, Gary

2003-09-01

Blood conservation techniques are being increasingly used because of the increased cost and lack of availability of allogeneic blood. Cell salvage offers great blood savings opportunities but is thought to be contraindicated in a number of areas (e.g., blood contaminated with bacteria). Several outcome studies have suggested the safety of this technique in trauma and colorectal surgery, but many practitioners are still hesitant to apply cell salvage in the face of frank bacterial contamination. This study was undertaken to assess the efficacy of bacterial removal when cell salvage was combined with leukocyte depletion filtration. Expired packed erythrocytes were obtained and inoculated with a fixed amount of a stock bacteria (Escherichia coli American Type Culture Collections [ATCC] 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213, or Bacteroides fragilis ATCC 25285) in amounts ranging from 2,000 to 4,000 colony forming units/ml. The blood was processed via a cell salvage machine. The washed blood was then filtered using a leukocyte reduction filter. The results for blood taken during each step of processing were compared using a repeated-measures design. Fifteen units of blood were contaminated with each of the stock bacteria. From the prewash sample to the postfiltration sample, 99.0%, 99.6%, 100%, and 97.6% of E. coli, S. aureus, P. aeruginosa, and B. fragilis were removed, respectively. Significant but not complete removal of contaminating bacteria was seen. An increased level of patient safety may be added to cell salvage by including a leukocyte depletion filter when salvaging blood that might be grossly contaminated with bacteria.

Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase

NARCIS (Netherlands)

Lunev, Sergey; Bosch, Soraya S; Batista, Fernando A; Wang, Chao; Li, Jingyao; Linzke, Marleen; Kruithof, Paul; Chamoun, George; Dömling, Alexander S S; Wrenger, Carsten; Groves, Matthew R

2018-01-01

Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of

Deoxynucleoside Salvage in Fission Yeast Allows Rescue of Ribonucleotide Reductase Deficiency but Not Spd1-Mediated Inhibition of Replication

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Oliver Fleck

2017-04-01

Full Text Available In fission yeast, the small, intrinsically disordered protein S-phase delaying protein 1 (Spd1 blocks DNA replication and causes checkpoint activation at least in part, by inhibiting the enzyme ribonucleotide reductase, which is responsible for the synthesis of DNA. The CRL4Cdt2 E3 ubiquitin ligase mediates degradation of Spd1 and the related protein Spd2 at S phase of the cell cycle. We have generated a conditional allele of CRL4Cdt2, by expressing the highly unstable substrate-recruiting protein Cdt2 from a repressible promoter. Unlike Spd1, Spd2 does not regulate deoxynucleotide triphosphate (dNTP pools; yet we find that Spd1 and Spd2 together inhibit DNA replication upon Cdt2 depletion. To directly test whether this block of replication was solely due to insufficient dNTP levels, we established a deoxy-nucleotide salvage pathway in fission yeast by expressing the human nucleoside transporter human equilibrative nucleoside transporter 1 (hENT1 and the Drosophila deoxynucleoside kinase. We present evidence that this salvage pathway is functional, as 2 µM of deoxynucleosides in the culture medium is able to rescue the growth of two different temperature-sensitive alleles controlling ribonucleotide reductase. However, salvage completely failed to rescue S phase delay, checkpoint activation, and damage sensitivity, which was caused by CRL4Cdt2 inactivation, suggesting that Spd1—in addition to repressing dNTP synthesis—together with Spd2, can inhibit other replication functions. We propose that this inhibition works at the point of the replication clamp proliferating cell nuclear antigen, a co-factor for DNA replication.

Recombinant human tissue factor pathway inhibitor exerts anticoagulant, anti-inflammatory and antimicrobial effects in murine pneumococcal pneumonia

NARCIS (Netherlands)

van den Boogaard, F. E.; Brands, X.; Schultz, M. J.; Levi, M. [=Marcel M.; Roelofs, J. J. T. H.; van 't Veer, C.; van der Poll, T.

2011-01-01

Background: Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway inhibitor (rh-TFPI) attenuates sepsis-induced coagulation and has been evaluated in clinical trials involving patients

Inhibitors of the 5-lipoxygenase arachidonic acid pathway induce ATP release and ATP-dependent organic cation transport in macrophages.

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da Silva-Souza, Hercules Antônio; Lira, Maria Nathalia de; Costa-Junior, Helio Miranda; da Cruz, Cristiane Monteiro; Vasconcellos, Jorge Silvio Silva; Mendes, Anderson Nogueira; Pimenta-Reis, Gabriela; Alvarez, Cora Lilia; Faccioli, Lucia Helena; Serezani, Carlos Henrique; Schachter, Julieta; Persechini, Pedro Muanis

2014-07-01

We have previously described that arachidonic acid (AA)-5-lipoxygenase (5-LO) metabolism inhibitors such as NDGA and MK886, inhibit cell death by apoptosis, but not by necrosis, induced by extracellular ATP (ATPe) binding to P2X7 receptors in macrophages. ATPe binding to P2X7 also induces large cationic and anionic organic molecules uptake in these cells, a process that involves at least two distinct transport mechanisms: one for cations and another for anions. Here we show that inhibitors of the AA-5-LO pathway do not inhibit P2X7 receptors, as judged by the maintenance of the ATPe-induced uptake of fluorescent anionic dyes. In addition, we describe two new transport phenomena induced by these inhibitors in macrophages: a cation-selective uptake of fluorescent dyes and the release of ATP. The cation uptake requires secreted ATPe, but, differently from the P2X7/ATPe-induced phenomena, it is also present in macrophages derived from mice deficient in the P2X7 gene. Inhibitors of phospholipase A2 and of the AA-cyclooxygenase pathway did not induce the cation uptake. The uptake of non-organic cations was investigated by measuring the free intracellular Ca(2+) concentration ([Ca(2+)]i) by Fura-2 fluorescence. NDGA, but not MK886, induced an increase in [Ca(2+)]i. Chelating Ca(2+) ions in the extracellular medium suppressed the intracellular Ca(2+) signal without interfering in the uptake of cationic dyes. We conclude that inhibitors of the AA-5-LO pathway do not block P2X7 receptors, trigger the release of ATP, and induce an ATP-dependent uptake of organic cations by a Ca(2+)- and P2X7-independent transport mechanism in macrophages. Copyright © 2014 Elsevier B.V. All rights reserved.

Salvage HIFU after radiotherapy and salvage radiotherapy after HIFU in locally recurrent prostate cancer: Retrospective analysis of morbidity

International Nuclear Information System (INIS)

Lee, J.-W.; Hannoun-Leviac, J.-M.; Chevallier, D.; Rouscoff, Y.; Durand, M.; Amiel, J.; Gal, J.; Natale, R.; Chand, M.-E.; Raffaelli, C.; Ambrosetti, D.

2012-01-01

To evaluate the toxicity of therapeutic sequences High Intensity Focused Ultrasound (HIFU)-salvage radiotherapy (HIFU-RT) or radiotherapy-salvage HIFU (RT-HIFU) in case of locally recurrent prostate cancer. Nineteen patients had a local recurrence of prostate cancer. Among them, 10 patients were treated by HIFU-RT and 9 patients by RT- HIFU (4 by external beam radiotherapy [EBR] and 5 by brachytherapy [BRACHY]). Urinary side effects were assessed using CTCAE v4. At the time of the initial management, the median age was 66.5 years (53 72), the median PSA was 10.8 ng/mL (3.4 50) and the median initial Gleason score was 6.3 (5 8). Median follow-up after salvage treatment was 46.3 months (2 108). Thirty percent of the patients in the HIFU-RT group and 33.3 % of the patients in the RT-HIFU group, all belonging to the sub-group BRACHY-HIFU, had urinary complication greater than or equal to grade 2. Among all the patients, only 1 had grade 1 gastrointestinal toxicity. BRACHY-HIFU sequence seems to be purveyor of many significant urinary side effects. A larger database is needed to confirm this conclusion. (authors)

Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma

Science.gov (United States)

Larson, Erik W; Peterson, Halloran E; Lamoreaux, Wayne T; MacKay, Alexander R; Fairbanks, Robert K; Call, Jason A; Carlson, Jonathan D; Ling, Benjamin C; Demakas, John J; Cooke, Barton S; Lee, Christopher M

2014-01-01

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with a survival prognosis of 14-16 mo for the highest functioning patients. Despite aggressive, multimodal upfront therapies, the majority of GBMs will recur in approximately six months. Salvage therapy options for recurrent GBM (rGBM) are an area of intense research. This study compares recent survival and quality of life outcomes following Gamma Knife radiosurgery (GKRS) salvage therapy. Following a PubMed search for studies using GKRS as salvage therapy for malignant gliomas, nine articles from 2005 to July 2013 were identified which evaluated rGBM treatment. In this review, we compare Overall survival following diagnosis, Overall survival following salvage treatment, Progression-free survival, Time to recurrence, Local tumor control, and adverse radiation effects. This report discusses results for rGBM patient populations alone, not for mixed populations with other tumor histology grades. All nine studies reported median overall survival rates (from diagnosis, range: 16.7-33.2 mo; from salvage, range: 9-17.9 mo). Three studies identified median progression-free survival (range: 4.6-14.9 mo). Two showed median time to recurrence of GBM. Two discussed local tumor control. Six studies reported adverse radiation effects (range: 0%-46% of patients). The greatest survival advantages were seen in patients who received GKRS salvage along with other treatments, like resection or bevacizumab, suggesting that appropriately tailored multimodal therapy should be considered with each rGBM patient. However, there needs to be a randomized clinical trial to test GKRS for rGBM before the possibility of selection bias can be dismissed. PMID:24829861

Effect of hypoxia on tissue factor pathway inhibitor expression in breast cancer.

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Cui, X Y; Tinholt, M; Stavik, B; Dahm, A E A; Kanse, S; Jin, Y; Seidl, S; Sahlberg, K K; Iversen, N; Skretting, G; Sandset, P M

2016-02-01

ESSENTIALS: A hypoxic microenvironment is a common feature of tumors that may influence activation of coagulation. MCF-7 and SK-BR-3 breast cancer cells and breast cancer tissue samples were used. The results showed transcriptional repression of tissue factor pathway inhibitor expression in hypoxia. Hypoxia-inducible factor 1α may be a target for the therapy of cancer-related coagulation and thrombosis. Activation of coagulation is a common finding in patients with cancer, and is associated with an increased risk of venous thrombosis. As a hypoxic microenvironment is a common feature of solid tumors, we investigated the role of hypoxia in the regulation of tissue factor (TF) pathway inhibitor (TFPI) expression in breast cancer. To explore the transcriptional regulation of TFPI by hypoxia-inducible factor (HIF)-1α in breast cancer cells and their correlation in breast cancer tissues. MCF-7 and SK-BR-3 breast cancer cells were cultured in 1% oxygen or treated with cobalt chloride (CoCl2 ) to mimic hypoxia. Time-dependent and dose-dependent downregulation of TFPI mRNA (quantitative RT-PCR) and of free TFPI protein (ELISA) were observed in hypoxia. Western blotting showed parallel increases in the levels of HIF-1α protein and TF. HIF-1α inhibitor abolished or attenuated the hypoxia-induced downregulation of TFPI. Luciferase reporter assay showed that both hypoxia and HIF-1α overexpression caused strong repression of TFPI promoter activity. Subsequent chromatin immunoprecipitation and mutagenesis analysis demonstrated a functional hypoxia response element within the TFPI promoter, located at -1065 to -1060 relative to the transcriptional start point. In breast cancer tissue samples, gene expression analyses showed a positive correlation between the mRNA expression of TFPI and that of HIF-1α. This study demonstrates that HIF-1α is involved in the transcriptional regulation of the TFPI gene, and suggests that a hypoxic microenvironment inside a breast tumor may

A comparison of salvage surgery following CRT and following BRT for advanced hypopharyngeal cancer

International Nuclear Information System (INIS)

Kamijo, Tomoyuki; Onitsuka, Tetsuro; Yokota, Tomoya

2016-01-01

There are still few comparison reports regarding the safety of salvage surgery for recurrence and persistence following platinum-based chemoradiotherapy (CRT) and cetuximab-based bioradiotherapy (BRT), which are frequently used as non-surgical therapies for advanced head and neck carcinomas. This study compared the safety of salvage surgery following CRT against that following BRT for advanced hypopharyngeal cancer. The study examined 34 cases who underwent salvage surgery following CRT and 7 cases who underwent salvage surgery following BRT from September 2002 to December 2015. The number of cases that were able to undergo salvage surgery was 34 among 67 recurrence and persistence cases following CRT and 7 of 8 cases following BRT. In terms of the surgical procedure, salvage neck dissection was conducted for 22 cases in the CRT group and 5 cases in the BRT group, with no significant differences observed between both including the surgical time and amount of bleeding, and with no major complications in either group. Total hypopharynx or total laryngectomy resection for salvage was conducted for 19 cases in the CRT group and 3 cases in the BRT group, upon which we observed anastomotic leakage in 3 cases in the CRT group and 1 case in the BRT group; however, there was no significant difference in the onset frequency. There was no clear difference regarding safety between salvage surgery following CRT and following BRT for locally advanced hypopharyngeal cancer. However, regarding the adaptation of salvage surgery, the possibility of limitations in the CRT group was suggested in comparison with the BRT group. (author)

PTP1B inhibitor promotes endothelial cell motility by activating the DOCK180/Rac1 pathway.

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Wang, Yuan; Yan, Feng; Ye, Qing; Wu, Xiao; Jiang, Fan

2016-04-07

Promoting endothelial cell (EC) migration is important not only for therapeutic angiogenesis, but also for accelerating re-endothelialization after vessel injury. Several recent studies have shown that inhibition of protein tyrosine phosphatase 1B (PTP1B) may promote EC migration and angiogenesis by enhancing the vascular endothelial growth factor receptor-2 (VEGFR2) signalling. In the present study, we demonstrated that PTP1B inhibitor could promote EC adhesion, spreading and migration, which were abolished by the inhibitor of Rac1 but not RhoA GTPase. PTP1B inhibitor significantly increased phosphorylation of p130Cas, and the interactions among p130Cas, Crk and DOCK180; whereas the phosphorylation levels of focal adhesion kinase, Src, paxillin, or Vav2 were unchanged. Gene silencing of DOCK180, but not Vav2, abrogated the effects of PTP1B inhibitor on EC motility. The effects of PTP1B inhibitor on EC motility and p130Cas/DOCK180 activation persisted in the presence of the VEGFR2 antagonist. In conclusion, we suggest that stimulation of the DOCK180 pathway represents an alternative mechanism of PTP1B inhibitor-stimulated EC motility, which does not require concomitant VEGFR2 activation as a prerequisite. Therefore, PTP1B inhibitor may be a useful therapeutic strategy for promoting EC migration in cardiovascular patients in which the VEGF/VEGFR functions are compromised.

In situ saphenous vein bypass for limb salvage.

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Sarcina, A; Carlesi, R; Bellosta, R; Agrifoglio, G

1993-02-01

A total of 130 infrapopliteal in situ saphenous vein bypasses were performed in 128 patients between January 1980 and June 1991. The indication for surgery was critical ischaemia with impending limb loss in 121 patients; seven suffered from severe claudication. The distal anastomosis was to the popliteal artery below the knee in 60 cases (46.2%) and in 70 (53.8%) to the tibioperoneal arteries. The results, in terms of secondary patency and limb salvage rates, of the first 68 procedures (1980-1985) and subsequent 62 (1986-June 1991) were compared. In the first period, a secondary patency rate of 42.6% and a limb salvage rate of 67.0% were obtained, compared with 71.3 and 80.8% respectively in the second. These differences are significant for patency (P < 0.005) and limb salvage (P < 0.01). These results show that the in situ technique can give acceptable results but a learning period with a high percentage of early failures is to be expected.

[Eyeball salvage treatment or enucleation for advanced retinoblastoma].

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Qian, J; Xue, K

2016-10-11

The management of retinoblastoma (RB) has dramatically changed over the past two decades. The introduction of chemotherapy has transformed treatment algorithms completely. Chemotherapy is currently used as a first line approach for children with RB and can be delivered by intravenous, intra-arterial and intravitreal routes. However, there still remains some controversy on the treatment of advanced RB, especially in eyeball salvage. This article described domestic and international approaches to eyeball salvage treatment. We would like to further discuss our opinion on the management of advanced RB based on our clinical experience for attracting more clinical concern on this issue. Many factors should be considered when choosing the appropriate conservative therapy. The choice of eyeball salvage treatment not only depends upon the tumor staging and laterality but also upon compliance and economic factors. Doctors and parents should not blindly pursue eye saving. However, there are still cases where enucleation is definitely the treatment of choice. (Chin J Ophthalmol, 2016, 52: 728-732) .

78 FR 74128 - Proposed CERCLA Administrative Cost Recovery Settlement; Cadie Auto Salvage Site, Belvidere...

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2013-12-10

... Recovery Settlement; Cadie Auto Salvage Site, Belvidere, Boone County, Illinois AGENCY: Environmental... Auto Salvage Site in Belvidere, Boone County, Illinois with the following settling parties: UOP, LLC... Cadie Auto Salvage Site, Belvidere, Boone County, Illinois and EPA Docket No. and should be addressed to...

78 FR 77673 - Proposed CERCLA Administrative Cost Recovery Settlement; Cadie Auto Salvage Site, Belvidere...

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2013-12-24

... Recovery Settlement; Cadie Auto Salvage Site, Belvidere, Boone County, Illinois AGENCY: Environmental... Auto Salvage Site in Belvidere, Boone County, Illinois with the following settling party: Helen E... reference the Cadie Auto Salvage Site, Belvidere, Boone County, Illinois and EPA Docket No. and should be...

Plasmin-dependent proteolysis of tissue factor pathway inhibitor in a mouse model of endotoxemia.

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Lupu, C; Herlea, O; Tang, H; Lijnen, R H; Lupu, F

2013-01-01

The development of a procoagulant state in sepsis, owing to aberrant expression of tissue factor (TF) and a sharp decrease in the level of its major inhibitor, TF pathway inhibitor (TFPI), could lead to microthrombotic organ failure. The mechanism for the decline in TFPI activity in the lung could involve plasmin-mediated cleavage of the inhibitor. To investigate the effect of plasmin generation on lung-associated TFPI activity, in normal conditions and during infusion of endotoxin (lipopolysaccharide [LPS]) in mice. Plasmin generation and TFPI activity were assayed in the lungs of mice deficient in tissue-type plasminogen (Plg) activator (t-PA) or Plg, at 2 h after LPS or saline injection. The sharp loss of lung-associated TFPI activity at 2 h after LPS challenge paralleled the abrupt increase in plasmin generation. TFPI activity was significantly retained in both t-PA(-/-) and Plg(-/-) mice, which are unable to generate plasmin. The increased plasmin generation during the early stages of sepsis could cleave/inactivate TFPI and thus lead to thrombotic complications. © 2012 International Society on Thrombosis and Haemostasis.

Isonicotinamide Enhances Sir2 Protein-mediated Silencing and Longevity in Yeast by Raising Intracellular NAD+ Concentration*

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McClure, Julie M.; Wierman, Margaret B.; Maqani, Nazif; Smith, Jeffrey S.

2012-01-01

Sirtuins are an evolutionarily conserved family of NAD+-dependent protein deacetylases that function in the regulation of gene transcription, cellular metabolism, and aging. Their activity requires the maintenance of an adequate intracellular NAD+ concentration through the combined action of NAD+ biosynthesis and salvage pathways. Nicotinamide (NAM) is a key NAD+ precursor that is also a byproduct and feedback inhibitor of the deacetylation reaction. In Saccharomyces cerevisiae, the nicotinamidase Pnc1 converts NAM to nicotinic acid (NA), which is then used as a substrate by the NAD+ salvage pathway enzyme NA phosphoribosyltransferase (Npt1). Isonicotinamide (INAM) is an isostere of NAM that stimulates yeast Sir2 deacetylase activity in vitro by alleviating the NAM inhibition. In this study, we determined that INAM stimulates Sir2 through an additional mechanism in vivo, which involves elevation of the intracellular NAD+ concentration. INAM enhanced normal silencing at the rDNA locus but only partially suppressed the silencing defects of an npt1Δ mutant. Yeast cells grown in media lacking NA had a short replicative life span, which was extended by INAM in a SIR2-dependent manner and correlated with increased NAD+. The INAM-induced increase in NAD+ was strongly dependent on Pnc1 and Npt1, suggesting that INAM increases flux through the NAD+ salvage pathway. Part of this effect was mediated by the NR salvage pathways, which generate NAM as a product and require Pnc1 to produce NAD+. We also provide evidence suggesting that INAM influences the expression of multiple NAD+ biosynthesis and salvage pathways to promote homeostasis during stationary phase. PMID:22539348

Isonicotinamide enhances Sir2 protein-mediated silencing and longevity in yeast by raising intracellular NAD+ concentration.

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McClure, Julie M; Wierman, Margaret B; Maqani, Nazif; Smith, Jeffrey S

2012-06-15

Sirtuins are an evolutionarily conserved family of NAD(+)-dependent protein deacetylases that function in the regulation of gene transcription, cellular metabolism, and aging. Their activity requires the maintenance of an adequate intracellular NAD(+) concentration through the combined action of NAD(+) biosynthesis and salvage pathways. Nicotinamide (NAM) is a key NAD(+) precursor that is also a byproduct and feedback inhibitor of the deacetylation reaction. In Saccharomyces cerevisiae, the nicotinamidase Pnc1 converts NAM to nicotinic acid (NA), which is then used as a substrate by the NAD(+) salvage pathway enzyme NA phosphoribosyltransferase (Npt1). Isonicotinamide (INAM) is an isostere of NAM that stimulates yeast Sir2 deacetylase activity in vitro by alleviating the NAM inhibition. In this study, we determined that INAM stimulates Sir2 through an additional mechanism in vivo, which involves elevation of the intracellular NAD(+) concentration. INAM enhanced normal silencing at the rDNA locus but only partially suppressed the silencing defects of an npt1Δ mutant. Yeast cells grown in media lacking NA had a short replicative life span, which was extended by INAM in a SIR2-dependent manner and correlated with increased NAD(+). The INAM-induced increase in NAD(+) was strongly dependent on Pnc1 and Npt1, suggesting that INAM increases flux through the NAD(+) salvage pathway. Part of this effect was mediated by the NR salvage pathways, which generate NAM as a product and require Pnc1 to produce NAD(+). We also provide evidence suggesting that INAM influences the expression of multiple NAD(+) biosynthesis and salvage pathways to promote homeostasis during stationary phase.

Tissue Factor Pathway Inhibitor: Multiple Anticoagulant Activities for a Single Protein.

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Mast, Alan E

2016-01-01

Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits early phases of the procoagulant response. Alternatively spliced isoforms of TFPI are differentially expressed by endothelial cells and human platelets and plasma. The TFPIβ isoform localizes to the endothelium surface where it is a potent inhibitor of TF-factor VIIa complexes that initiate blood coagulation. The TFPIα isoform is present in platelets. TFPIα contains a stretch of 9 amino acids nearly identical to those found in the B-domain of factor V that are well conserved in mammals. These amino acids provide exosite binding to activated factor V, which allows for TFPIα to inhibit prothrombinase during the initiation phase of blood coagulation. Endogenous inhibition at this point in the coagulation cascade was only recently recognized and has provided a biochemical rationale to explain the pathophysiological mechanisms underlying several clinical disorders. These include the east Texas bleeding disorder that is caused by production of an altered form of factor V with high affinity for TFPI and a paradoxical procoagulant effect of heparins. In addition, these findings have led to ideas for pharmacological targeting of TFPI that may reduce bleeding in hemophilia patients. © 2015 American Heart Association, Inc.

Aerobic, Metal-Free, and Catalytic Dehydrogenative Coupling of Heterocycles: En Route to Hedgehog Signaling Pathway Inhibitors.

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Bering, Luis; Paulussen, Felix M; Antonchick, Andrey P

2018-04-06

The nitrosonium ion-catalyzed dehydrogenative coupling of heteroarenes under mild reaction conditions is reported. The developed method utilizes ambient molecular oxygen as a terminal oxidant, and only water is produced as byproduct. Dehydrogenative coupling of heteroarenes translated into the rapid discovery of novel hedgehog signaling pathway inhibitors, emphasizing the importance of the developed methodology.

Coupled Responses of Sewol, Twin Barges and Slings During Salvage

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Yao, Zong; Wang, Wei-ping; Jiang, Yan; Chen, Shi-hai

2018-04-01

Korean Sewol is successfully lifted up with the strand jack system based on twin barges. During the salvage operation, two barges and Sewol encounter offshore environmental conditions of wave, current and wind. It is inevitable that the relative motions among the three bodies are coupled with the sling tensions, which may cause big dynamic loads for the lifting system. During the project engineering phase and the site operation, it is necessary to build up a simulation model that can precisely generate the coupled responses in order to define a suitable weather window and monitor risks for the salvage operation. A special method for calculating multibody coupled responses is introduced into Sewol salvage project. Each body's hydrodynamic force and moment in multibody configuration is calculated in the way that one body is treated as freely moving in space, while other bodies are set as fixed globally. The hydrodynamic force and moment are then applied into a numerical simulation model with some calibration coefficients being inserted. These coefficients are calibrated with the model test results. The simulation model built up this way can predict coupled responses with the similar accuracy as the model test and full scale measurement, and particularly generate multibody shielding effects. Site measured responses and the responses only resulted from from the simulation keep project management simultaneously to judge risks of each salvage stage, which are important for success of Sewol salvage.

A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors.

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Loboda, Andrey; Nebozhyn, Michael; Klinghoffer, Rich; Frazier, Jason; Chastain, Michael; Arthur, William; Roberts, Brian; Zhang, Theresa; Chenard, Melissa; Haines, Brian; Andersen, Jannik; Nagashima, Kumiko; Paweletz, Cloud; Lynch, Bethany; Feldman, Igor; Dai, Hongyue; Huang, Pearl; Watters, James

2010-06-30

Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.

A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors

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Paweletz Cloud

2010-06-01

Full Text Available Abstract Background Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. Methods We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. Results The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90% sensitivity but relatively low (50% specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. Conclusions These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical

A randomized controlled trial of cell salvage in routine cardiac surgery.

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Klein, Andrew A; Nashef, Samer A M; Sharples, Linda; Bottrill, Fiona; Dyer, Matthew; Armstrong, Johanna; Vuylsteke, Alain

2008-11-01

Previous trials have indicated that cell salvage may reduce allogeneic blood transfusion during cardiac surgery, but these studies have limitations, including inconsistent use of other blood transfusion-sparing strategies. We designed a randomized controlled trial to determine whether routine cell salvage for elective uncomplicated cardiac surgery reduces blood transfusion and is cost effective in the setting of a rigorous transfusion protocol and routine administration of antifibrinolytics. Two-hundred-thirteen patients presenting for first-time coronary artery bypass grafting and/or cardiac valve surgery were prospectively randomized to control or cell salvage groups. The latter group had blood aspirate during surgery and mediastinal drainage the first 6 h after surgery processed in a cell saver device and autotransfused. All patients received tranexamic acid and were subjected to an algorithm for red blood cell and hemostatic blood factor transfusion. There was no difference between the two groups in the proportion of patients exposed to allogeneic blood (32% in both groups, relative risk 1.0 P = 0.89). At current blood products and cell saver prices, the use of cell salvage increased the costs per patient by a minimum of $103. When patients who had mediastinal re-exploration for bleeding were excluded (as planned in the protocol), significantly fewer units of allogeneic red blood cells were transfused in the cell salvage compared with the control group (65 vs 100 U, relative risk 0.71 P = 0.04). In patients undergoing routine first-time cardiac surgery in an institution with a rigorous blood conservation program, the routine use of cell salvage does not further reduce the proportion of patients exposed to allogeneic blood transfusion. However, patients who do not have excessive bleeding after surgery receive significantly fewer units of blood with cell salvage. Although the use of cell savage may reduce the demand for blood products during cardiac surgery, this

Salvage surgery for radiation failure in oral, oropharyngeal, and hypopharyngeal squamous cell carcinoma

International Nuclear Information System (INIS)

Suzuki, Masahiro; Terada, Akihiro; Ogawa, Tetsuya; Suzuki, Hidenori; Hasegawa, Yasuhisa

2007-01-01

Few reports have covered salvage surgery after radiotherapy, especially with chemotherapy for oral, oropharyngeal, and hypopharyngeal squamous cell carcinoma. The feasibility of salvage surgery is unclear. We analyzed postoperative complications and prognosis after salvage surgery for local recurrence after definitive radiotherapy. Subjects were 37 patients with oral, oropharyngeal, and hypopharyngeal squamous cell carcinoma treated from 1994 to 2003. Of these, 14 (37.8%) had postoperative complications. The complication rate was significantly high in the reconstructive operation group (p=0.031) and the chemotherapy group (p=0.049). The 5-year overall survival rate after salvage surgery was 70.7%. Although there was no significant improvement, the prognosis was good in early-stage groups with primary tumors. We found that salvage surgery after definitive radiotherapy was effective for recurrent oral, oropharyngeal, and hypopharyngeal squamous cell carcinoma. We stress the need to pay attention to postoperative complications in reconstructive operation and chemotherapy groups. (author)

Postoperative Prostate-Specific Antigen Velocity Independently Predicts for Failure of Salvage Radiotherapy After Prostatectomy

International Nuclear Information System (INIS)

King, Christopher R.; Presti, Joseph C.; Brooks, James D.; Gill, Harcharan; Spiotto, Michael T.

2008-01-01

Purpose: Identification of patients most likely to benefit from salvage radiotherapy (RT) using postoperative (postop) prostate-specific antigen (PSA) kinetics. Methods and Materials: From 1984 to 2004, 81 patients who fit the following criteria formed the study population: undetectable PSA after radical prostatectomy (RP); pathologically negative nodes; biochemical relapse defined as a persistently detectable PSA; salvage RT; and two or more postop PSAs available before salvage RT. Salvage RT included the whole pelvic nodes in 55 patients and 4 months of total androgen suppression in 56 patients. The median follow-up was >5 years. All relapses were defined as a persistently detectable PSA. Kaplan-Meier and Cox proportional hazards multivariable analysis were performed for all clinical, pathological, and treatment factors predicting for biochemical relapse-free survival (bRFS). Results: There were 37 biochemical relapses observed after salvage RT. The 5-year bRFS after salvage RT for patients with postop prostate-specific antigen velocity ≤1 vs. >1 ng/ml/yr was 59% vs. 29%, p = 0.002. In multivariate analysis, only postop PSAV (p = 0.0036), pre-RT PSA level ≤1 (p = 0.037) and interval-to-relapse >10 months (p = 0.012) remained significant, whereas pelvic RT, hormone therapy, and RT dose showed a trend (p = ∼0.06). PSAV, but not prostate-specific antigen doubling time, predicted successful salvage RT, suggesting an association of zero-order kinetics with locally recurrent disease. Conclusions: Postoperative PSA velocity independently predicts for the failure of salvage RT and can be considered in addition to high-risk features when selecting patients in need of systemic therapy following biochemical failure after RP. For well-selected patients, salvage RT can achieve high cure rates

Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia

International Nuclear Information System (INIS)

Moskalev, Evgeny A; Pötz, Oliver; Joos, Thomas O; Hoheisel, Jörg D; Luckert, Katrin; Vorobjev, Ivan A; Mastitsky, Sergey E; Gladkikh, Aleena A; Stephan, Achim; Schrenk, Marita; Kaplanov, Kamil D; Kalashnikova, Olga B

2012-01-01

The Wnt/β-catenin signalling is aberrantly activated in primary B cell chronic lymphocytic leukaemia (CLL). Epigenetic silencing of pathway inhibitor genes may be a mechanism for its activation. In this study, we investigated systematically and quantitatively the methylation status of 12 Wnt/β-catenin pathway inhibitor genes – CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1 – in the cell lines EHEB and MEC-1 as well as patient samples. Quantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and β-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models. For 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2´-deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/β-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2´-deoxycytidine caused accumulation of β-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with β-catenin and thus demonstrating its epigenetically regulated inhibition effect. The results suggest an

Simulation and Analysis of Passive Rolling Compensation of High Sea Salvage System

Directory of Open Access Journals (Sweden)

Lin Liqun

2017-01-01

Full Text Available Method and device of a flexible interception and salvage system was introduced in this paper. In order to study the effect of wave motion on salvage operation, we proposed a passive wave compensation scheme that utilizes a combination of variable-pitch cylinders and accumulators, and established the mathematical vibration model of the rolling motion of the salvage compensation system. With the relationships between the stiffness coefficient and the accumulator parametric of passive compensated gas-liquid system, we determined the effective compensation stiffness range through Mathematica simulation analysis. The relationship between the roll displacement of the salvage arm and the initial volume Vo of the accumulator has been analysed. The results show that the accumulatorVo in a certain range has a great influence on the passive compensation. However, when the volume is greater than 20m3, the compensation effect is weakened, and tend to a certain value, irrespective of the passive system accumulator volume capacity, it does not achieve full compensation. The results have important guidance on the design and optimization of rolling passive compensation of the practical high sea salvage system.

Psychosocial reactions to upper extremity limb salvage: A case series.

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Sposato, Lindsay; Yancosek, Kathleen; Cancio, Jill

2017-11-30

Case series. A salvaged limb is one that has undergone a major traumatic injury, followed by repeated surgical attempts in order to avoid amputation. Psychological recovery for individuals with lower extremity limb salvage has been examined in a number of studies. However, psychosocial reactions for individuals with upper extremity (UE) limb salvage are understudied in the literature. The purpose of this study was to explore the process of psychosocial adaptation for 3 trauma cases after UE limb salvage. The Reactions to Impairment and Disability Inventory was used to assess psychosocial adaptation. Physical function outcomes (pain, range of motion, edema, sensation, and dexterity) are presented. The Disabilities of the Arm, Shoulder, and Hand measure was used to assess perceived disability. Medical and rehabilitation history are discussed for each case, in order to provide in-depth understanding of the impact of these injuries. Reactions to injury varied across the cases; however, outcomes suggest that psychosocial adaptation may be influenced by the experience of pain, the ability to participate in valued roles and activities, and having a supportive social network. For this population, therapists may consider emphasizing pain management, focusing on client-centered goals and interventions, and facilitating peer support. Providers should closely monitor patients for signs of poor adaptation, such as hand-hiding behaviors. This study is among the first to examine psychological outcomes for the UE limb salvage population. Future research would be beneficial to provide deeper understanding of the psychosocial challenges for these individuals. Copyright © 2017 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.

Long-Term Outcomes After High-Dose Postprostatectomy Salvage Radiation Treatment

International Nuclear Information System (INIS)

Goenka, Anuj; Magsanoc, Juan Martin; Pei Xin; Schechter, Michael; Kollmeier, Marisa; Cox, Brett; Scardino, Peter T.; Eastham, James A.; Zelefsky, Michael J.

2012-01-01

Purpose: To review the impact of high–dose radiotherapy (RT) in the postprostatectomy salvage setting on long-term biochemical control and distant metastases–free survival, and to identify clinical and pathologic predictors of outcomes. Methods and Materials: During 1988–2007, 285 consecutive patients were treated with salvage RT (SRT) after radical prostatectomy. All patients were treated with either three-dimensional conformal RT or intensity-modulated RT. Two hundred seventy patients (95%) were treated to a dose ≥66 Gy, of whom 205 (72%) received doses ≥70 Gy. Eighty-seven patients (31%) received androgen-deprivation therapy as a component of their salvage treatment. All clinical and pathologic records were reviewed to identify treatment risk factors and response. Results: The median follow-up time after SRT was 60 months. Seven-year actuarial prostate-specific antigen (PSA) relapse-free survival and distant metastases–free survival were 37% and 77%, respectively. Independent predictors of biochemical recurrence were vascular invasion (p 0.4 ng/mL (p < 0.01), androgen-deprivation therapy (p = 0.03), Gleason score ≥7 (p = 0.02), and seminal vesicle involvement (p = 0.05). Salvage RT dose ≥70 Gy was not associated with improvement in biochemical control. A doubling time <3 months was the only independent predictor of metastatic disease (p < 0.01). There was a trend suggesting benefit of SRT dose ≥70 Gy in preventing clinical local failure in patients with radiographically visible local disease at time of SRT (7 years: 90% vs. 79.1%, p = 0.07). Conclusion: Salvage RT provides effective long-term biochemical control and freedom from metastasis in selected patients presenting with detectable PSA after prostatectomy. Androgen-deprivation therapy was associated with improvement in biochemical progression-free survival. Clinical local failures were rare but occurred most commonly in patients with greater burden of disease at time of SRT as reflected by

Long-Term Outcomes After High-Dose Postprostatectomy Salvage Radiation Treatment

Energy Technology Data Exchange (ETDEWEB)

Goenka, Anuj; Magsanoc, Juan Martin; Pei Xin; Schechter, Michael; Kollmeier, Marisa; Cox, Brett [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Scardino, Peter T.; Eastham, James A. [Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Zelefsky, Michael J., E-mail: zelefskm@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (United States)

2012-09-01

Purpose: To review the impact of high-dose radiotherapy (RT) in the postprostatectomy salvage setting on long-term biochemical control and distant metastases-free survival, and to identify clinical and pathologic predictors of outcomes. Methods and Materials: During 1988-2007, 285 consecutive patients were treated with salvage RT (SRT) after radical prostatectomy. All patients were treated with either three-dimensional conformal RT or intensity-modulated RT. Two hundred seventy patients (95%) were treated to a dose {>=}66 Gy, of whom 205 (72%) received doses {>=}70 Gy. Eighty-seven patients (31%) received androgen-deprivation therapy as a component of their salvage treatment. All clinical and pathologic records were reviewed to identify treatment risk factors and response. Results: The median follow-up time after SRT was 60 months. Seven-year actuarial prostate-specific antigen (PSA) relapse-free survival and distant metastases-free survival were 37% and 77%, respectively. Independent predictors of biochemical recurrence were vascular invasion (p < 0.01), negative surgical margins (p < 0.01), presalvage PSA level >0.4 ng/mL (p < 0.01), androgen-deprivation therapy (p = 0.03), Gleason score {>=}7 (p = 0.02), and seminal vesicle involvement (p = 0.05). Salvage RT dose {>=}70 Gy was not associated with improvement in biochemical control. A doubling time <3 months was the only independent predictor of metastatic disease (p < 0.01). There was a trend suggesting benefit of SRT dose {>=}70 Gy in preventing clinical local failure in patients with radiographically visible local disease at time of SRT (7 years: 90% vs. 79.1%, p = 0.07). Conclusion: Salvage RT provides effective long-term biochemical control and freedom from metastasis in selected patients presenting with detectable PSA after prostatectomy. Androgen-deprivation therapy was associated with improvement in biochemical progression-free survival. Clinical local failures were rare but occurred most commonly in

Prognostic factors for survival after salvage total laryngectomy following radiotherapy or chemoradiation failure

DEFF Research Database (Denmark)

Wulff, N B; Andersen, E; Kristensen, C A

2017-01-01

with higher N classification and need for lymph node excision during salvage total laryngectomy along with use of frozen sections. The high number of patients with recurrence within 1 year after salvage total laryngectomy occurred although thorough and regular follow-up visits were performed.......OBJECTIVE: The primary aims were to determine the rates of and prognostic factors for overall survival, disease-specific survival and disease-free survival following salvage total laryngectomy. DESIGN: Retrospective longitudinal study. SETTING: Tertiary medical centres. PARTICIPANTS: A total of 142...... survival, disease-specific survival and disease-free survival were 37.7%, 54.9% and 55.3%, respectively. N classification at primary diagnosis, lymph node excision and postoperative complications within 1 year after salvage total laryngectomy were prognostic factors for shorter overall survival, disease...

American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma

DEFF Research Database (Denmark)

Giralt, Sergio; Garderet, Laurent; Durie, Brian

2015-01-01

convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop...... a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high...... inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage...

Second salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer

Directory of Open Access Journals (Sweden)

Metha Maenhout

2017-04-01

Full Text Available Purpose : Salvage treatments for localized radiorecurrent prostate cancer can be performed safely when a focal and image guided approach is used. Due to the low toxicity, the opportunity exists to investigate a second salvage treatment when a second locally recurrent prostate cancer occurs. Here, we describe a second salvage treatment procedure of 4 patients. Material and methods : Four patients with a pathologically proven second local recurrence were treated in an outpatient magnetic resonance imaging (MRI-guided setting with a single fraction of 19 Gy focal high-dose-rate brachytherapy (HDR-BT. Delineation was performed using choline-PET-CT or a 68Ga-PSMA PET in combination with multiparametric 3 Tesla MRI in all four patients. Toxicity was measured using common toxicity criteria for adverse events (CTCAE version 4.0. Results : With a median follow-up of 12 months (range, 6-15, there were 2 patients with biochemical recurrence as defined by the Phoenix-definition. There were no patients with grade 3 or more toxicity. In all second salvage HDR-BT treatments, the constraints for rectum, bladder, and urethra were met. Median treatment volume (GTV was 4.8 cc (range, 1.9-6.6 cc. A median of 8 catheters (range, 6-9 were used, and the median dose to the treatment volume (GTV was a D95: 19.3 Gy (SD 15.5-19.4 Gy. Conclusions : Second focal salvage MRI-guided HDR-BT for a select group of patients with a second locally recurrent prostate cancer is feasible. There was no grade 3 or more acute toxicity for these four patients.

Adjuvant radiotherapy after salvage lymph node dissection because of nodal relapse of prostate cancer versus salvage lymph node dissection only

International Nuclear Information System (INIS)

Rischke, Hans Christian; Schultze-Seemann, Wolfgang; Kroenig, Malte; Schlager, Daniel; Jilg, Cordula Annette; Wieser, Gesche; Drendel, Vanessa; Stegmaier, Petra; Henne, Karl; Volegova-Neher, Natalia; Grosu, Anca-Ligia; Krauss, Tobias; Kirste, Simon

2015-01-01

Nodal pelvic/retroperitoneal recurrent prostate cancer (PCa) after primary therapy can be treated with salvage lymph node dissection (salvage-LND) in order to delay disease progression and offer cure for a subset of patients. Whether adjuvant radiotherapy (ART) in affected regions improves the outcome by elimination of residual tumour burden remains unclear. A total of 93 patients with exclusively nodal PCa relapse underwent choline-positron-emission tomography-computed-tomography-directed pelvic/retroperitoneal salvage-LND; 46 patients had surgery only and 47 patients received ART in regions with proven lymph node metastases. In case of subsequent prostate specific antigen (PSA) progression, different imaging modalities were performed to confirm next relapse within or outside the treated region (TR). Mean follow-up was 3.2 years. Lymphatic tumour burden was balanced between the two groups. Additional ART resulted in delayed relapse within TR (5-year relapse-free rate 70.7 %) versus surgery only (5-year relapse-free rate 26.3 %, p < 0.0001). In both treatment arms, time to next relapse outside the TR was almost equal (median 27 months versus 29.6 months, p = 0.359). With respect to the detection of the first new lesion, regardless if present within or outside the TR, 5 years after the treatment 34.3 % of patients in the group with additional ART were free of relapse, versus 15.4 % in the surgery only group (p = 0.0122). ART had no influence on the extent of PSA reduction at latest follow-up compared to treatment with surgery only. ART after salvage-LND provides stable local control in TR and results in overall significant improved next-relapse-free survival, compared to patients who received surgery only in case of nodal PCa-relapse. (orig.) [de

Forest structure following tornado damage and salvage logging in northern Maine, USA

Science.gov (United States)

Shawn Fraver; Kevin J. Dodds; Laura S. Kenefic; Rick Morrill; Robert S. Seymour; Eben Sypitkowski

2017-01-01

Understanding forest structural changes resulting from postdisturbance management practices such as salvage logging is critical for predicting forest recovery and developing appropriate management strategies. In 2013, a tornado and subsequent salvage operations in northern Maine, USA, created three conditions (i.e., treatments) with contrasting forest structure:...

Survival outcomes following salvage surgery for oropharyngeal squamous cell carcinoma: systematic review.

Science.gov (United States)

Kao, S S; Ooi, E H

2018-04-01

Recurrent oropharyngeal squamous cell carcinoma causes great morbidity and mortality. This systematic review analyses survival outcomes following salvage surgery for recurrent oropharyngeal squamous cell carcinoma. A comprehensive search of various electronic databases was conducted. Studies included patients with recurrent or residual oropharyngeal squamous cell carcinoma treated with salvage surgery. Primary outcomes were survival rates following salvage surgery. Secondary outcomes included time to recurrence, staging at time of recurrence, post-operative complications, and factors associated with mortality and recurrence. Methodological appraisal and data extraction were conducted as per Joanna Briggs Institute methodology. Eighteen articles were included. The two- and five-year survival rates of the patients were 52 per cent and 30 per cent respectively. Improvements in treatment modalities for recurrent oropharyngeal squamous cell carcinoma were associated with improvements in two-year overall survival rates, with minimal change to five-year overall survival rates. Various factors were identified as being associated with long-term overall survival, thus assisting clinicians in patient counselling and selection for salvage surgery.

Biosynthetic pathway of the phytohormone auxin in insects and screening of its inhibitors.

Science.gov (United States)

Suzuki, Hiroyoshi; Yokokura, Junpei; Ito, Tsukasa; Arai, Ryoma; Yokoyama, Chiaki; Toshima, Hiroaki; Nagata, Shinji; Asami, Tadao; Suzuki, Yoshihito

2014-10-01

Insect galls are abnormal plant tissues induced by galling insects. The galls are used for food and habitation, and the phytohormone auxin, produced by the insects, may be involved in their formation. We found that the silkworm, a non-galling insect, also produces an active form of auxin, indole-3-acetic acid (IAA), by de novo synthesis from tryptophan (Trp). A detailed metabolic analysis of IAA using IAA synthetic enzymes from silkworms indicated an IAA biosynthetic pathway composed of a three-step conversion: Trp → indole-3-acetaldoxime → indole-3-acetaldehyde (IAAld) → IAA, of which the first step is limiting IAA production. This pathway was shown to also operate in gall-inducing sawfly. Screening of a chemical library identified two compounds that showed strong inhibitory activities on the conversion step IAAld → IAA. The inhibitors can be efficiently used to demonstrate the importance of insect-synthesized auxin in gall formation in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

Salvage surgery following radiation failure in squamous cell carcinoma of the supraglottic larynx

International Nuclear Information System (INIS)

Parsons, James T.; Mendenhall, William M.; Stringer, Scott P.; Cassisi, Nicholas J.; Million, Rodney R.

1995-01-01

Purpose: We analyzed the clinical course of patients who developed local (primary) recurrence following high-dose irradiation of squamous cell carcinoma of the supraglottic larynx. Methods and Materials: Between October 1964 and July 1991, 206 patients with previously untreated squamous cell carcinoma of the supraglottic larynx underwent radiotherapy with curative intent. Local failure occurred in 46 (22%) patients. Successful surgical salvage was defined as no evidence of recurrent cancer for at least 2 years after salvage surgery and continuously thereafter. Results: Sixteen patients did not undergo salvage surgery because of refusal (7 patients), severe medical illness (2 patients), concurrent distant metastasis (5 patients), or unresectable neck disease (2 patients). Twenty-six patients underwent total laryngectomy, and 4 patients had a voice-sparing procedure. Successful salvage was achieved in 50% of patients who underwent surgery. The rate of successful salvage did not correlate with preirradiation T-stage or time to failure after irradiation. Most of the failures after surgery were because of failure to control the primary cancer. The overall rate of postsurgical complications was 37%. No operative or perioperative deaths occurred. The 5-year survival rate for all 46 patients, calculated from the date of irradiation failure, was 20%, while the 5-year survival rate after salvage surgery for the 30 patients who underwent the procedure was 29%. Conclusion: There are few data in the literature regarding the clinical outcome in patients whose tumors are not controlled by initial radiotherapy. In the current and previous series, one-half to two-thirds of patients who developed primary failure underwent salvage surgery, which was successful in approximately half of the operated patients, leading to a 25-30% rate of long-term disease-free survival among the entire group of patients who developed failure

Acyclic Nucleoside Phosphonates Containing 9-Deazahypoxanthine and a Five-Membered Heterocycle as Selective Inhibitors of Plasmodial 6-Oxopurine Phosphoribosyltransferases

Czech Academy of Sciences Publication Activity Database

Kaiser, Martin Maxmilian; Baszczyňski, Ondřej; Hocková, Dana; Poštová Slavětínská, Lenka; Dračínský, Martin; Keough, D. T.; Guddat, L. W.; Janeba, Zlatko

2017-01-01

Roč. 12, č. 14 (2017), s. 1133-1141 ISSN 1860-7179 R&D Projects: GA ČR(CZ) GA16-06049S Institutional support: RVO:61388963 Keywords : inhibitors * nucleosides * malaria * phosphonates * purine salvage Subject RIV: CC - Organic Chemistry OBOR OECD: Organic chemistry Impact factor: 3.225, year: 2016

A second pathway to degrade pyrimidine nucleic acid precursors in eukaryotes

DEFF Research Database (Denmark)

Andersen, Gorm; Bjornberg, Olof; Polakova, Silvia

2008-01-01

Pyrimidine bases are the central precursors for RNA and DNA, and their intracellular pools are determined by de novo, salvage and catabolic pathways. In eukaryotes, degradation of uracil has been believed to proceed only via the reduction to dihydrouracil. Using a yeast model, Saccharomyces kluyv...... of the eukaryotic or prokaryotic genes involved in pyrimidine degradation described to date.......Pyrimidine bases are the central precursors for RNA and DNA, and their intracellular pools are determined by de novo, salvage and catabolic pathways. In eukaryotes, degradation of uracil has been believed to proceed only via the reduction to dihydrouracil. Using a yeast model, Saccharomyces......, respectively. The gene products of URC1 and URC4 are highly conserved proteins with so far unknown functions and they are present in a variety of prokaryotes and fungi. In bacteria and in some fungi, URC1 and URC4 are linked on the genome together with the gene for uracil phosphoribosyltransferase (URC6). Urc1...

Voriconazole salvage treatment of invasive candidiasis.

NARCIS (Netherlands)

Ostrosky-Zeichner, L.; Oude Lashof, A.M.L.; Kullberg, B.J.; Rex, J.H.

2003-01-01

Data on the salvage treatment of invasive candidiasis with voriconazole in 52 patients intolerant of other antifungal agents or with infection refractory to other antifungal agents were analyzed. Patients had received a mean of two previous antifungal agents (range, 1-4 agents), and 83% had received

Immediate free jejunum transfer for salvage surgery of gastric tube necrosis.

Science.gov (United States)

Umezawa, Hiroki; Matsutani, Takeshi; Ogawa, Rei; Hyakusoku, Hiko

2014-01-01

Gastric tube necrosis after esophagus cancer surgery is a rare but critical situation. Salvage reconstruction of the esophagus remains a challenging procedure for head and neck surgeons. Historically, surgeons have employed a two-stage salvage surgery consisting of debridement followed by reconstruction. While this procedure generates good results, the time to restart oral alimentation is long. The present report describes the case of a 62-year-old male who developed gastric tube necrosis 3 days after undergoing surgery for thoracic-cervical esophageal cancer and immediate reconstruction with the retrosternal gastric pullup technique. He was treated with debridement and simultaneous free jejunum transfer 4 days after the primary surgery. He was able to restart oral alimentation 10 days after the salvage surgery. This rapid return to oral alimentation is a major advantage of the one-stage immediate esophagus salvage reconstruction. Another advantage is the ease of the reconstructive procedure: the absence of scarring and prolonged inflammation, which are disadvantages of the two-stage procedure, meant that recipient vessel selection and anastomosis were uncomplicated. The one-step procedure may be particularly useful in cases where the inflammation is discovered early.

Salvage image guided radiation therapy to the prostate after cryotherapy failure

Directory of Open Access Journals (Sweden)

Austin B. Hopper, BS

2018-01-01

Conclusions: High-dose IG-IMRT results in high rates of salvage and extremely low rates of serious late toxicity for patients with locally recurrent prostate cancer after cryotherapy. Although the results are encouraging, given the small number of patients in this and other series, we remain cautious with regard to this treatment and believe the use of salvage radiation therapy after cryotherapy warrants further study.

Metabolic signature of sun exposed skin suggests catabolic pathway overweighs anabolic pathway.

Directory of Open Access Journals (Sweden)

Manpreet Randhawa

Full Text Available Skin chronically exposed to sun results in phenotypic changes referred as photoaging. This aspect of aging has been studied extensively through genomic and proteomic tools. Metabolites, the end product are generated as a result of biochemical reactions are often studied as a culmination of complex interplay of gene and protein expression. In this study, we focused exclusively on the metabolome to study effects from sun-exposed and sun-protected skin sites from 25 human subjects. We generated a highly accurate metabolomic signature for the skin that is exposed to sun. Biochemical pathway analysis from this data set showed that sun-exposed skin resides under high oxidative stress and the chains of reactions to produce these metabolites are inclined toward catabolism rather than anabolism. These catabolic activities persuade the skin cells to generate metabolites through the salvage pathway instead of de novo synthesis pathways. Metabolomic profile suggests catabolic pathways and reactive oxygen species operate in a feed forward fashion to alter the biology of sun exposed skin.

Clinical results for salvage surgery in head and neck carcinoma after chemoradiation or radiation

International Nuclear Information System (INIS)

Ishida, Katsuhiro; Makino, Yohjiroh; Nagaoka, Masato; Seino, Youichi; Hama, Takanori; Aoki, Kensuke; Uchida, Mitsuru; Kato, Takakuni

2013-01-01

The objective of this study was to examine the post-operative complications of surgical procedures in oral or pharyngeal carcinoma by analyzing and comparing between patients who underwent salvage surgery after chemoradiation and radiation. A retrospective review was performed of 18 patients who underwent salvage surgery and reconstruction after concurrent chemoradiotherapy (CCRT group), and another 41 patients who underwent salvage surgery and reconstruction after radiation therapy (RT group). No perioperative deaths or life threatening systemic complications occurred, and all flaps survived completely in both groups. Surgical site infection (SSI) occurred in five patients (12.2%) in the RT group and seven patients (38%) in the CCRT group. SSI other than donor site infection occurred in four patients (9%) in the RT group and four patients (22%) in the CCRT group. The rate of SSI excluding donor site infection did not differ significantly between patients who underwent salvage surgery after CCRT and RT. The rate of donor site infection was higher in the CCRT group than in the RT group (p=0.04). This study showed that salvage surgery after CCRT or RT can be performed safely, without significant morbidity or mortality. However, patients who received CCRT are at risk for major complications caused by minor troubles, and thus reconstruction after salvage surgery should be performed with sufficient care. (author)

Hedgehog Pathway Inhibitor HhAntag691 Is a Potent Inhibitor of ABCG2/BCRP and ABCB1/Pgp

Directory of Open Access Journals (Sweden)

Yimao Zhang

2009-01-01

Full Text Available HhAntag691 (GDC-0449, a low-molecular weight inhibitor of the tumor-promoting hedgehog (Hh signaling pathway, has been used to treat medulloblastoma in animal models and has recently entered clinical trials for a variety of solid tumors. Here, we show that HhAntag691 inhibits multiple ATP-binding cassette (ABC transporters. ATP-binding cassette transporters are within a family of membrane proteins, the overexpression of which is associated with multidrug resistance, a major impediment to successful cancer treatment. HhAntag691 is a potent inhibitor of two ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, HhAntag691 increased retention of the fluorescent ABCG2 substrate BODIPY-prazosin and resensitized these cells to mitoxantrone, an antineoplastic ABCG2 substrate. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, HhAntag691 increased the retention of calcein-AM and resensitized them to colchicine. HhAntag691 also resensitized human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, to mitoxantrone, and to topotecan or SN-38. The IC50 values of HhAntag691 for inhibition of ABCG2 and Pgp were ∼1.4 and ∼3.0 µM, respectively. Because ABC transporters are highly expressed at the blood-brain barrier and on many tumor cells, they contribute significantly to treatment failure of many types of cancer, particularly of those within the neuraxis. In addition to its effect on Hh signaling, the ability of HhAntag691 and related compounds to inhibit two key ABC transporters could contribute to their effectiveness in treating malignancies.

Antitumor activity of a novel and orally available inhibitor of serine palmitoyltransferase

International Nuclear Information System (INIS)

Yaguchi, Masahiro; Shibata, Sachio; Satomi, Yoshinori; Hirayama, Megumi; Adachi, Ryutaro; Asano, Yasutomi; Kojima, Takuto; Hirata, Yasuhiro; Mizutani, Akio; Kiba, Atsushi; Sagiya, Yoji

2017-01-01

Metabolic reprogramming is an essential hallmark of neoplasia. Therefore, targeting cancer metabolism, including lipid synthesis, has attracted much interest in recent years. Serine palmitoyltransferase (SPT) plays a key role in the initial and rate-limiting step of de novo sphingolipid biosynthesis, and inhibiting SPT activity prevents the proliferation of certain cancer cells. Here, we identified a novel and orally available SPT inhibitor, compound-2. Compound-2 showed an anti-proliferative effect in several cancer cell models, reducing the levels of the sphingolipids ceramide and sphingomyelin. In the presence of compound-2, exogenously added S1P partially compensated the intracellular sphingolipid levels through the salvage pathway by partially rescuing compound-2-induced cytotoxicity. This suggested that the mechanism underlying the anti-proliferative effect of compound-2 involved the reduction of sphingolipid levels. Indeed, compound-2 promoted multinuclear formation with reduced endogenous sphingomyelin levels specifically in a compound-2-sensitive cell line, indicating that the effect was induced by sphingolipid reduction. Furthermore, compound-2 showed potent antitumor activity without causing significant body weight loss in the PL-21 acute myeloid leukemia mouse xenograft model. Therefore, SPT may be an attractive therapeutic anti-cancer drug target for which compound-2 may be a promising new drug. - Highlights: • We discovered compound-2, a novel and orally available SPT inhibitor. • Compound-2 was cytotoxic against PL-21 acute myeloid leukemia cells. • Compound-2 showed antitumor activity in the PL-21 mouse xenograft model.

Saphenous vein grafts for perforator flap salvage in autologous breast reconstruction.

Science.gov (United States)

Flores, Jaime I; Rad, Ariel N; Shridharani, Sachin M; Stapleton, Sahael M; Rosson, Gedge D

2009-01-01

Although the use of saphenous vein grafts in free-flap salvage and extremity replantation is relatively common, their use in breast reconstruction is rare. These two case reports represent extreme alternatives for breast reconstruction flap salvage. In our normal daily practice, the overwhelming majority of elective breast reconstructions proceed smoothly. However, the occasional patient may require saphenous vein graft flap rescue for completion of the reconstruction. (c) 2008 Wiley-Liss, Inc.

2-Fluoro-L-Fucose Is a Metabolically Incorporated Inhibitor of Plant Cell Wall Polysaccharide Fucosylation

Science.gov (United States)

Wallace, Ian S.

2015-01-01

The monosaccharide L-fucose (L-Fuc) is a common component of plant cell wall polysaccharides and other plant glycans, including the hemicellulose xyloglucan, pectic rhamnogalacturonan-I (RG-I) and rhamnogalacturonan-II (RG-II), arabinogalactan proteins, and N-linked glycans. Mutations compromising the biosynthesis of many plant cell wall polysaccharides are lethal, and as a result, small molecule inhibitors of plant cell wall polysaccharide biosynthesis have been developed because these molecules can be applied at defined concentrations and developmental stages. In this study, we characterize novel small molecule inhibitors of plant fucosylation. 2-fluoro-L-fucose (2F-Fuc) analogs caused severe growth phenotypes when applied to Arabidopsis seedlings, including reduced root growth and altered root morphology. These phenotypic defects were dependent upon the L-Fuc salvage pathway enzyme L-Fucose Kinase/ GDP-L-Fucose Pyrophosphorylase (FKGP), suggesting that 2F-Fuc is metabolically converted to the sugar nucleotide GDP-2F-Fuc, which serves as the active inhibitory molecule. The L-Fuc content of cell wall matrix polysaccharides was reduced in plants treated with 2F-Fuc, suggesting that this molecule inhibits the incorporation of L-Fuc into these polysaccharides. Additionally, phenotypic defects induced by 2F-Fuc treatment could be partially relieved by the exogenous application of boric acid, suggesting that 2F-Fuc inhibits RG-II biosynthesis. Overall, the results presented here suggest that 2F-Fuc is a metabolically incorporated inhibitor of plant cellular fucosylation events, and potentially suggest that other 2-fluorinated monosaccharides could serve as useful chemical probes for the inhibition of cell wall polysaccharide biosynthesis. PMID:26414071

Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

Energy Technology Data Exchange (ETDEWEB)

Fu, Meili [Department of Infectious Disease, Linyi People’s Hospital, Linyi (China); Shi, Wenhong [Department of Radiotherapy, Linyi Tumor Hospital, Linyi (China); Li, Zhengling [Department of Nursing, Tengzhou Central People’s Hospital, Tengzhou (China); Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com [Department of Nursing, Linyi People’s Hospital, No. 27 Jiefang Road, Linyi 276000, Shandong (China)

2016-09-02

Over-expression and aberrant activation of histone deacetylases (HDACs) are often associated with poor prognosis of hepatocellular carcinoma (HCC). Here, we evaluated the potential anti-hepatocellular carcinoma (HCC) cell activity by resminostat, a novel pan HDAC inhibitor (HDACi). We demonstrated that resminostat induced potent cytotoxic and anti-proliferative activity against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, resminostat treatment in HCC cells activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway, which was evidenced by physical association of cyclophilin-D and adenine nucleotide translocator 1 (ANT-1), mitochondrial depolarization, cytochrome C release and caspase-9 activation. Intriguingly, the mPTP blockers (sanglifehrin A and cyclosporine A), shRNA knockdown of cyclophilin-D or the caspase-9 inhibitor dramatically attenuated resminostat-induced HCC cell apoptosis and cytotoxicity. Reversely, HCC cells with exogenous cyclophilin-D over-expression were hyper-sensitive to resminostat. Intriguingly, a low concentration of resminostat remarkably potentiated sorafenib-induced mitochondrial apoptosis pathway activation, leading to a profound cytotoxicity in HCC cells. The results of this preclinical study indicate that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. - Highlights: • Resminostat inhibits human HCC cell survival and proliferation. • Resminostat activates mPTP-dependent mitochondrial apoptosis pathway in HCC cells. • Resminostat potentiates sorafenib-induced mitochondrial apoptosis pathway activation. • mPTP or caspase-9 inhibition attenuates apoptosis by resminostat or plus sorafenib.

19 CFR 4.97 - Salvage vessels.

Science.gov (United States)

2010-04-01

... United States and Great Britain ‘concerning reciprocal rights for United States and Canada in the... meaning of this statute. (e) A Mexican vessel may engage in a salvage operation on a Mexican vessel in any territorial waters of the United States in which Mexican vessels are permitted to conduct such operations by...

Salvage Stereotactic Body Radiation Therapy (SBRT) for Local Failure After Primary Lung SBRT

Energy Technology Data Exchange (ETDEWEB)

Hearn, Jason W.D., E-mail: hearnj@ccf.org; Videtic, Gregory M.M.; Djemil, Toufik; Stephans, Kevin L.

2014-10-01

Purpose: Local failure after definitive stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) is uncommon. We report the safety and efficacy of SBRT for salvage of local failure after previous SBRT with a biologically effective dose (BED) of ≥100 Gy{sub 10}. Methods and Materials: Using an institutional review board–approved lung SBRT registry, we identified all patients initially treated for early-stage NSCLC between August 2004 and January 2012 who received salvage SBRT for isolated local failure. Failure was defined radiographically and confirmed histologically unless contraindicated. All patients were treated on a Novalis/BrainLAB system using ExacTrac for image guidance, and received a BED of ≥100 Gy{sub 10} for each SBRT course. Tumor motion control involved a Bodyfix vacuum system for immobilization along with abdominal compression. Results: Of 436 patients treated from August 2004 through January 2012, we identified 22 patients with isolated local failure, 10 of whom received SBRT for salvage. The median length of follow-up was 13.8 months from salvage SBRT (range 5.3-43.5 months). Median tumor size was 3.4 cm (range 1.7-4.8 cm). Two of the 10 lesions were “central” by proximity to the mediastinum, but were outside the zone of the proximal bronchial tree. Since completing salvage, 3 patients are alive and without evidence of disease. A fourth patient died of medical comorbidities without recurrence 13.0 months after salvage SBRT. Two patients developed distant disease only. Four patients had local failure. Toxicity included grade 1-2 fatigue (3 patients) and grade 1-2 chest wall pain (5 patients). There was no grade 3-5 toxicity. Conclusions: Repeat SBRT with a BED of ≥100 Gy{sub 10} after local failure in patients with early-stage medically inoperable NSCLC was well tolerated in this series and may represent a viable salvage strategy in select patients with peripheral tumors ≤5 cm.

Identification of an inhibitor of the MurC enzyme, which catalyzes an essential step in the peptidoglycan precursor synthesis pathway.

Science.gov (United States)

Zawadzke, Laura E; Norcia, Michael; Desbonnet, Charlene R; Wang, Hong; Freeman-Cook, Kevin; Dougherty, Thomas J

2008-02-01

The pathway for synthesis of the peptidoglycan precursor UDP-N-acetylmuramyl pentapeptide is essential in Gram-positive and Gram-negative bacteria. This pathway has been exploited in the recent past to identify potential new antibiotics as inhibitors of one or more of the Mur enzymes. In the present study, a high-throughput screen was employed to identify potential inhibitors of the Escherichia coli MurC (UDP-N-acetylmuramic acid:L-alanine ligase), the first of four paralogous amino acid-adding enzymes. Inhibition of ATP consumed during the MurC reaction, using an adaptation of a kinase assay format, identified a number of potential inhibitory chemotypes. After nonspecific inhibition testing and chemical attractiveness were assessed, C-1 emerged as a compound for further characterization. The inhibition of MurC by this compound was confirmed in both a kinetic-coupled enzyme assay and a direct nuclear magnetic resonance product detection assay. C-1 was found to be a low micromolar inhibitor of the E. coli MurC reaction, with preferential inhibition by one of two enantiomeric forms. Experiments indicated that it was a competitive inhibitor of ATP binding to the MurC enzyme. Further work with MurC enzymes from several bacterial sources revealed that while the compound was equally effective at inhibiting MurC from genera (Proteus mirabilis and Klebsiella pneumoniae) closely related to E. coli, MurC enzymes from more distant Gram-negative species such as Haemophilus influenzae, Acinetobacter baylyi, and Pseudomonas aeruginosa were not inhibited.

Postoperative internal iliac artery embolisation as salvage therapy ...

African Journals Online (AJOL)

Postoperative internal iliac artery embolisation as salvage therapy for ... of blood products. Damage control surgery was performed, and bleeding was ultimately only ... abdomen was packed with adrenalin-soaked swabs. Coagulation.

Nucleotide metabolism in Lactococcus lactis: Salvage pathways of exogenous pyrimidines

DEFF Research Database (Denmark)

Martinussen, Jan; Andersen, Paal Skytt; Hammer, Karin

1994-01-01

By measuring enzyme activities in crude extracts and studying the effect of toxic analogs (5-fluoropyrimidines) on cell growth, the metabolism of pyrimidines in Lactococcus lactis was analyzed. Pathways by which uracil, uridine, deoxyuridine, cytidine, and deoxycytidine are metabolized in L. lact...

Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction.

Science.gov (United States)

Yang, Dezhong; Fu, Wenbin; Li, Liangpeng; Xia, Xuewei; Liao, Qiao; Yue, Rongchuan; Chen, Hongmei; Chen, Xiongwen; An, Songzhu; Zeng, Chunyu; Wang, Wei Eric

2017-12-15

After myocardial infarction (MI), the heart is difficult to repair because of great loss of cardiomyoctyes and lack of cardiac regeneration. Novel drug candidates that aim at reducing pathological remodeling and stimulating cardiac regeneration are highly desirable. In the present study, we identified if and how a novel porcupine inhibitor CGX1321 influenced MI and cardiac regeneration. Permanent ligation of left anterior descending (LAD) coronary artery was performed in mice to induce MI injury. Cardiac function was measured by echocardiography, infarct size was examined by TTC staining. Fibrosis was evaluated with Masson's trichrome staining and vimentin staining. As a result, CGX1321 administration blocked the secretion of Wnt proteins, and inhibited both canonical and non-canonical Wnt signaling pathways. CGX1321 improved cardiac function, reduced myocardial infarct size, and fibrosis of post-MI hearts. CGX1321 significantly increased newly formed cardiomyocytes in infarct border zone of post-MI hearts, evidenced by the increased EdU + cardiomyocytes. Meanwhile, CGX1321 increased Ki67 + and phosphohistone H3 (PH3 + ) cardiomyocytes in culture, indicating enhanced cardiomyocyte proliferation. The mRNA microarray showed that CGX1321 up-regulated cell cycle regulating genes such as Ccnb1 and Ccne1 CGX1321 did not alter YAP protein phosphorylation and nuclear translocation in cardiomyocytes. In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP-independent pathway. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Effects of definitive and salvage radiotherapy on the distribution of lymphocyte subpopulations in prostate cancer patients

Energy Technology Data Exchange (ETDEWEB)

Sage, Eva K.; Gehrmann, Mathias; Sedelmayr, Michael [Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); Schmid, Thomas E.; Combs, Stephanie E.; Multhoff, Gabriele [Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); HelmholtzZentrum Muenchen, Department of Radiation Sciences (DRS), Institute of Innovate Radiotherapy (iRT), Munich (Germany); Deutsches Konsortium fuer Translationale Krebsforschung (DKTK), Partner Site Munich, Munich (Germany); Geinitz, Hans [Johannes Kepler University, Department of Radiation Oncology, Ordensklinikum Linz, Krankenhaus der Barmherzigen Schwestern and Medical Faculty, Linz (Austria); Duma, Marciana N. [Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); HelmholtzZentrum Muenchen, Department of Radiation Sciences (DRS), Institute of Innovate Radiotherapy (iRT), Munich (Germany)

2017-08-15

Radiotherapy (RT) is an established treatment for patients with primary and recurrent prostate cancer. Herein, the effects of definitive and salvage RT on the composition of lymphocyte subpopulations were investigated in patients with prostate cancer to study potential immune effects. A total of 33 prostate cancer patients were treated with definitive (n = 10) or salvage RT (n = 23) after biochemical relapse. The absolute number of lymphocytes and the distribution of lymphocyte subpopulations were analyzed by multiparameter flow cytometry before RT, at the end of RT, and in the follow-up period. Absolute lymphocyte counts decreased significantly after RT in both patient groups and a significant drop was observed in the percentage of B cells directly after RT from 10.1 ± 1.3 to 6.0 ± 0.7% in patients with definitive RT and from 9.2 ± 0.8 to 5.8 ± 0.7% in patients with salvage RT. In contrast, the percentages of T and natural killer (NK) cells remained unaltered directly after RT in both patient groups. However, 1 year after RT, the percentage of CD3{sup +} T cells was significantly lower in patients with definitive and salvage RT. The percentage of regulatory T cells was slightly upregulated in primary prostate cancer patients after definitive RT, but not after salvage RT. Definitive and salvage RT exert similar effects on the composition of lymphocyte subpopulations in prostate cancer patients. Total lymphocyte counts are lower in both patient groups compared to healthy controls and further decreased after RT. B cells are more sensitive to definitive and salvage RT than T and NK cells. (orig.) [German] Die Strahlentherapie (RT) ist eine bewaehrte Behandlung beim primaeren und rezidivierten Prostatakarzinoms. In dieser Studie wurde der Einfluss einer definitiven und Salvage RT auf die Zusammensetzung der Lymphozytensubpopulationen verglichen, um potenzielle Immuneffekte einer RT zu analysieren. In die Studie wurden 33 Prostatakarzinompatienten eingeschlossen

Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway

Science.gov (United States)

Lorenz, Christian; Dougherty, Thomas J.

2016-01-01

ABSTRACT In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. IMPORTANCE Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. PMID

Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway.

Science.gov (United States)

Lorenz, Christian; Dougherty, Thomas J; Lory, Stephen

2016-12-01

In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. Copyright © 2016 Lorenz et al.

Washed cell salvage in surgical patients: A review and meta-analysis of prospective randomized trials under PRISMA.

Science.gov (United States)

Meybohm, Patrick; Choorapoikayil, Suma; Wessels, Anke; Herrmann, Eva; Zacharowski, Kai; Spahn, Donat R

2016-08-01

Cell salvage is commonly used as part of a blood conservation strategy. However concerns among clinicians exist about the efficacy of transfusion of washed cell salvage. We performed a meta-analysis of randomized controlled trials in which patients, scheduled for all types of surgery, were randomized to washed cell salvage or to a control group with no cell salvage. Data were independently extracted, risk ratio (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random effects model. The primary endpoint was the number of patients exposed to allogeneic red blood cell (RBC) transfusion. Out of 1140 search results, a total of 47 trials were included. Overall, the use of washed cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 39% (RR = 0.61; 95% CI 0.57 to 0.65; P platelets, or rate of myocardial infarction and stroke. Washed cell salvage is efficacious in reducing the need for allogeneic RBC transfusion and risk of infection in surgery.

Potential for water salvage by removal of non-native woody vegetation from dryland river systems

Science.gov (United States)

Doody, T.M.; Nagler, P.L.; Glenn, E.P.; Moore, G.W.; Morino, K.; Hultine, K.R.; Benyon, R.G.

2011-01-01

Globally, expansion of non-native woody vegetation across floodplains has raised concern of increased evapotranspiration (ET) water loss with consequent reduced river flows and groundwater supplies. Water salvage programs, established to meet water supply demands by removing introduced species, show little documented evidence of program effectiveness. We use two case studies in the USA and Australia to illustrate factors that contribute to water salvage feasibility for a given ecological setting. In the USA, saltcedar (Tamarix spp.) has become widespread on western rivers, with water salvage programs attempted over a 50-year period. Some studies document riparian transpiration or ET reduction after saltcedar removal, but detectable increases in river base flow are not conclusively shown. Furthermore, measurements of riparian vegetation ET in natural settings show saltcedar ET overlaps the range measured for native riparian species, thereby constraining the possibility of water salvage by replacing saltcedar with native vegetation. In Australia, introduced willows (Salix spp.) have become widespread in riparian systems in the Murray-Darling Basin. Although large-scale removal projects have been undertaken, no attempts have been made to quantify increases in base flows. Recent studies of ET indicate that willows growing in permanently inundated stream beds have high transpiration rates, indicating water savings could be achieved from removal. In contrast, native Eucalyptus trees and willows growing on stream banks show similar ET rates with no net water salvage from replacing willows with native trees. We conclude that water salvage feasibility is highly dependent on the ecohydrological setting in which the non-native trees occur. We provide an overview of conditions favorable to water salvage. Copyright ?? 2011 John Wiley & Sons, Ltd.

Adjuvant and Salvage Radiotherapy After Prostatectomy for Prostate Cancer: A Literature Review

International Nuclear Information System (INIS)

Pasquier, David; Ballereau, Charles

2008-01-01

Purpose: Given that postprostatectomy recurrence of prostate cancer occurs in 10-40% of patients, the best use of immediate postoperative radiotherapy (RT) in high-risk patients and salvage RT for biochemical recurrence remains a topic of debate. We assessed the levels of evidence (in terms of efficacy, prognostic factors, and toxicity) for the following treatment strategies: immediate postoperative RT alone, salvage RT alone, and the addition of androgen deprivation therapy to the two RT strategies. Methods and Materials: A systematic literature search for controlled randomized trials, noncontrolled trials, and retrospective studies between 1990 and 2008 was performed on PubMed, CancerLit, and MEDLINE. Only relevant articles that had appeared in peer-reviewed journals were selected. We report on the levels of evidence (according to the National Cancer Institute guidelines) supporting the various treatment strategies. Results: Immediate postoperative RT improves biochemical and clinical progression-free survival (Level of evidence, 1.ii) but has no significant effect on metastasis-free survival or overall survival. A pathologic review is of particular importance for correctly analyzing the treatment strategies. Low-grade morbidity has been significantly greater in the postoperative groups, but no severe toxicity has been observed. The influence of immediate postoperative RT on postprostatectomy continence appears to be slight; therefore, immediate postoperative RT should be considered in patients with major risk factors for local relapse (Level of evidence, 1.ii). On the basis of extensive retrospective data, salvage RT is effective in biochemical relapse after prostatectomy; some patients with few adverse prognostic factors might also benefit from salvage RT (Level of evidence, 3.ii). The addition of androgen deprivation therapy to immediate postoperative or salvage RT has only been supported by weak, retrospective data (Level of evidence, 3.ii). Conclusion

Singular and interactive effects of blowdown, salvage logging, and wildfire in sub-boreal pine systems

Science.gov (United States)

D'Amato, A.W.; Fraver, S.; Palik, B.J.; Bradford, J.B.; Patty, L.

2011-01-01

The role of disturbance in structuring vegetation is widely recognized; however, we are only beginning to understand the effects of multiple interacting disturbances on ecosystem recovery and development. Of particular interest is the impact of post-disturbance management interventions, particularly in light of the global controversy surrounding the effects of salvage logging on forest ecosystem recovery. Studies of salvage logging impacts have focused on the effects of post-disturbance salvage logging within the context of a single natural disturbance event. There have been no formal evaluations of how these effects may differ when followed in short sequence by a second, high severity natural disturbance. To evaluate the impact of this management practice within the context of multiple disturbances, we examined the structural and woody plant community responses of sub-boreal Pinus banksiana systems to a rapid sequence of disturbances. Specifically, we compared responses to Blowdown (B), Fire (F), Blowdown-Fire, and Blowdown-Salvage-Fire (BSF) and compared these to undisturbed control (C) stands. Comparisons between BF and BSF indicated that the primary effect of salvage logging was a decrease in the abundance of structural legacies, such as downed woody debris and snags. Both of these compound disturbance sequences (BF and BSF), resulted in similar woody plant communities, largely dominated by Populus tremuloides; however, there was greater homogeneity in community composition in salvage logged areas. Areas experiencing solely fire (F stands) were dominated by P. banksiana regeneration, and blowdown areas (B stands) were largely characterized by regeneration from shade tolerant conifer species. Our results suggest that salvage logging impacts on woody plant communities are diminished when followed by a second high severity disturbance; however, impacts on structural legacies persist. Provisions for the retention of snags, downed logs, and surviving trees as part

Association of Preoperative Nutritional Status with Prognosis in Patients with Esophageal Cancer Undergoing Salvage Esophagectomy.

Science.gov (United States)

Sakai, Makoto; Sohda, Makoto; Miyazaki, Tatsuya; Yoshida, Tomonori; Kumakura, Yuji; Honjo, Hiroaki; Hara, Keigo; Ozawa, Daigo; Suzuki, Shigemasa; Tanaka, Naritaka; Yokobori, Takehiko; Kuwano, Hiroyuki

2018-02-01

To investigate whether malnutrition is associated with poor prognosis of patients who undergo salvage esophagectomy. We examined the association between the preoperative prognostic nutritional index (PNI) and prognosis of patients who undergo salvage esophagectomy. We conducted a single-center retrospective study and reviewed hospital patient records for tumor characteristics and patient outcomes. Univariate and multivariate survival analyses were carried out using the Cox proportional hazards regression model. Thirty-two patients with esophageal squamous cell carcinoma (ESCC) who underwent salvage esophagectomy between 1998 and 2015 at our Institute were included in this study. Univariate analysis revealed that clinical response (p=0.045), preoperative PNI (pnutritional status is associated with the prognosis of patients undergoing salvage esophagectomy. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Salvage surgery for local failure of oral squamous cell carcinoma

International Nuclear Information System (INIS)

Omura, Ken; Harada, Hiroyuki; Shimamoto, Hiroaki

2003-01-01

Local failure rates following treatment for squamous cell carcinoma of the oral cavity have been reported to be in the range of 25%-48%. This study investigated the pattern of failure for squamous cell carcinoma (SCC) of the oral cavity and evaluated salvage surgery for local recurrent disease. The tumor files of 549 patients undergoing treatment for SCC of the oral cavity between 1980 and 2000 at Chiba Cancer Center Hospital were reviewed. Of 549 patients, 289 were initially treated with radiation therapy for their primary tumor, and 260 with surgery, either with or without radiation therapy. One hundred and sixty-one patients developed failures, yielding a failure rate of 29.3%. The site of recurrent tumor was local in 72 (13.1%) patients, regional in 89 (16.2%) patients, and distant in 5 (0.9%) patients. Local failure developed in 49 (17.0%) patients with radiation therapy and in 23 (8.8%) patients with surgery. Out of these 72 patients with local failure, 41 (56.9%) patients had salvage surgery for their disease. Twenty-five (73.5%) of the 34 patients initially treated with radiation therapy were salvaged with surgery, and 4 (57.1%) of the 7 patients initially treated with surgery were cured with further surgery. For the treatment of patients with local failure, the disease should be diagnosed more carefully than untreated disease. The disease that has recurred after radiation therapy may be more likely to be salvaged by surgery, however, the disease that has developed after surgery may have a limited indication for re-surgery. (author)

Thymidine kinases share a conserved function for nucleotide salvage and play an essential role in Arabidopsis thaliana growth and development.

Science.gov (United States)

Xu, Jing; Zhang, Lin; Yang, Dong-Lei; Li, Qun; He, Zuhua

2015-12-01

Thymidine kinases (TKs) are important components in the nucleotide salvage pathway. However, knowledge about plant TKs is quite limited. In this study, the molecular function of TKs in Arabidopsis thaliana was investigated. Two TKs were identified and named AtTK1 and AtTK2. Expression of both genes was ubiquitous, but AtTK1 was strongly expressed in high-proliferation tissues. AtTK1 was localized to the cytosol, whereas AtTK2 was localized to the mitochondria. Mutant analysis indicated that the two genes function coordinately to sustain normal plant development. Enzymatic assays showed that the two TK proteins shared similar catalytic specificity for pyrimidine nucleosides. They were able to complement an Escherichia coli strain lacking TK activity. 5'-Fluorodeoxyuridine (FdU) resistance and 5-ethynyl 2'-deoxyuridine (EdU) incorporation assays confirmed their activity in vivo. Furthermore, the tk mutant phenotype could be alleviated by nucleotide feeding, establishing that the biosynthesis of pyrimidine nucleotides was disrupted by the TK deficiency. Finally, both human and rice (Oryza sativa) TKs were able to rescue the tk mutants, demonstrating the functional conservation of TKs across organisms. Taken together, our findings clarify the specialized function of two TKs in A. thaliana and establish that the salvage pathway mediated by the kinases is essential for plant growth and development. © 2015 Institute of Plant Physiology and Ecology, SIBS, CAS New Phytologist © 2015 New Phytologist Trust.

Elucidation of salvage laryngectomy pathologic and clinical variables to guide further treatment intensification investigation.

Science.gov (United States)

Scharpf, Joseph; Ward, Matthew; Adelstein, David; Koyfman, Shlomo; Li, Mingsi

2018-04-01

There are limited treatment options beyond surgical salvage for patients who fail nonoperative treatment for laryngeal squamous cell carcinoma. In this study, we examine the failure patterns after surgical salvage and the potential pathologic and clinical prognostic variables that might guide further postoperative intensification investigation. Retrospective analysis at a tertiary academic referral center. From an institutional review board-approved institutional head and neck cancer registry, a consecutive series of 147 patients who underwent salvage laryngectomy for squamous cell cancer recurrence or persistence after radiotherapy with or without chemotherapy between May 1995 and May 2016 were identified. Variables potentially associated with oncologic outcome after surgical salvage were then collected and retrospectively evaluated. The projected 2-year locoregional failure rate was 21.8% (95% confidence interval [CI], 14.6%-29.0%]), and the overall survival 65% (95% CI, 57.5%-74.3%) for the entire cohort after salvage laryngectomy. On multivariable analysis, sarcomatoid/spindle cell pathology (hazard ratio [HR], 3.147; 95% CI, 1.181-8.386; P = 0.022), lymphovascular space invasion (LVSI) (positive vs. negative; HR, 2.31; 95% CI, 1.21-4.42; P = 0.011), and advanced initial American Joint Committee on Cancer 7th Edition grouped stage (stages III-IVB vs. stages I-II; HR, 1.64; 95% CI, 1.04-2.6; P = 0.035) were found to be independently associated with inferior disease-free survival. No other clinical or pathologic variables predicted failure. Salvage laryngectomy after nonoperative treatment failure results in successful locoregional control rates and survival in the majority of patients failing initial therapy. This should temper enthusiasm for routine treatment intensification with postoperative re-irradiation and/or other systemic treatments for the vast majority of patients. Sarcomatoid pathology, LVSI, and an advanced initial stage are associated with inferior

Long-term oncologic results of salvage radical prostatectomy for locally recurrent prostate cancer after radiotherapy

International Nuclear Information System (INIS)

Bianco, Fernando J.; Scardino, Peter T.; Stephenson, Andrew J.; DiBlasio, Christopher J.; Fearn, Paul A.; Eastham, James A.

2005-01-01

Purpose: Salvage radical prostatectomy (RP) may potentially cure patients who have isolated local prostate cancer recurrence after radiotherapy (RT). We report the long-term cancer control associated with salvage RP in a consecutive cohort of patients and identify the variables associated with disease progression and cancer survival. Methods and Materials: A total of 100 consecutive patients underwent salvage RP with curative intent for biopsy-confirmed, locally recurrent, prostate cancer after RT. Disease progression after salvage RP was defined as a prostate-specific antigen (PSA) level of ≥0.2 ng/mL or by initiation of androgen deprivation therapy. Cancer-specific mortality was defined as active clinical disease progression despite castration. Cox regression analysis was used to evaluate these endpoints. The median follow-up from RT was 10 years (range, 3-27 years) and from salvage RP was 5 years (range, 1-20 years). Results: Overall, the 5-year progression-free probability was 55% (95% confidence interval, 46-64%), and the median progression-free interval was 6.4 years. The preoperative PSA level was the only significant pretreatment predictor of disease progression in the multivariate analysis (p = 0.01). The 5-year progression-free probability for patients with a preoperative PSA level of 10 ng/mL was 86%, 55%, and 37%, respectively. The 10-year and 15-year cancer-specific mortality after salvage RP was 27% and 40%, respectively. The median time from disease progression to cancer-specific death was 10.3 years (95% confidence interval, 7.6-12.9). After multivariate analysis, the preoperative serum PSA level and seminal vesicle or lymph node status correlated independently with disease progression. Conclusions: Greater preoperative PSA levels are associated with disease progression and cancer-specific death. Long-term control of locally recurrent prostate cancer after definitive RT is possible when salvage RP is performed early in the course of recurrent

Discovery of novel inhibitors for Leishmania nucleoside diphosphatase kinase (NDK) based on its structural and functional characterization

Science.gov (United States)

Mishra, Arjun K.; Singh, Nidhi; Agnihotri, Pragati; Mishra, Shikha; Singh, Saurabh P.; Kolli, Bala K.; Chang, Kwang Poo; Sahasrabuddhe, Amogh A.; Siddiqi, M. I.; Pratap, J. Venkatesh

2017-06-01

Nucleoside diphosphate kinases (NDKs) are ubiquitous enzymes that catalyze the transfer of the γ-phosphate moiety from an NTP donor to an NDP acceptor, crucial for maintaining the cellular level of nucleoside triphosphates (NTPs). The inability of trypanosomatids to synthesize purines de novo and their dependence on the salvage pathway makes NDK an attractive target to develop drugs for the diseases they cause. Here we report the discovery of novel inhibitors for Leishmania NDK based on the structural and functional characterization of purified recombinant NDK from Leishmania amazonensis. Recombinant LaNDK possesses auto-phosphorylation, phosphotransferase and kinase activities with Histidine 117 playing an essential role. LaNDK crystals were grown by hanging drop vapour diffusion method in a solution containing 18% PEG-MME 500, 100 mM Bis-Tris propane pH 6.0 and 50 mM MgCl2. It belongs to the hexagonal space group P6322 with unit cell parameters a = b = 115.18, c = 62.18 Å and α = β = 90°, γ = 120°. The structure solved by molecular replacement methods was refined to crystallographic R-factor and Rfree values of 22.54 and 26.52%, respectively. Molecular docking and dynamics simulation -based virtual screening identified putative binding compounds. Protein inhibition studies of selected hits identified five inhibitors effective at micromolar concentrations. One of the compounds showed 45% inhibition of Leishmania promastigotes proliferation. Analysis of inhibitor-NDK complexes reveals the mode of their binding, facilitating design of new compounds for optimization of activities as drugs against leishmaniasis.

Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

International Nuclear Information System (INIS)

Azuma, Koichi; Tsurutani, Junji; Sakai, Kazuko; Kaneda, Hiroyasu; Fujisaka, Yasuhito; Takeda, Masayuki; Watatani, Masahiro; Arao, Tokuzo; Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu; Nishio, Kazuto; Nakagawa, Kazuhiko

2011-01-01

Highlights: → A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. → Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. → Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC 50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

Energy Technology Data Exchange (ETDEWEB)

Azuma, Koichi [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Tsurutani, Junji, E-mail: tsurutani_j@dotd.med.kindai.ac.jp [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Sakai, Kazuko; Kaneda, Hiroyasu [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Fujisaka, Yasuhito; Takeda, Masayuki [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Watatani, Masahiro [Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Arao, Tokuzo [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nishio, Kazuto [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nakagawa, Kazuhiko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan)

2011-04-01

Highlights: {yields} A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. {yields} Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. {yields} Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC{sub 50} of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

TEXTILE SALVAGE

CERN Multimedia

Relations with the Host States Service

2002-01-01

Readers are reminded that Geneva's agency for salvaging used clothing, other textiles and old shoes (Coordination d'oeuvres d'entraide pour la récupération de vêtements, textiles et chaussures usagés dans le canton de Genève) has a container in the car park outside CERN's Meyrin site. In 2001, 1000 tonnes of such items were collected in the Canton of Geneva (as compared with 840 tonnes in 2000), of which 4460 kg came from the container outside the Meyrin site. The operation's organisers (Caritas, Centre Social Protestant, the Geneva Section of the Swiss Red Cross, Terre des Hommes, the Geneva branch of Terre des Hommes Suisse and Emmaüs, Geneva) would like to thank all those who have donated clothing or otherwise supported their campaign. Relations with the Host States Service Tel. 72848 http://www.cern.ch/relations/

Upfront Androgen Deprivation Therapy With Salvage Radiation May Improve Biochemical Outcomes in Prostate Cancer Patients With Post-Prostatectomy Rising PSA

Energy Technology Data Exchange (ETDEWEB)

Jang, Joanne W. [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Hwang, Wei-Ting [Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Guzzo, Thomas J.; Wein, Alan J. [Department of Urology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Haas, Naomi B. [Department of Medical Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Both, Stefan [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Vapiwala, Neha, E-mail: vapiwala@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States)

2012-08-01

Purpose: The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT. Methods and Materials: Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Security Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT. Results: One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores {<=}7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013). Conclusions: These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in

Predictors of biochemical failure in patients undergoing prostate whole-gland salvage cryotherapy: a novel risk stratification model.

Science.gov (United States)

Spiess, Philippe E; Levy, David A; Mouraviev, Vladimir; Pisters, Louis L; Jones, J Stephen

2013-08-01

What's known on the subject? and what does the study add?: Previous studies have identified the most important prognostic factors of the likely outcomes of salvage prostate whole-gland ablation, including initial clinical stage, biopsy Gleason score, and PSA (total and doubling time). There is potential for further optimization of candidate selection for salvage cryoablation with curative intent and nadir PSA achieved after whole-gland cryotherapy may provide additional prognostic value. The study shows that the most important prognostic factors of biochemical progression-free survival for patients who have undergone whole-gland salvage prostate cryotherapy are nadir PSA achieved after therapy and pre-therapy biopsy Gleason score. Based on these two prognostic variables, we have identified risk stratification groups (low, intermediate and high) which help predict the expected outcomes of salvage whole-gland prostate cryotherapy in a given patient. This risk stratification constitutes a useful clinical tool in defining which patients maybe best suited for this local salvage treatment method. To assess the prognostic variables predicting the risk of biochemical progression-free survival (bPFS) after salvage prostate whole-gland cryotherapy using the Phoenix definition of bPFS. A total of 132 patients underwent prostate whole-gland salvage cryotherapy with curative intent. No patient underwent neoadjuvant/adjuvant hormonal ablative therapy, and all had extended post-salvage prostate-specific antigen (PSA) follow-up data. Cox univariate and multivariate logistic regression analyses of potential predictors of bPFS were conducted. Kaplan-Meier analyses of bPFS was also performed. At a mean (range) follow-up of 4.3 (0.9-12.7) years, the median (range) post-cryotherapy nadir PSA achieved was 0.17 (0-33.9) ng/mL. On multivariate analysis, predictors of bPFS were nadir PSA post-cryotherapy and pre-salvage biopsy Gleason score (P 2.5 ng/mL or biopsy Gleason score ≥ 7, with

28 CFR 25.56 - Responsibilities of junk yards and salvage yards and auto recyclers.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Responsibilities of junk yards and salvage yards and auto recyclers. 25.56 Section 25.56 Judicial Administration DEPARTMENT OF JUSTICE... Responsibilities of junk yards and salvage yards and auto recyclers. (a) By no later than March 31, 2009, and...

Influence of [18F] fluorodeoxyglucose positron emission tomography on salvage treatment decision making for locally persistent nasopharyngeal carcinoma

International Nuclear Information System (INIS)

Zheng Xiaojang; Chen Longhua; Wang Quanshi; Wu Fubing

2006-01-01

Purpose: The purpose of this study was to evaluate the role of [ 18 F] fluorodeoxyglucose positron emission tomography (FDG-PET) in influencing salvage treatment decision making for locally persistent nasopharyngeal carcinoma (NPC). Methods and Materials: A total of 33 NPC patients with histologic persistence at nasopharynx 1 to 6 weeks after a full course of radiotherapy underwent both computed tomography (CT) and FDG-PET/CT simulation at the same treatment position. The salvage treatment decisions, with regard to the decision to offer salvage treatment and the definition of gross tumor volume (GTV), were made before knowledge of the FDG-PET findings. Subsequently the salvage treatment decisions were made again based on the FDG-PET findings and compared with the pre-FDG-PET decisions. Results: All 33 patients were referred for salvage treatment in the pre-FDG-PET decision. After knowledge of the FDG-PET results, the decision to offer salvage treatment was withdrawn in 4 of 33 patients (12.1%), as no abnormal uptake of FDG was found at nasopharynx. Spontaneous remission was observed in repeat biopsies and no local recurrence was found in these 4 cases. For the remaining 29 patients, GTV based on FDG-PET was smaller than GTV based on CT in 24 (82.8%) cases and was greater in 5 (17.2%) cases, respectively. The target volume had to be significantly modified in 9 of 29 patients (31%), as GTV based on FDG-PET images failed to be enclosed by the treated volume in the salvage treatment plan performed based on GTV based on CT simulation images. Conclusion: Use of FDG-PET was found to influence the salvage treatment decision making for locally persistent NPC by identifying patients who were not likely to benefit from additional treatment and by improving accuracy of GTV definition in salvage treatment planning

Effects of salvage logging and pile-and-burn on fuel loading, potential fire behaviour, fuel consumption and emissions

Science.gov (United States)

Morris C. Johnson; Jessica E. Halofsky; David L. Peterson

2013-01-01

We used a combination of field measurements and simulation modelling to quantify the effects of salvage logging, and a combination of salvage logging and pile-and-burn fuel surface fuel treatment (treatment combination), on fuel loadings, fire behaviour, fuel consumption and pollutant emissions at three points in time: post-windstorm (before salvage logging), post-...

Enhancing GDP-fucose production in recombinant Escherichia coli by metabolic pathway engineering.

Science.gov (United States)

Zhai, Yafei; Han, Donglei; Pan, Ying; Wang, Shuaishuai; Fang, Junqiang; Wang, Peng; Liu, Xian-wei

2015-02-01

Guanosine 5'-diphosphate (GDP)-fucose is the indispensible donor substrate for fucosyltransferase-catalyzed synthesis of fucose-containing biomolecules, which have been found involving in various biological functions. In this work, the salvage pathway for GDP-fucose biosynthesis from Bacterioides fragilis was introduced into Escherichia coli. Besides, the biosynthesis of guanosine 5'-triphosphate (GTP), an essential substrate for GDP-fucose biosynthesis, was enhanced via overexpression of enzymes involved in the salvage pathway of GTP biosynthesis. The production capacities of metabolically engineered strains bearing different combinations of recombinant enzymes were compared. The shake flask fermentation of the strain expressing Fkp, Gpt, Gmk and Ndk obtained the maximum GDP-fucose content of 4.6 ± 0.22 μmol/g (dry cell mass), which is 4.2 fold that of the strain only expressing Fkp. Through fed-batch fermentation, the GDP-fucose content further rose to 6.6 ± 0.14 μmol/g (dry cell mass). In addition to a better productivity than previous fermentation processes based on the de novo pathway for GDP-fucose biosynthesis, the established schemes in this work also have the advantage to be a potential avenue to GDP-fucose analogs encompassing chemical modification on the fucose residue. Copyright © 2014 Elsevier Inc. All rights reserved.

Percutaneous Endovascular Salvage Techniques for Implanted Venous Access Device Dysfunction

International Nuclear Information System (INIS)

Breault, Stéphane; Glauser, Frédéric; Babaker, Malik; Doenz, Francesco; Qanadli, Salah Dine

2015-01-01

PurposeImplanted venous access devices (IVADs) are often used in patients who require long-term intravenous drug administration. The most common causes of device dysfunction include occlusion by fibrin sheath and/or catheter adherence to the vessel wall. We present percutaneous endovascular salvage techniques to restore function in occluded catheters. The aim of this study was to evaluate the feasibility, safety, and efficacy of these techniques.Methods and MaterialsThrough a femoral or brachial venous access, a snare is used to remove fibrin sheath around the IVAD catheter tip. If device dysfunction is caused by catheter adherences to the vessel wall, a new “mechanical adhesiolysis” maneuver was performed. IVAD salvage procedures performed between 2005 and 2013 were analyzed. Data included clinical background, catheter tip position, success rate, recurrence, and rate of complication.ResultsEighty-eight salvage procedures were performed in 80 patients, mostly women (52.5 %), with a mean age of 54 years. Only a minority (17.5 %) of evaluated catheters were located at an optimal position (i.e., cavoatrial junction ±1 cm). Mechanical adhesiolysis or other additional maneuvers were used in 21 cases (24 %). Overall technical success rate was 93.2 %. Malposition and/or vessel wall adherences were the main cause of technical failure. No complications were noted.ConclusionThese IVAD salvage techniques are safe and efficient. When a catheter is adherent to the vessel wall, mechanical adhesiolysis maneuvers allow catheter mobilization and a greater success rate with no additional risk. In patients who still require long-term use of their IVAD, these procedures can be performed safely to avoid catheter replacement

Percutaneous Endovascular Salvage Techniques for Implanted Venous Access Device Dysfunction

Energy Technology Data Exchange (ETDEWEB)

Breault, Stéphane, E-mail: stephane.breault@chuv.ch [Lausanne University Hospital, Diagnostic and Interventional Radiology Department (Switzerland); Glauser, Frédéric, E-mail: frederic.glauser@chuv.ch [Lausanne University Hospital, Angiology and Diagnostic and Interventional Radiology Departments (Switzerland); Babaker, Malik, E-mail: malik.babaker@chuv.ch; Doenz, Francesco, E-mail: francesco.doenz@chuv.ch; Qanadli, Salah Dine, E-mail: salah.qanadli@chuv.ch [Lausanne University Hospital, Diagnostic and Interventional Radiology Department (Switzerland)

2015-06-15

PurposeImplanted venous access devices (IVADs) are often used in patients who require long-term intravenous drug administration. The most common causes of device dysfunction include occlusion by fibrin sheath and/or catheter adherence to the vessel wall. We present percutaneous endovascular salvage techniques to restore function in occluded catheters. The aim of this study was to evaluate the feasibility, safety, and efficacy of these techniques.Methods and MaterialsThrough a femoral or brachial venous access, a snare is used to remove fibrin sheath around the IVAD catheter tip. If device dysfunction is caused by catheter adherences to the vessel wall, a new “mechanical adhesiolysis” maneuver was performed. IVAD salvage procedures performed between 2005 and 2013 were analyzed. Data included clinical background, catheter tip position, success rate, recurrence, and rate of complication.ResultsEighty-eight salvage procedures were performed in 80 patients, mostly women (52.5 %), with a mean age of 54 years. Only a minority (17.5 %) of evaluated catheters were located at an optimal position (i.e., cavoatrial junction ±1 cm). Mechanical adhesiolysis or other additional maneuvers were used in 21 cases (24 %). Overall technical success rate was 93.2 %. Malposition and/or vessel wall adherences were the main cause of technical failure. No complications were noted.ConclusionThese IVAD salvage techniques are safe and efficient. When a catheter is adherent to the vessel wall, mechanical adhesiolysis maneuvers allow catheter mobilization and a greater success rate with no additional risk. In patients who still require long-term use of their IVAD, these procedures can be performed safely to avoid catheter replacement.

2-Fluoro-L-Fucose Is a Metabolically Incorporated Inhibitor of Plant Cell Wall Polysaccharide Fucosylation.

Directory of Open Access Journals (Sweden)

Jose A Villalobos

Full Text Available The monosaccharide L-fucose (L-Fuc is a common component of plant cell wall polysaccharides and other plant glycans, including the hemicellulose xyloglucan, pectic rhamnogalacturonan-I (RG-I and rhamnogalacturonan-II (RG-II, arabinogalactan proteins, and N-linked glycans. Mutations compromising the biosynthesis of many plant cell wall polysaccharides are lethal, and as a result, small molecule inhibitors of plant cell wall polysaccharide biosynthesis have been developed because these molecules can be applied at defined concentrations and developmental stages. In this study, we characterize novel small molecule inhibitors of plant fucosylation. 2-fluoro-L-fucose (2F-Fuc analogs caused severe growth phenotypes when applied to Arabidopsis seedlings, including reduced root growth and altered root morphology. These phenotypic defects were dependent upon the L-Fuc salvage pathway enzyme L-Fucose Kinase/ GDP-L-Fucose Pyrophosphorylase (FKGP, suggesting that 2F-Fuc is metabolically converted to the sugar nucleotide GDP-2F-Fuc, which serves as the active inhibitory molecule. The L-Fuc content of cell wall matrix polysaccharides was reduced in plants treated with 2F-Fuc, suggesting that this molecule inhibits the incorporation of L-Fuc into these polysaccharides. Additionally, phenotypic defects induced by 2F-Fuc treatment could be partially relieved by the exogenous application of boric acid, suggesting that 2F-Fuc inhibits RG-II biosynthesis. Overall, the results presented here suggest that 2F-Fuc is a metabolically incorporated inhibitor of plant cellular fucosylation events, and potentially suggest that other 2-fluorinated monosaccharides could serve as useful chemical probes for the inhibition of cell wall polysaccharide biosynthesis.

Process for gasification of heavy hydrocarbons or salvaged oil. [German patent

Energy Technology Data Exchange (ETDEWEB)

Koch, C

1978-09-14

The invention refers to the separation of solids which are carried over during evaporation of salvaged oil (oil recovered from used oil or fat). They are removed by exposing the oil vapour to an acceleration of 500 g to 20,000g in a hot gas cyclone. Subsequently the cleaned gas is converted to fission gas in a fission gas generator using an air-water gas mixture and is taken to the combustion equipment. By this process salvaged oil and heavy hydrocarbons can be used for burning in Diesel engines without previous refining.

Risk factors predicting the outcome of salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy

International Nuclear Information System (INIS)

Kinoshita, Hidefumi; Shimizu, Yosuke; Mizowaki, Takashi

2013-01-01

Salvage radiotherapy is the only curative treatment for patients with prostate cancer showing biochemical progression after radical prostatectomy. In this study, we evaluated the clinicopathological parameters that influence the outcome of salvage radiotherapy. Medical records of 49 patients who underwent salvage radiotherapy after radical prostatectomy from 1997 to 2008 at the Graduate School of Medicine, Kyoto University, were retrospectively reviewed. Radiotherapy was carried out with 66 Gy on the prostatic bed. Biochemical progression-free survival after salvage radiotherapy at 2, 5 and 7 years was 51.0%, 42.2% and 42.2%, respectively. Significant parameters predicting biochemical progression after salvage radiotherapy by Cox regression analysis were prostatectomy Gleason score sum ≥8 (hazard ratio 0.08; 95% confidence interval 0.03-0.22; P=0.001), prostate-specific antigen nadir after radical prostatectomy ≥0.04 ng/mL (hazard ratio 0.30; 95% confidence interval 0.13-0.69; P=0.005) and negative surgical margin (hazard ratio 0.28; 95% confidence interval 0.12-0.70; P=0.006). When the patients were subgrouped by these risk factors, the 5-year progression-free survival rates after salvage radiotherapy were 77.8%, 50.0% and 6.7% in patients with 0, 1 and ≥2 predictors, respectively. In order to discriminate favorable candidates for salvage radiotherapy, Gleason score of prostatectomy, prostate-specific antigen nadir after prostatectomy and positive surgical margin represent independent predictors. Thus, progression-free survival might be more precisely predicted according to the presence/absence of these risk factors. The significance of this risk classification should be confirmed by large prospective studies. (author)

Effects of definitive and salvage radiotherapy on the distribution of lymphocyte subpopulations in prostate cancer patients

International Nuclear Information System (INIS)

Sage, Eva K.; Gehrmann, Mathias; Sedelmayr, Michael; Schmid, Thomas E.; Combs, Stephanie E.; Multhoff, Gabriele; Geinitz, Hans; Duma, Marciana N.

2017-01-01

Radiotherapy (RT) is an established treatment for patients with primary and recurrent prostate cancer. Herein, the effects of definitive and salvage RT on the composition of lymphocyte subpopulations were investigated in patients with prostate cancer to study potential immune effects. A total of 33 prostate cancer patients were treated with definitive (n = 10) or salvage RT (n = 23) after biochemical relapse. The absolute number of lymphocytes and the distribution of lymphocyte subpopulations were analyzed by multiparameter flow cytometry before RT, at the end of RT, and in the follow-up period. Absolute lymphocyte counts decreased significantly after RT in both patient groups and a significant drop was observed in the percentage of B cells directly after RT from 10.1 ± 1.3 to 6.0 ± 0.7% in patients with definitive RT and from 9.2 ± 0.8 to 5.8 ± 0.7% in patients with salvage RT. In contrast, the percentages of T and natural killer (NK) cells remained unaltered directly after RT in both patient groups. However, 1 year after RT, the percentage of CD3 + T cells was significantly lower in patients with definitive and salvage RT. The percentage of regulatory T cells was slightly upregulated in primary prostate cancer patients after definitive RT, but not after salvage RT. Definitive and salvage RT exert similar effects on the composition of lymphocyte subpopulations in prostate cancer patients. Total lymphocyte counts are lower in both patient groups compared to healthy controls and further decreased after RT. B cells are more sensitive to definitive and salvage RT than T and NK cells. (orig.) [de

Yeast Interacting Proteins Database: YGR010W, YLR328W [Yeast Interacting Proteins Database

Lifescience Database Archive (English)

Full Text Available 1 Nicotinic acid mononucleotide adenylyltransferase, involved in pathways of NAD biosynthesis, including the... de novo, NAD(+) salvage, and nicotinamide riboside salvage pathways Rows with th...ne name NMA1 Prey description Nicotinic acid mononucleotide adenylyltransferase, involved in pathways of NAD... biosynthesis, including the de novo, NAD(+) salvage, and nicotinamide riboside salvage pathways

Treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy for prostate cancer

International Nuclear Information System (INIS)

Wadasaki, Koichi; Kaneyasu, Yuko; Kenjo, Masahiro; Matsuura, Kanji; Murakami, Yuji; Hashimoto, Yasutoshi; Ito, Katsuhide; Kiriu, Hiroshi; Ito, Atsushi

2007-01-01

The indications for and the efficacy of radiation therapy after radical operation for patients with prostate cancer are not clear. We analyzed the treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy. Between September 1997 and November 2004, 57 patients received adjuvant radiotherapy or salvage radiotherapy after radical prostatectomy. Fifteen patients received radiation therapy because of positive margins and/or extracapsular invasion in surgical specimens (adjuvant group). Forty-two patients received radiation therapy because of rising prostate-specific antigen (PSA) during follow-up (salvage group). Radiation therapy was delivered to the fossa of the prostate±seminal vesicles by a three-dimensional (3-D) conformal technique to a total dose of 60-66 Gy (median, 60 Gy). Biochemical control was defined as the maintenance of a PSA level of less than 0.2 ng/ml. The median follow-up period after radiation therapy was 33 months (range, 12-98 months). Three-year biochemical control rates were 87% for the adjuvant group and 61% for the salvage group. For patients in the salvage group treated without hormone therapy, the preradiation PSA value was the most significant factor for the biochemical control rate. The 3-year biochemical control rate was 93% in patients whose preradiation PSA was 0.5 ng/ml or less and 29% in patients whose preradiation PSA was more than 0.5 ng/ml. No severe adverse effects (equal to or more than grade 3) were seen in treated patients. Radiation therapy after radical prostatectomy seemed to be effective for adjuvant therapy and for salvage therapy in patients with a preradiation PSA of 0.5 ng/ml or less. Also, radiation to the fossa of the prostate±seminal vesicles, to a total dose of 60-66 Gy, using a three-dimensional (3-D) conformal technique, seemed to be safe. (author)

Limb Salvage After Failed Initial Operative Management of Bimalleolar Ankle Fractures in Diabetic Neuropathy.

Science.gov (United States)

Vaudreuil, Nicholas J; Fourman, Mitchell S; Wukich, Dane K

2017-03-01

Ankle fractures in patients with diabetes mellitus (DM) can be difficult to manage, especially in the presence of peripheral neuropathy. In patients who fail initial operative management, attempts at limb salvage can be challenging, and no clear treatment algorithm exists. This study examined outcomes of different procedures performed for limb salvage in this population. This study retrospectively reviewed 17 patients with DM complicated by peripheral neuropathy who sustained a bimalleolar ankle fracture and failed initial operative management. Patients were treated with revision open reduction internal fixation (ORIF) (3/17), closed reduction external fixation (CREF) (8/17), or primary ankle joint fusion (3/17 tibiotalocalcaneal fusion with hindfoot nail [TTCN] and 3/17 with tibiotalar arthrodesis using plates and screws [TTA]). Median follow-up was 20 months. The overall rate of limb salvage was 82.3% (14/17). All patients who went on to amputation presented with infection and were treated initially with CREF (3/3). All patients who achieved successful limb salvage ended up with a clinically fused ankle joint (14/14); 9 underwent a primary or delayed formal fusion and 5 had a clinically fused ankle joint at study conclusion after undergoing revision ORIF or CREF with adjunctive procedures. This small study suggests that in this complicated group of patients it is difficult to achieve limb salvage with an end result of a functional ankle joint. CREF can be a viable option in cases where underlying infection or poor bone quality is present. Treatment with revision ORIF frequently requires supplementary external fixator or tibiotalar Steinman pin placement for additional stability. All patients who underwent revision ORIF ended up with clinically fused ankle joints at the end of the study period. Primary fusion procedures (TTA, TTCN) were associated with a high rate of limb salvage and a decreased number of operations. Level III, retrospective case series.

Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

Energy Technology Data Exchange (ETDEWEB)

Wilsbacher, Julie L.; Cheng, Min; Cheng, Dong; Trammell, Samuel A.J.; Shi, Yan; Guo, Jun; Koeniger, Stormy L.; Kovar, Peter J.; He, Yupeng; Selvaraju, Sujatha; Heyman, H. Robin; Sorensen, Bryan K.; Clark, Richard F.; Hansen, T. Matthew; Longenecker, Kenton L.; Raich, Diana; Korepanova, Alla V.; Cepa, Steven; Towne, Danli L.; Abraham, Vivek C.; Tang, Hua; Richardson, Paul L.; McLoughlin, Shaun M.; Badagnani, Ilaria; Curtin, Michael L.; Michaelides, Michael R.; Maag, David; Buchanan, F. Gregory; Chiang, Gary G.; Gao, Wenqing; Rosenberg, Saul H.; Brenner, Charles; Tse, Chris (AbbVie)

2017-05-03

Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45.

In vitro metabolic engineering for the salvage synthesis of NAD(.).

Science.gov (United States)

Honda, Kohsuke; Hara, Naoya; Cheng, Maria; Nakamura, Anna; Mandai, Komako; Okano, Kenji; Ohtake, Hisao

2016-05-01

Excellent thermal and operational stabilities of thermophilic enzymes can greatly increase the applicability of biocatalysis in various industrial fields. However, thermophilic enzymes are generally incompatible with thermo-labile substrates, products, and cofactors, since they show the maximal activities at high temperatures. Despite their pivotal roles in a wide range of enzymatic redox reactions, NAD(P)(+) and NAD(P)H exhibit relatively low stabilities at high temperatures, tending to be a major obstacle in the long-term operation of biocatalytic chemical manufacturing with thermophilic enzymes. In this study, we constructed an in vitro artificial metabolic pathway for the salvage synthesis of NAD(+) from its degradation products by the combination of eight thermophilic enzymes. The enzymes were heterologously produced in recombinant Escherichia coli and the heat-treated crude extracts of the recombinant cells were directly used as enzyme solutions. When incubated with experimentally optimized concentrations of the enzymes at 60°C, the NAD(+) concentration could be kept almost constant for 15h. Copyright © 2016 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Yeast Interacting Proteins Database: YLR328W, YLR328W [Yeast Interacting Proteins Database

Lifescience Database Archive (English)

Full Text Available YLR328W NMA1 Nicotinic acid mononucleotide adenylyltransferase, involved in pathways... of NAD biosynthesis, including the de novo, NAD(+) salvage, and nicotinamide riboside salvage pathways Row...ylyltransferase, involved in pathways of NAD biosynthesis, including the de novo,... NAD(+) salvage, and nicotinamide riboside salvage pathways Rows with this prey as prey (4) Rows with this p... description Nicotinic acid mononucleotide adenylyltransferase, involved in pathways

Peripheral Sympathectomy for Raynaud's Phenomenon: A Salvage Procedure

Directory of Open Access Journals (Sweden)

Wen-Her Wang

2006-10-01

Full Text Available We retrospectively reviewed the effectiveness of peripheral sympathectomy for severe Raynaud's phenomenon. In this study, a total of 14 digits from six patients with chronic digital ischemic change were included. All patients had pain, ulcer, or gangrenous change in the affected digits and were unresponsive to pharmacologic or other nonsurgical therapies. In all cases, angiography showed multifocal arterial lesions, so microvascular reconstruction was unfeasible. Peripheral sympathectomy was performed as a salvage procedure to prevent digit amputation. The results were analyzed according to reduction of pain, healing of ulcers, and prevention of amputation. In 12 of the 14 digits, the ulcers healed and amputation was avoided. In the other two digits, the ulcers improved and progressive gangrene was limited. As a salvage procedure for Raynaud's phenomenon recalcitrant to conservative treatment, peripheral sympathectomy improves perfusion to ischemic digits and enables amputation to be avoided.

Grande-Baie tugboat sinking and salvage operations

International Nuclear Information System (INIS)

Dussault, M.; Gauthier, F.

2009-01-01

This paper described the operations that took place during an oil spill that occurred in December 2007 when the Grande-Baie tugboat sank at the wharf in Port Alfred, in the Ha-Ha Bay on the Saguenay River, Quebec. Approximately 100 tonnes of diesel fuel was onboard the tug. Although the exact amount of diesel spilled during this event is not known, it is assumed that half of the ship's load in diesel was spilled into the ice-infested waters. Poor weather, the presence of pack ice and tides of 2.5 meters were present at the time. Two Canadian Coast Guard officers, one emergency officer from Environment Quebec and one from Environment Canada were called for response purposes, particularly to avoid spreading of the diesel fuel and to ensure that the oily water was recovered from inside the vessel during salvage operations. One of the key objectives was to prevent diesel spills by capping vessel vents, which proved to be very challenging. Oily water was pumped from inside the boat directly in the bay of the Saguenay River to facilitate salvage of the ship. This was the first time that this method was used in Canada, and was successful because of proper risk assessment. Many conditions were followed for the purpose of environmental protection, such as confinement, good observations by divers, agreed upon criteria to stop pumping, and adequate monitoring the the Regional Environmental Emergency Team (REET). The salvage operation lasted 19 days. The challenges associated with the migration and recovery of oil in icy waters were discussed along with the environmental issues associated with the spill, particularly with the imminent opening of the ice fishing season. 2 refs., 2 tabs.,5 figs.

Post-fire salvage logging alters species composition and reduces cover, richness, and diversity in Mediterranean plant communities.

Science.gov (United States)

Leverkus, Alexandro B; Lorite, Juan; Navarro, Francisco B; Sánchez-Cañete, Enrique P; Castro, Jorge

2014-01-15

An intense debate exists on the effects of post-fire salvage logging on plant community regeneration, but scant data are available derived from experimental studies. We analyzed the effects of salvage logging on plant community regeneration in terms of species richness, diversity, cover, and composition by experimentally managing a burnt forest on a Mediterranean mountain (Sierra Nevada, S Spain). In each of three plots located at different elevations, three replicates of three treatments were implemented seven months after the fire, differing in the degree of intervention: "Non-Intervention" (all trees left standing), "Partial Cut plus Lopping" (felling 90% of the trees, cutting the main branches, and leaving all the biomass in situ), and "Salvage Logging" (felling and piling the logs, and masticating the woody debris). Plant composition in each treatment was monitored two years after the fire in linear point transects. Post-fire salvage logging was associated with reduced species richness, Shannon diversity, and total plant cover. Moreover, salvaged sites hosted different species assemblages and 25% lower cover of seeder species (but equal cover of resprouters) compared to the other treatments. Cover of trees and shrubs was also lowest in Salvage Logging, which could suggest a potential slow-down of forest regeneration. Most of these results were consistent among the three plots despite plots hosting different plant communities. Concluding, our study suggests that salvage logging may reduce species richness and diversity, as well as the recruitment of woody species, which could delay the natural regeneration of the ecosystem. Copyright © 2013 Elsevier Ltd. All rights reserved.

Didymin Alleviates Hepatic Fibrosis Through Inhibiting ERK and PI3K/Akt Pathways via Regulation of Raf Kinase Inhibitor Protein

Directory of Open Access Journals (Sweden)

Xing Lin

2016-12-01

Full Text Available Background: Didymin has been reported to have anti-cancer potential. However, the effect of didymin on liver fibrosis remains illdefined. Methods: Hepatic fibrosis was induced by CCl4 in rats. The effects of didymin on liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminases activities and collagen-related indicators levels were determined by commercially available kits. Moreover, the effects of didymin on hepatic stellate cell apoptosis and cell cycle were analyzed by flow cytometry. Mitochondrial membrane potential was detected by using rhodamine-123 dye. The expression of Raf kinase inhibitor protein (RKIP and the phosphorylation of the ERK/MAPK and PI3K/Akt pathways were assessed by Western blot. Results: Didymin significantly ameliorated chronic liver injury and collagen deposition. It strongly inhibited hepatic stellate cells proliferation, induced apoptosis and caused cell cycle arrest in G2/M phase. Moreover, didymin notably attenuated mitochondrial membrane potential, accompanied by release of cytochrome C. Didymin significantly inhibited the ERK/MAPK and PI3K/Akt pathways. The effects of didymin on the collagen accumulation in rats and on the biological behaviors of hepatic stellate cells were largely abolished by the specific RKIP inhibitor locostatin. Conclusion: Didymin alleviates hepatic fibrosis by inhibiting ERK/MAPK and PI3K/Akt pathways via regulation of RKIP expression.

Proposed salvage treatment strategy for biochemical failure after radical prostatectomy in patients with prostate cancer: a retrospective study

International Nuclear Information System (INIS)

Miyake, Makito; Tanaka, Nobumichi; Asakawa, Isao; Morizawa, Yosuke; Anai, Satoshi; Torimoto, Kazumasa; Aoki, Katsuya; Yoneda, Tatsuo; Hasegawa, Masatoshi; Konishi, Noboru; Fujimoto, Kiyohide

2014-01-01

Treatment options for patients with recurrent disease after radical prostatectomy include salvage radiotherapy of the prostatic bed and/or androgen deprivation therapy. To establish an effective treatment strategy for recurrent disease after radical prostatectomy, we retrospectively analyzed the outcome of salvage radiation monotherapy in such cases. Data from 61 men who had undergone salvage radiation monotherapy for biochemical recurrent disease after radical prostatectomy were retrospectively reviewed. In all patients, salvage radiotherapy consisted of iraradiation to the prostatic bed (70 Gy) using three-dimensional conformal radiotherapy techniques. Treatment outcome was analyzed to identify predictive factors of salvage radiotherapy. The biochemical recurrence-free survival after salvage radiation monotherapy at 2 and 5 years was 55% and 38%, respectively. Cox proportional regression models revealed that the independent predictive factors for biochemical recurrence were Gleason Score ≥ 8, negative surgical margin, and PSA velocity ≥ 0.38 ng/mL/year. Negative surgical margin and PSA velocity ≥ 0.8 ng/mL/year were significantly associated with poor response in the serum PSA levels after salvage radiotherapy. Based on our findings, we propose a treatment strategy for biochemical recurrent disease after radical prostatectomy. Patients with Gleason score ≤ 7, positive surgical margin, and PSA velocity < 0.38 ng/mL/year are categorized the most favorable group, so that eradication by salvage radiation monotherapy could be expected. Other patients could be divided to two groups depending on surgical margin status and PSA velocity: 1) patients who might require combination of SRT and short-term androgen deprivation therapy and 2) patients who should be treated by androgen deprivation monotherapy

Development of Composite Case Salvage Procedures

Science.gov (United States)

1982-04-01

impacted by the high pressure water. Figure 25 shows damage to EPDM rubber from an MX case. Figure 26 shows the effect of the water on the V-45 ( NBR ... Rubber plus Polyester plus Degradation Elastomer Polyether Cleavage Recycling Reclamation Solvolysis Also: Salvage Rubber Reclamation Elastomers... rubber . 2. Analysis of the material extracted from the insu- lation showed that plasticizer (phthalates) was removed by the solvents. 3. After

The potential roles of hepatocyte growth factor (HGF-MET pathway inhibitors in cancer treatment

Directory of Open Access Journals (Sweden)

Parikh RA

2014-06-01

Full Text Available Rahul A Parikh,1 Peng Wang,2 Jan H Beumer,3 Edward Chu,1 Leonard J Appleman11Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; 2Division of Medical Oncology, University of Kentucky College of Medicine, Markey Cancer Center, Lexington, KY, USA; 3University of Pittsburgh School of Pharmacy, Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USAAbstract: MET is located on chromosome 7q31 and is a proto-oncogene that encodes for hepatocyte growth factor (HGF receptor, a member of the receptor tyrosine kinase (RTK family. HGF, also known as scatter factor (SF, is the only known ligand for MET. MET is a master regulator of cell growth and division (mitogenesis, mobility (motogenesis, and differentiation (morphogenesis; it plays an important role in normal development and tissue regeneration. The HGF-MET axis is frequently dysregulated in cancer by MET gene amplification, translocation, and mutation, or by MET or HGF protein overexpression. MET dysregulation is associated with an increased propensity for metastatic disease and poor overall prognosis across multiple tumor types. Targeting the dysregulated HGF-MET pathway is an area of active research; a number of monoclonal antibodies to HGF and MET, as well as small molecule inhibitors of MET, are under development. This review summarizes the key biological features of the HGF-MET axis, its dysregulation in cancer, and the therapeutic agents targeting the HGF-MET axis, which are in development.Keywords: MET inhibitor, HGF inhibitor, cancer

Yeast Interacting Proteins Database: YNL189W, YLR328W [Yeast Interacting Proteins Database

Lifescience Database Archive (English)

Full Text Available ait as prey (0) YLR328W NMA1 Nicotinic acid mononucleotide adenylyltransferase, involved in pathways... of NAD biosynthesis, including the de novo, NAD(+) salvage, and nicotinamide riboside salvage pathways... Nicotinic acid mononucleotide adenylyltransferase, involved in pathways of NAD biosynthesis, including the ...de novo, NAD(+) salvage, and nicotinamide riboside salvage pathways Rows with this prey as prey Rows with th

Yeast Interacting Proteins Database: YML064C, YLR328W [Yeast Interacting Proteins Database

Lifescience Database Archive (English)

Full Text Available th this bait as prey (0) YLR328W NMA1 Nicotinic acid mononucleotide adenylyltransferase, involved in pathways... of NAD biosynthesis, including the de novo, NAD(+) salvage, and nicotinamide riboside salvage pathways...ic acid mononucleotide adenylyltransferase, involved in pathways of NAD biosynthe...sis, including the de novo, NAD(+) salvage, and nicotinamide riboside salvage pathways Rows with this prey a

Iodine-125 brachytherapy as upfront and salvage treatment for brain metastases. A comparative analysis

Energy Technology Data Exchange (ETDEWEB)

Romagna, Alexander; Schwartz, Christoph; Tonn, Joerg-Christian; Kreth, Friedrich-Wilhelm [Ludwig-Maximilians-University, Department of Neurosurgery, Munich (Germany); Egensperger, Rupert [Ludwig-Maximilians-University, Center for Neuropathology and Prion Research, Munich (Germany); Watson, Juliana; Belka, Claus; Nachbichler, Silke Birgit [Ludwig-Maximilians-University, Department of Radiation-Oncology, Munich (Germany)

2016-11-15

Outcome and toxicity profiles of salvage stereotactic ablative radiation strategies for recurrent pre-irradiated brain metastases are poorly defined. This study compared risk-benefit profiles of upfront and salvage iodine-125 brachytherapy (SBT) for small brain metastases. As the applied SBT treatment algorithm required histologic proof of metastatic brain disease in all patients, we additionally aimed to elucidate the value of biopsy before SBT. Patients with small untreated (n = 20) or pre-irradiated (n =28) suspected metastases intended for upfront or salvage SBT, respectively, were consecutively included. Temporary iodine-125 implants were used (median reference dose: 50 Gy, median dose rate: 15 cGy/h). Cumulative biologically effective doses (BED) were calculated and used for risk assessment. Treatment toxicity was classified according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. Upfront SBT was initiated in 20 patients and salvage SBT in 23. In 5 patients, salvage SBT was withheld because of proven radiation-induced lesions. Treatment groups exhibited similar epidemiologic data except for tumor size (which was slightly smaller in the salvage group). One-year local/distant tumor control rates after upfront and salvage SBT were similar (94 %/65 % vs. 87 %/57 %, p = 0.45, respectively). Grade I/II toxicity was suffered by 2 patients after salvage SBT (cumulative BED: 192.1 Gy{sub 3} and 249.6 Gy{sub 3}). No toxicity-related risk factors were identified. SBT combines diagnostic yield with effective treatment in selected patients. The low toxicity rate in the salvage group points to protective radiobiologic characteristics of continuous low-dose rate irradiation. Upfront and salvage SBT are similarly effective and safe. Histologic reevaluation should be reconsidered after previous radiotherapy to avoid under- or overtreatment. (orig.) [German] Daten zu Risiko und Effizienz ablativer

Modified endoscopic medial maxillectomy for zygomatic implant salvage.

Science.gov (United States)

Schwartz, Joseph S; Tajudeen, Bobby A; Adappa, Nithin D; Palmer, James N

2016-01-01

Odontogenic chronic rhinosinusitis (CRS) is an epidemiologically important disease process due, in part, to the increasingly commonplace use of dental restorative procedures such as zygomatic implantation. Traditional management of this clinical entity typically entails extraction of the infected hardware via an open or endoscopic approach. We describe a novel management strategy of odontogenic CRS following bilateral zygomatic implantation for oral rehabilitation that we surgically salvaged via a modified endoscopic medial maxillectomy. We describe the presentation and management of a case of metachronous development of bilateral CRS subsequent to zygomatic implantation. The patient's postoperative course was characterized by marked endoscopic, radiologic, and symptomatic improvement as measured by the 22-item Sino-Nasal Outcome Test. We describe a novel treatment strategy for the management of odontogenic sinusitis resulting from erroneous zygomatic implant placement. Modified endoscopic medial maxillectomy in this clinical context facilitates mucosal normalization of the affected sinus, while permitting preservation of oral function through salvage of the displaced implant.

Is Atherectomy the Best First-Line Therapy for Limb Salvage in Patients With Critical Limb Ischemia?

Science.gov (United States)

Loor, Gabriel; Skelly, Christopher L.; Wahlgren, Carl-Magnus; Bassiouny, Hisham S.; Piano, Giancarlo; Shaalan, Wael

2010-01-01

Objective To determine the efficacy of atherectomy for limb salvage compared with open bypass in patients with critical limb ischemia. Methods Ninety-nine consecutive bypass and atherectomy procedures performed for critical limb ischemia between January 2003 and October 2006 were reviewed. Results A total of 99 cases involving TASC C (n = 43, 44%) and D (n = 56, 56%) lesions were treated with surgical bypass in 59 patients and atherectomy in 33 patients. Bypass and atherectomy achieved similar 1-year primary patency (64% vs 63%; P = .2). However, the 1-year limb salvage rate was greater in the bypass group (87% vs 69%; P = .004). In the tissue loss subgroup, there was a greater limb salvage rate for bypass patients versus atherectomy (79% vs 60%; P = .04). Conclusions Patients with critical limb ischemia may do better with open bypass compared with atherectomy as first-line therapy for limb salvage. PMID:19640919

12 CFR 714.6 - Are you required to retain salvage powers over the leased property?

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Are you required to retain salvage powers over the leased property? 714.6 Section 714.6 Banks and Banking NATIONAL CREDIT UNION ADMINISTRATION REGULATIONS AFFECTING CREDIT UNIONS LEASING § 714.6 Are you required to retain salvage powers over the leased...

The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells [v1; ref status: indexed, http://f1000r.es/yx

Directory of Open Access Journals (Sweden)

Michael Hartmann

2013-08-01

Full Text Available We have established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, based on the expression of a dexamethasone-inducible GFP fused to the carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL. By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP pathway with known inhibitors like oxoclomazone and fosmidomycin, as well as inhibition of the protein geranylgeranyltransferase type 1 (PGGT-1, shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA pathway with mevinolin did not affect the localization. During the present work, this test system has been used to examine the effect of newly designed inhibitors of the MEP pathway and inhibitors of sterol biosynthesis such as squalestatin, terbinafine and Ro48-8071. In addition, we also studied the impact of different post-prenylation inhibitors or those suspected to affect the transport of proteins to the plasma membrane on the localization of the geranylgeranylable fusion protein GFP-BD-CVIL.

Autologous Latissimus Dorsi Breast Reconstruction Flap Salvage: Microvascular Anastomosis with Serratus Branch

Directory of Open Access Journals (Sweden)

Victoria Kuta, BScH

2017-07-01

Full Text Available Summary:. Autologous breast reconstruction has become a standard option during the recovery of breast cancer survivors. Although pedicle damage is a rare complication of this procedure, extensive torsion or tension can lead to partial or total flap failure. We report a case of partial flap salvage after accidental transection of the pedicled blood supply within the intramuscular course of a latissimus dorsi musculocutaneous flap. This salvage technique involved microvascular anastomosis between the remaining vasculature of the latissimus dorsi pedicle and the serratus branch of the thoracodorsal artery and vein.

Salvage Stereotactic Body Radiotherapy (SBRT) Following In-Field Failure of Initial SBRT for Spinal Metastases.

Science.gov (United States)

Thibault, Isabelle; Campbell, Mikki; Tseng, Chia-Lin; Atenafu, Eshetu G; Letourneau, Daniel; Yu, Eugene; Cho, B C John; Lee, Young K; Fehlings, Michael G; Sahgal, Arjun

2015-10-01

We report our experience in salvaging spinal metastases initially irradiated with stereotactic body radiation therapy (SBRT), who subsequently progressed with imaging-confirmed local tumor progression, and were re-irradiated with a salvage second SBRT course to the same level. From a prospective database, 56 metastatic spinal segments in 40 patients were identified as having been irradiated with a salvage second SBRT course to the same level. In addition, 24 of 56 (42.9%) segments had initially been irradiated with conventional external beam radiation therapy before the first course of SBRT. Local control (LC) was defined as no progression on magnetic resonance imaging at the treated segment, and calculated according to the competing risk model. Overall survival (OS) was evaluated for each patient treated by use of the Kaplan-Meier method. The median salvage second SBRT total dose and number of fractions was 30 Gy in 4 fractions (range, 20-35 Gy in 2-5 fractions), and for the first course of SBRT was 24 Gy in 2 fractions (range, 20-35 Gy in 1-5 fractions). The median follow-up time after salvage second SBRT was 6.8 months (range, 0.9-39 months), the median OS was 10.0 months, and the 1-year OS rate was 48%. A longer time interval between the first and second SBRT courses predicted for better OS (P=.02). The crude LC was 77% (43/56), the 1-year LC rate was 81%, and the median time to local failure was 3.0 months (range, 2.7-16.7 months). Of the 13 local failures, 85% (11/13) and 46% (6/13) showed progression within the epidural space and paraspinal soft tissues, respectively. Absence of baseline paraspinal disease predicted for better LC (Pinitial SBRT is a feasible and efficacious salvage treatment option. Copyright © 2015 Elsevier Inc. All rights reserved.

Involvement of HDAC1 and the PI3K/PKC signaling pathways in NF-κB activation by the HDAC inhibitor apicidin

International Nuclear Information System (INIS)

Kim, Yong Kee; Seo, Dong-Wan; Kang, Dong-Won; Lee, Hoi Young; Han, Jeung-Whan; Kim, Su-Nam

2006-01-01

Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-κB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-κB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-κB and the expression of its target genes, IL-8 and TNF-α. TNF-α expression by apicidin is induced at earlier time points than NF-κB activation or IL-8 expression. In addition, our data show that the early expression of TNF-α does not lead to activation of NF-κB, because disruption of TNF-α activity by a neutralizing antibody does not affect nuclear translocation of NF-κB, IκBα degradation or reporter gene activation by apicidin. However, this activation of NF-κB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-κB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-κB reporter gene activity. Collectively, our results suggest that activation of NF-κB signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin

Results of salvage surgery for mammary recurrence following breast-conserving therapy

International Nuclear Information System (INIS)

Kurtz, J.M.; Amalric, R.; Brandone, H.; Ayme, Y.; Spitalier, J.M.

1988-01-01

A retrospective analysis was performed of 118 surgically treated mammary recurrences, occurring following primary conservative excision and radiation therapy for clinical Stages I and II breast cancer. Actuarial cancer-specific survival following salvage surgery was 72% at 5 years and 58% at 10 years. With a median followup of 7 years, further local-regional recurrences were observed in 20 of the 118 patients, many of whom could be treated by further surgery. Actuarial survival after recurrence was significantly influenced by initial clinical stage, as well as by the disease-free interval following primary therapy, but was similar for both premenopausal and postmenopausal patients and for patients treated by radical or breast-conserving salvage operations. For recurrences after the fifth year, actuarial survival following salvage surgery was 83% and 68% at 5 and 10 years, respectively. Survival for Stage I patients was favorable regardless of disease-free interval. It is concluded that recurrences in the breast following primary treatment with limited surgery and irradiation have a considerably more favorable prognosis than that of local failures after primary radical surgery. Suggestions for the management of these recurrences are presented

Tissue factor pathway inhibitor 2 is found in skin and its C-terminal region encodes for antibacterial activity.

Science.gov (United States)

Papareddy, Praveen; Kalle, Martina; Sørensen, Ole E; Lundqvist, Katarina; Mörgelin, Matthias; Malmsten, Martin; Schmidtchen, Artur

2012-01-01

Tissue factor pathway inhibitor 2 (TFPI-2) is a matrix-associated serine protease inhibitor with an enigmatic function in vivo. Here, we describe that TFPI-2 is present in fibrin of wounds and also expressed in skin, where it is up-regulated upon wounding. Neutrophil elastase cleaved TFPI-2, and a C-terminal fragment was found to bind to bacteria. Similarly, a prototypic peptide representing this C-terminal part, EDC34, bound to bacteria and bacterial lipopolysaccharide, and induced bacterial permeabilization. The peptide also induced leakage in artificial liposomes, and displayed a random coil conformation upon interactions with liposomes as well as lipopolysaccharide. EDC34 was antibacterial against both Gram-negative and Gram-positive bacteria in physiological buffer conditions. The results demonstrate that the C-terminus of TFPI-2 encodes for antimicrobial activity, and may be released during wounding.

Enzyme-ligand interactions that drive active site rearrangements in the Helicobacter pylori 5´-methylthioadenosine/S-adenosylhomocysteine nucleosidase

Energy Technology Data Exchange (ETDEWEB)

Ronning, Donald R; Iacopelli, Natalie M; Mishra, Vidhi [Toledo

2012-03-15

The bacterial enzyme 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) plays a central role in three essential metabolic pathways in bacteria: methionine salvage, purine salvage, and polyamine biosynthesis. Recently, its role in the pathway that leads to the production of autoinducer II, an important component in quorum-sensing, has garnered much interest. Because of this variety of roles, MTAN is an attractive target for developing new classes of inhibitors that influence bacterial virulence and biofilm formation. To gain insight toward the development of new classes of MTAN inhibitors, the interactions between the Helicobacter pylori-encoded MTAN and its substrates and substrate analogs were probed using X-ray crystallography. The structures of MTAN, an MTAN-Formycin A complex, and an adenine bound form were solved by molecular replacement and refined to 1.7, 1.8, and 1.6 Å, respectively. The ribose-binding site in the MTAN and MTAN-adenine cocrystal structures contain a tris[hydroxymethyl]aminomethane molecule that stabilizes the closed form of the enzyme and displaces a nucleophilic water molecule necessary for catalysis. This research gives insight to the interactions between MTAN and bound ligands that promote closing of the enzyme active site and highlights the potential for designing new classes of MTAN inhibitors using a link/grow or ligand assembly development strategy based on the described H. pylori MTAN crystal structures.

TA-60 Warehouse and Salvage SWPPP Rev 2 Jan 2017-Final

Energy Technology Data Exchange (ETDEWEB)

Burgin, Jillian Elizabeth [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

2017-02-07

The Stormwater Pollution Prevention Team (PPT) for the TA-60-0002 Salvage and Warehouse Area consists of operations and management personnel from the facility, Multi-Sector General Permitting (MSGP) stormwater personnel from Environmental Compliance Programs (EPC-CP) organization, and Deployed Environmental Professionals. The EPC-CP representative is responsible for Laboratory compliance under the National Pollutant Discharge Elimination System (NPDES) permit regulations. The team members are selected on the basis of their familiarity with the activities at the facility and the potential impacts of those activities on stormwater runoff. The Warehouse and Salvage Yard are a single shift operation; therefore, a member of the PPT is always present during operations.

Long-Term Outcome and Toxicity of Salvage Brachytherapy for Local Failure After Initial Radiotherapy for Prostate Cancer

International Nuclear Information System (INIS)

Burri, Ryan J.; Stone, Nelson N.; Unger, Pam; Stock, Richard G.

2010-01-01

Purpose: To describe long-term outcomes and toxicity after salvage brachytherapy (BT) for local failure after initial radiotherapy for prostate cancer. Methods and Materials: Between 1994 and 2008, 37 men with local failure after initial prostate radiotherapy (32 external-beam radiation therapy [EBRT] and 5 BT) underwent salvage BT with 103 Pd or 125 I. Estimates of freedom from biochemical failure (FFbF, Phoenix definition) and cause-specific survival (CSS) were calculated using the Kaplan-Meier method. Toxicities were graded using CTCv3.0. Results: Median follow-up was 86 months (range, 2-156). The median dose to 90% of the prostate volume was 122 Gy (range, 67-166). The 10-year FFbF and CSS were 54% and 96%, respectively. On univariate analysis, prostate-specific antigen (PSA) >10 ng/mL at initial diagnosis was significantly associated with FFbF (p = 0.01), and there were trends for both age <70 years (p = 0.08) and PSA <6 ng/mL (p = 0.08) at the time of salvage BT. On multivariate analysis, only presalvage PSA <6 ng/mL (p = 0.046) was significantly associated with improved FFbF. There were three Grade 3 toxicities and one Grade 4 toxicity. Pelvic lymph node dissection before salvage BT was the only variable significantly associated with Grade ≥2 toxicity (p = 0.03). Conclusion: With a median follow-up of 86 months, salvage prostate BT was associated with a 10-year FFbF of 54% and CSS of 96%. Improved FFbF was associated with a presalvage PSA <6 ng/mL. Toxicity was worse in patients who had undergone pelvic lymph node dissection before salvage BT. Careful patient selection for salvage BT may result in improved outcomes and reduced toxicity.

Distinction of salvaged and infarcted myocardium within the ischaemic area-at-risk with T2 mapping

DEFF Research Database (Denmark)

Hammer-Hansen, Sophia; Ugander, Martin; Hsu, Li-Yueh

2014-01-01

values from T2 maps and signal intensities on T2-weighted images were measured in the corresponding areas. RESULTS: At both imaging time points, the T2 of the salvaged myocardium was longer than of remote (66.0 ± 6.9 vs. 51.4 ± 3.5 ms, P ...AIM: Area-at-risk (AAR) measurements often rely on T2-weighted images, but subtle differences in T2 may be overlooked with this method. To determine the differences in oedema between salvaged and infarcted myocardium, we performed quantitative T2 mapping of the AAR. We also aimed to determine...... (14.7 ± 5.6 vs. 8.7 ± 5.1 ms, P = 0.02). CONCLUSIONS: T2 relaxation parameters are different in the infarcted and salvaged myocardium, and both are significantly longer than remote. Furthermore, the magnitude of increase in T2 was less in the salvaged myocardium after longer reperfusion, indicating...

Nelfinavir and Non-Nucleoside Reverse Transcriptase Inhibitor-Based Salvage Regimes in Heavily Hiv Pretreated Patients

Directory of Open Access Journals (Sweden)

Jean-Guy Baril

2003-01-01

Full Text Available OBJECTIVE: To assess the efficacy of nelfinavir mesylate (NFV in combination with delavirdine mesylate(DLV or efavirenz (EFV and other antiretroviral agents following virological failure on other protease inhibitor (PI-based regimens.

33 CFR 155.4035 - Required pre-incident information and arrangements for the salvage and marine firefighting...

Science.gov (United States)

2010-07-01

... and arrangements for the salvage and marine firefighting resource providers listed in response plans... marine firefighting resource providers listed in response plans. (a) You must provide the information listed in §§ 155.1035(c) and 155.1040(c) to your salvage and marine firefighting resource providers. (b...

33 CFR 155.4045 - Required agreements or contracts with the salvage and marine firefighting resource providers.

Science.gov (United States)

2010-07-01

... with the salvage and marine firefighting resource providers. 155.4045 Section 155.4045 Navigation and... agreements or contracts with the salvage and marine firefighting resource providers. (a) You may only list resource providers in your plan that have been arranged by contract or other approved means. (b) You must...

Salvage surgery for local failures after stereotactic ablative radiotherapy for early stage non-small cell lung cancer

NARCIS (Netherlands)

N. Verstegen (Naomi); A.W.P.M. Maat (Alex); F.J. Lagerwaard (Frank); M.A. Paul (Marinus); M. Versteegh (Michel); J.J. Joosten (Joris); W. Lastdrager (Willem); E.F. Smit (Egbert); B.J. Slotman (Ben); J.J.M.E. Nuyttens (Joost); S. Senan (Suresh)

2016-01-01

markdownabstract__Introduction:__ The literature on surgical salvage, i.e. lung resections in patients who develop a local recurrence following stereotactic ablative radiotherapy (SABR), is limited. We describe our experience with salvage surgery in nine patients who developed a local recurrence

Transcriptomic analysis of genes in the nitrogen recycling pathway of meat-type chickens divergently selected for feed efficiency.

Science.gov (United States)

Aggrey, S E; Lee, J; Karnuah, A B; Rekaya, R

2014-04-01

The understanding of the dynamics of ammonia detoxification and excretion in uricotelic species is lagging behind ureotelic species. The relative expression of genes involved in nitrogen recycling and feed efficiency in chickens is unknown. The objective of this study was to investigate the transcriptomics differences in key genes in the nitrogen (N) metabolism and purine biosynthesis pathway in a chicken population divergently selected for low (LRFI) or high (HRFI) residual feed intake at days 35 and 42 using duodenum, liver, pectoralis major (P. major) and kidney. There was a significant positive correlation between RFI and fecal N. The purine salvage pathway was activated in the LRFI compared with HRFI at days 42. The birds in the LRFI population attained greater feed efficiency by having lower FI, increasing their protein retention and producing adequate glutamine to maintain growth compared with the HRFI line. To maintain growth, excess N is deaminated mostly to generate purine nucleotides. Generating purine nucleotides primarily from the purine biosynthesis pathway is energetically costly, and to preserve energy, they preferentially generate nucleotides from the purine salvage pathway. The LRFI birds need to generate sufficient nucleotides to maintain growth despite reduced FI that then results in reduced fecal N. © 2013 Stichting International Foundation for Animal Genetics.

Salvage definitive chemo-radiotherapy for locally recurrent oesophageal carcinoma after primary surgery: retrospective review

International Nuclear Information System (INIS)

Baxi, S. H.; Burmeister, B.; Harvey, J. A.; Smithers, M.; Thomas, J.

2008-01-01

Full text: To determine the overall survival and gastrointestinal toxicity for patients treated with salvage definitive chemo-radiotherapy after primary surgery for locoregional relapse of oesophageal carcinoma. A retrospective review of 525 patients who had a resection for oesophageal or oesophagogastric carcinoma at Princess Alexandra Hospital identified 14 patients treated with salvage definitive radiotherapy or chemo-radiotherapy, following localized recurrence of their disease. We analysed the patient and treatment characteristics to determine the median overall survival as the primary end point. Gastrointestinal toxicity was examined to determine if increased toxicity occurred when the stomach was irradiated within the intrathoracic radiotherapy field. The median overall survival for patients treated with curative intent using salvage definitive chemo-radiotherapy was 16 months and the 2-year overall survival is 21%. One patient is in clinical remission more than 5 years after therapy. Age <60 years old and nodal recurrence were favourable prognostic factors. Treatment compliance was 93% with only one patient unable to complete the intended schedule. Fourteen per cent of patients experienced grade 3 or 4 gastrointestinal toxicity. Salvage definitive chemo-radiotherapy should be considered for good performance status patients with oesophageal carcinoma who have a locoregional relapse after primary surgery. The schedule is tolerable with low toxicity and an acceptable median survival

Surgical and cryosurgical salvage of oral and oropharyngeal cancer recurring after radical radiotherapy

International Nuclear Information System (INIS)

Meyza, J.W.; Towpik, E.

1991-01-01

The results of salvage surgery or cryosurgery performed in 62 cases or oral or oropharyngeal cancer, recurring or persisting after radical radiotherapy, were analysed retrospectively. Salvage surgery was performed in 33 cases. The relatively high frequency of postoperative complications observed in years 1973-1984 has declined since 1985, concomitant with the introduction of myocutaneous flaps for reconstruction. Twenty-nine patients who were disqualified from major surgery, were treated by cryosurgery. Using both methods, 3-year overall survival was obtained in 24.1% of cases. (author)

Salvage high-dose-rate brachytherapy for local prostate cancer recurrence after radical radiotherapy

Directory of Open Access Journals (Sweden)

V. A. Solodkiy

2016-01-01

Full Text Available Studies salvage interstitial radiation therapy for recurrent prostate cancer, launched at the end of the XX century. In recent years, more and more attention is paid to high-dose-rate brachytherapy (HDR-BT as a method of treating local recurrence.The purpose of research – preliminary clinical results of salvage high-dose-rate brachytherapy applied in cases of suspected local recurrence or of residual tumour after radiotherapy.Preliminary findings indicate the possibility of using HDR-BT, achieving local tumor control with low genitourinary toxicity.

Comparative evaluation of the efficacy of the cyclooxygenase pathway inhibitor and nitric oxide synthase inhibitor in the reduction of alveolar bone loss in ligature induced periodontitis in rats: An experimental study

Directory of Open Access Journals (Sweden)

Rekha Jagadish

2014-01-01

Full Text Available Background: Alveolar bone loss is the most striking feature of periodontal disease. The aim of this study was to investigate the effect of a cyclooxygenase (COX pathway inhibitor and nitric oxide synthase (NOS inhibitor in the reduction of alveolar bone loss in an experimental periodontal disease (EPD model. Materials and Methods: The study was conducted on 60 Wistar rats divided into three groups of 20 rats each and then subjected to a ligature placement around the left maxillary second molars. Group 1 rats were treated with COX inhibitor (diclofenac sodium 10 mg/kg/d, group 2 with NOS inhibitor (aminoguanidine hydrochloride 10 mg/kg/d and group 3 served as controls, receiving only saline, intraperitoneally 1h before EPD induction and daily until the sacrifice on the 11 th day. Leukogram was performed before ligation, at 6 h and at the first, seventh and 11 th days after EPD induction. After sacrifice, all the excised maxillae were subjected to morphometric and histometric analysis to measure the alveolar bone loss. Histopathological analysis was carried out to estimate cell influx, alveolar bone and cementum integrity. Results: Induction of experimental periodontitis in the rat model produced pronounced leucocytosis, which was significantly reduced by the administration of diclofenac sodium and aminoguanidine on the 11 th day. In morphometric and histometric examinations, both the test drugs significantly (P < 0.05 inhibited the alveolar bone loss as compared with the control group. Conclusion: Both COX inhibitor and NOS inhibitor are equally effective in inhibiting the inflammatory bone resorption in an experimental periodontitis model.

Time of hepatocellular carcinoma recurrence after liver resection and alpha-fetoprotein are important prognostic factors for salvage liver transplantation.

Science.gov (United States)

Lee, Sanghoon; Hyuck David Kwon, Choon; Man Kim, Jong; Joh, Jae-Won; Woon Paik, Seung; Kim, Bong-Wan; Wang, Hee-Jung; Lee, Kwang-Woong; Suh, Kyung-Suk; Lee, Suk-Koo

2014-09-01

Salvage liver transplantation (LT) is considered a feasible option for the treatment of recurrent hepatocellular carcinoma (HCC). We performed this multicenter study to assess the risk factors associated with the recurrence of HCC and patient survival after salvage LT. Between January 2000 and December 2011, 101 patients who had previously undergone liver resection (LR) for HCC underwent LT at 3 transplant centers in Korea. Sixty-nine patients' data were retrospectively reviewed for the analysis. The recurrence of HCC was diagnosed at a median of 10.6 months after the initial LR, and patients underwent salvage LT. Recurrences were within the Milan criteria in 48 cases and were outside the Milan criteria in 21 cases. After salvage LT, 31 patients had HCC recurrence during a median follow-up period of 24.5 months. There were 24 deaths, and 20 were due to HCC recurrence. The 5-year overall survival rate was approximately 54.6%, and the 5-year recurrence-free survival rate was 49.3%. HCC recurrence within the 8 months after LR [hazard ratio (HR) = 3.124, P = 0.009], an alpha-fetoprotein level higher than 200 ng/mL (HR = 2.609, P = 0.02), and HCC outside the Milan criteria at salvage LT (HR = 2.219, P = 0.03) were independent risk factors for poor recurrence-free survival after salvage LT. In conclusion, the timing and extent of HCC recurrence after primary LR both play significant roles in the outcome of salvage LT. © 2014 American Association for the Study of Liver Diseases.

C-terminal peptides of tissue factor pathway inhibitor are novel host defense molecules.

Science.gov (United States)

Papareddy, Praveen; Kalle, Martina; Kasetty, Gopinath; Mörgelin, Matthias; Rydengård, Victoria; Albiger, Barbara; Lundqvist, Katarina; Malmsten, Martin; Schmidtchen, Artur

2010-09-03

Tissue factor pathway inhibitor (TFPI) inhibits tissue factor-induced coagulation, but may, via its C terminus, also modulate cell surface, heparin, and lipopolysaccharide interactions as well as participate in growth inhibition. Here we show that C-terminal TFPI peptide sequences are antimicrobial against the gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungi Candida albicans and Candida parapsilosis. Fluorescence studies of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen for the "classic" human antimicrobial peptide LL-37. The killing of E. coli, but not P. aeruginosa, by the C-terminal peptide GGLIKTKRKRKKQRVKIAYEEIFVKNM (GGL27), was enhanced in human plasma and largely abolished in heat-inactivated plasma, a phenomenon linked to generation of antimicrobial C3a and activation of the classic pathway of complement activation. Furthermore, GGL27 displayed anti-endotoxic effects in vitro and in vivo in a mouse model of LPS shock. Importantly, TFPI was found to be expressed in the basal layers of normal epidermis, and was markedly up-regulated in acute skin wounds as well as wound edges of chronic leg ulcers. Furthermore, C-terminal fragments of TFPI were associated with bacteria present in human chronic leg ulcers. These findings suggest a new role for TFPI in cutaneous defense against infections.

New insights into the consequences of post-windthrow salvage logging revealed by functional structure of saproxylic beetles assemblages.

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Simon Thorn

Full Text Available Windstorms, bark beetle outbreaks and fires are important natural disturbances in coniferous forests worldwide. Wind-thrown trees promote biodiversity and restoration within production forests, but also cause large economic losses due to bark beetle infestation and accelerated fungal decomposition. Such damaged trees are often removed by salvage logging, which leads to decreased biodiversity and thus increasingly evokes discussions between economists and ecologists about appropriate strategies. To reveal the reasons behind species loss after salvage logging, we used a functional approach based on four habitat-related ecological traits and focused on saproxylic beetles. We predicted that salvage logging would decrease functional diversity (measured as effect sizes of mean pairwise distances using null models as well as mean values of beetle body size, wood diameter niche and canopy cover niche, but would increase decay stage niche. As expected, salvage logging caused a decrease in species richness, but led to an increase in functional diversity by altering the species composition from habitat-filtered assemblages toward random assemblages. Even though salvage logging removes tree trunks, the most negative effects were found for small and heliophilous species and for species specialized on wood of small diameter. Our results suggested that salvage logging disrupts the natural assembly process on windthrown trees and that negative ecological impacts are caused more by microclimate alteration of the dead-wood objects than by loss of resource amount. These insights underline the power of functional approaches to detect ecosystem responses to anthropogenic disturbance and form a basis for management decisions in conservation. To mitigate negative effects on saproxylic beetle diversity after windthrows, we recommend preserving single windthrown trees or at least their tops with exposed branches during salvage logging. Such an extension of the green

New insights into the consequences of post-windthrow salvage logging revealed by functional structure of saproxylic beetles assemblages.

Science.gov (United States)

Thorn, Simon; Bässler, Claus; Gottschalk, Thomas; Hothorn, Torsten; Bussler, Heinz; Raffa, Kenneth; Müller, Jörg

2014-01-01

Windstorms, bark beetle outbreaks and fires are important natural disturbances in coniferous forests worldwide. Wind-thrown trees promote biodiversity and restoration within production forests, but also cause large economic losses due to bark beetle infestation and accelerated fungal decomposition. Such damaged trees are often removed by salvage logging, which leads to decreased biodiversity and thus increasingly evokes discussions between economists and ecologists about appropriate strategies. To reveal the reasons behind species loss after salvage logging, we used a functional approach based on four habitat-related ecological traits and focused on saproxylic beetles. We predicted that salvage logging would decrease functional diversity (measured as effect sizes of mean pairwise distances using null models) as well as mean values of beetle body size, wood diameter niche and canopy cover niche, but would increase decay stage niche. As expected, salvage logging caused a decrease in species richness, but led to an increase in functional diversity by altering the species composition from habitat-filtered assemblages toward random assemblages. Even though salvage logging removes tree trunks, the most negative effects were found for small and heliophilous species and for species specialized on wood of small diameter. Our results suggested that salvage logging disrupts the natural assembly process on windthrown trees and that negative ecological impacts are caused more by microclimate alteration of the dead-wood objects than by loss of resource amount. These insights underline the power of functional approaches to detect ecosystem responses to anthropogenic disturbance and form a basis for management decisions in conservation. To mitigate negative effects on saproxylic beetle diversity after windthrows, we recommend preserving single windthrown trees or at least their tops with exposed branches during salvage logging. Such an extension of the green-tree retention

Outcome of salvage radiotherapy for biochemical failure after radical prostatectomy with or without hormonal therapy

International Nuclear Information System (INIS)

Cheung, Rex; Kamat, Ashish M.; Crevoisier, Renaud de; Allen, Pamela K.; Lee, Andrew K.; Tucker, Susan L.; Pisters, Louis; Babaian, Richard J.; Kuban, Deborah

2005-01-01

Background: This study analyzed the outcome of salvage radiotherapy for biochemical failure after radical prostatectomy (RP). By comparing the outcomes for patients who received RT alone and for those who received combined RT and hormonal therapy, we assessed the potential benefits of hormonal therapy. Patients and Methods: This cohort was comprised of 101 patients who received salvage RT between 1990 and 2001 for biochemical failure after RP. Fifty-nine of these patients also received hormone. Margin status (positive vs. negative), extracapsular extension (yes vs. no), seminal vesicle involvement (yes vs. no), pathologic stage, Gleason score, pre-RP PSA, post-RP PSA, pre-RT PSA, hormonal use, radiotherapy dose and technique, RP at M. D. Anderson Cancer Center, and time from RP to salvage RT were analyzed. Statistically significant variables were used to construct prognostic groups. Results: Independent prognostic factors for the RT-alone group were margin status and pre-RT PSA. RP at M. D. Anderson Cancer Center was marginally significant (p = 0.06) in multivariate analysis. Pre-RT PSA was the only significant prognostic factor for the combined-therapy group. We used a combination of margin status and pre-RT PSA to construct a prognostic model for response to the salvage treatment based on the RT group. We identified the favorable group as those patients with positive margin and pre-RT PSA ≤0.5 ng/mL vs. the unfavorable group as otherwise. This stratification separates patients into clinically meaningful groups. The 5-year PSA control probabilities for the favorable vs. the unfavorable group were 83.7% vs. 61.7% with radiotherapy alone (p = 0.03). Androgen ablation seemed to be most beneficial in the unfavorable group. Conclusion: After prostatectomy, favorable-group patients may fare well with salvage radiotherapy alone. These patients may be spared the toxicity of androgen ablation. The other patients may benefit most from a combined approach with hormonal

Implant breast reconstruction after salvage mastectomy in previously irradiated patients.

Science.gov (United States)

Persichetti, Paolo; Cagli, Barbara; Simone, Pierfranco; Cogliandro, Annalisa; Fortunato, Lucio; Altomare, Vittorio; Trodella, Lucio

2009-04-01

The most common surgical approach in case of local tumor recurrence after quadrantectomy and radiotherapy is salvage mastectomy. Breast reconstruction is the subsequent phase of the treatment and the plastic surgeon has to operate on previously irradiated and manipulated tissues. The medical literature highlights that breast reconstruction with tissue expanders is not a pursuable option, considering previous radiotherapy a contraindication. The purpose of this retrospective study is to evaluate the influence of previous radiotherapy on 2-stage breast reconstruction (tissue expander/implant). Only patients with analogous timing of radiation therapy and the same demolitive and reconstructive procedures were recruited. The results of this study prove that, after salvage mastectomy in previously irradiated patients, implant reconstruction is still possible. Further comparative studies are, of course, advisable to draw any conclusion on the possibility to perform implant reconstruction in previously irradiated patients.

Outcome and renal function following salvage surgery for bilateral ...

African Journals Online (AJOL)

Objective: The aim of this study was to determine the surgical outcomes and renal function following salvage surgery for bilateral Wilms tumor (BWT). Summary background data The challenge for the surgeon treating BWT lies in striking a fine balance between renal preservation and oncological clearance. Methods: This is ...

MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish

DEFF Research Database (Denmark)

Lundegaard, Pia R.; Anastasaki, Corina; Grant, Nicola J.

2015-01-01

Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors...... as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult...... zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance...

Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61.

Science.gov (United States)

Calcaterra, Andrea; Iovine, Valentina; Botta, Bruno; Quaglio, Deborah; D'Acquarica, Ilaria; Ciogli, Alessia; Iazzetti, Antonia; Alfonsi, Romina; Lospinoso Severini, Ludovica; Infante, Paola; Di Marcotullio, Lucia; Mori, Mattia; Ghirga, Francesca

2018-12-01

This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription. Here, we combined chemical synthesis, NMR spectroscopy, analytical studies, molecular modelling and functional cell assays to characterise the GANT61 hydrolysis pathway. Our results show that GANT61-D is the bioactive form of GANT61 in NIH3T3 Shh-Light II cells and SuFu -/- mouse embryonic fibroblasts, and clarify the structural requirements for GANT61-D binding to Gli1. This study paves the way to the design of GANT61 derivatives with improved potency and chemical stability.

An Ixodes ricinus Tick Salivary Lectin Pathway Inhibitor Protects Borrelia burgdorferi sensu lato from Human Complement.

Science.gov (United States)

Wagemakers, Alex; Coumou, Jeroen; Schuijt, Tim J; Oei, Anneke; Nijhof, Ard M; van 't Veer, Cornelis; van der Poll, Tom; Bins, Adriaan D; Hovius, Joppe W R

2016-04-01

We previously identified tick salivary lectin pathway inhibitor (TSLPI) in Ixodes scapularis, a vector for Borrelia burgdorferi sensu stricto (s.s.) in North America. TSLPI is a salivary protein facilitating B. burgdorferi s.s. transmission and acquisition by inhibiting the host lectin complement pathway through interference with mannose binding lectin (MBL) activity. Since Ixodes ricinus is the predominant vector for Lyme borreliosis in Europe and transmits several complement sensitive B. burgdorferi sensu lato (s.l.) strains, we aimed to identify, describe, and characterize the I. ricinus ortholog of TSLPI. We performed (q)PCRs on I. ricinus salivary gland cDNA to identify a TSLPI ortholog. Next, we generated recombinant (r)TSLPI in a Drosophila expression system and examined inhibition of the MBL complement pathway and complement-mediated killing of B. burgdorferi s.l. in vitro. We identified a TSLPI ortholog in I. ricinus salivary glands with 93% homology at the RNA and 89% at the protein level compared to I. scapularis TSLPI, which was upregulated during tick feeding. In silico analysis revealed that TSLPI appears to be part of a larger family of Ixodes salivary proteins among which I. persulcatus basic tail salivary proteins and I. scapularis TSLPI and Salp14. I. ricinus rTSLPI inhibited the MBL complement pathway and protected B. burgdorferi s.s. and Borrelia garinii from complement-mediated killing. We have identified a TSLPI ortholog, which protects B. burgdorferi s.l. from complement-mediated killing in I. ricinus, the major vector for tick-borne diseases in Europe.

Trauma center variation in splenic artery embolization and spleen salvage: a multicenter analysis.

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Banerjee, Aman; Duane, Therese M; Wilson, Sean P; Haney, Starre; O'Neill, Patrick J; Evans, Heather L; Como, John J; Claridge, Jeffrey A

2013-07-01

This study aimed to evaluate if variation in management of blunt splenic injury (BSI) among Level I trauma centers is associated with different outcomes related to the use of splenic artery embolization (SAE). All adult patients admitted for BSI from 2008 to 2010 at 4 Level I trauma centers were reviewed. Use of SAE was determined, and outcomes of spleen salvage and nonoperative management (NOM) failure were evaluated. A priori, a 10% SAE rate was used to group centers into high- or low-use groups. There were 1,275 BSI patients. There were intercenter differences in age, injury severity, and grade of spleen injury (Spleen Injury Scale [SIS]). Mortality was similar by center; however, BSI treatment varied significantly by center. Overall, SAE use was highest at center A compared with B, C, and D (19%, 11%, 1%, and 4%, respectively; p trauma centers. Centers with higher rates of SAE use have higher spleen salvage and less NOM failure. SAE was shown to be an independent predictor of spleen salvage. Therapeutic study, level IV.

Advanced basal cell carcinoma, the hedgehog pathway, and treatment options – role of smoothened inhibitors

Science.gov (United States)

Fecher, Leslie A; Sharfman, William H

2015-01-01

Cutaneous basal cell carcinoma (BCC) is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449), a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA)-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery. PMID:26604681

The impact of post-fire salvage logging on microbial nitrogen cyclers in Mediterranean forest soil.

Science.gov (United States)

Pereg, Lily; Mataix-Solera, Jorge; McMillan, Mary; García-Orenes, Fuensanta

2018-04-01

Forest fires are a regular occurrence in the Mediterranean basin. High severity fires and post-fire management can affect biological, chemical and physical properties of soil, including the composition and abundance of soil microbial communities. Salvage logging is a post-fire management strategy, which involves the removal of burnt wood from land after a fire. The main objective of this work was to evaluate the impact of post-fire salvage logging and microaggregation on soil microbial communities, specifically on the abundance of nitrogen cyclers and, thus, the potential of the soil for microbial nitrogen cycling. The abundance of nitrogen cyclers was assessed by quantification of microbial nitrogen cycling genes in soil DNA, including nifH (involved in nitrogen fixation), nirS/K and nosZ (involved in denitrification), amoA-B and amoA-Arch (involved in bacterial and archaeal nitrification, respectively). It was demonstrated that salvage logging reduced bacterial load post-fire when compared to tree retention control and resulted in significant changes to the abundance of functional bacteria involved in nitrogen cycling. Microbial gene pools involved in various stages of the nitrogen cycle were larger in control soil than in soil subjected to post-fire salvage logging and were significantly correlated with organic matter, available phosphorous, nitrogen and aggregate stability. The microaggregate fraction of the soil, which has been associated with greater organic carbon, was shown to be a hotspot for nitrogen cyclers particularly under salvage logging. The impact of post-fire management strategies on soil microbial communities needs to be considered in relation to maintaining ecosystem productivity, resilience and potential impact on climate change. Copyright © 2017 Elsevier B.V. All rights reserved.

26 CFR 1.167(f)-1 - Reduction of salvage value taken into account for certain personal property.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Reduction of salvage value taken into account for certain personal property. 1.167(f)-1 Section 1.167(f)-1 Internal Revenue INTERNAL REVENUE SERVICE... for Individuals and Corporations § 1.167(f)-1 Reduction of salvage value taken into account for...

Long-term follow-up of salvage radiotherapy in Hodgkin's lymphoma after chemotherapy failure

International Nuclear Information System (INIS)

Campbell, Belinda; Wirth, Andrew; Milner, Alvin; Di Iulio, Juliana; MacManus, Michael; Ryan, Gail M.

2005-01-01

Purpose: To evaluate the long-term results of salvage radiotherapy (SRT) for Hodgkin's lymphoma after chemotherapy failure. Methods and Materials: We reviewed 81 patients undergoing SRT for persistent or recurrent Hodgkin's lymphoma after chemotherapy; 19 also received conventional-dose salvage chemotherapy. Results: At SRT, the median patient age was 31 years. Of the 81 patients, 81% had Stage I-II, 25.9% had B symptoms, 14.8% had bulky disease, and 7.4% had extranodal disease. A less than a complete response (CR) to the last chemotherapy regimen occurred in 47%. SRT was generally limited to one side of the diaphragm, and the median dose was 36 Gy. After SRT, 75% of patients achieved a CR, with 82% retaining durable in-field control. In-field failure was associated with less than a CR to the last chemotherapy regimen (p = 0.0287). Most failures were at distant sites, with 60% in previously involved sites. The 10-year freedom from treatment failure and overall survival rates were 32.8% and 45.7%, respectively. The adverse prognostic factors for freedom from treatment failure were age >50 years (p 50 years (p < 0.001), B symptoms (p = 0.002), and less than a CR to the last chemotherapy regimen (p = 0.002). Favorable cohorts had a 10-year freedom from treatment failure rate of 51% and overall survival rate of 92%. Conclusions: Salvage radiotherapy is effective for selected patients with Hodgkin's lymphoma after chemotherapy failure and should be considered for incorporation into salvage programs

The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux.

Science.gov (United States)

Long, Zhou; Chen, BaiJun; Liu, Qian; Zhao, Jiang; Yang, ZhenXing; Dong, XingYou; Xia, LiuBin; Huang, ShengQuan; Hu, XiaoYan; Song, Bo; Li, LongKun

2016-07-05

We explored the effects of KB-R7943, an inhibitor of reverse-mode NCX1 activity, in prostate cancer (PCa). NCX1 was overexpressed in PCa tissues and cell lines, and higher NCX1 levels were associated higher PCa grades. At concentrations greater than 10 μM, KB-R7943 dose-dependently decreased PC3 and LNCaP cell viability. KB-R7943 also increased cell cycle G1/S phase arrest and induced apoptosis in PC3 cells. KB-R7943 increased autophagosome accumulation in PCa cells as indicated by increases in LC3-II levels and eGFP-LC3 puncta. Combined treatment with chloroquine (CQ) and KB-R7943 decreased P62 and increased LC3-II protein levels in PC3 cells, indicating that KB-R7943 blocked autophagic flux. KB-R7943 induced autophagosome accumulation mainly by downregulating the PI3K/AKT/m-TOR pathway and upregulating the JNK pathway. In xenograft experiments, KB-R7943 inhibited tumor growth. Combined treatment with KB-R7943 and an autophagy inhibitor inhibited growth and increased apoptosis. These results indicate that KB-R7943 promotes cell death in PCa by activating the JNK signaling pathway and blocking autophagic flux.

Salvage radiotherapy for prostate-specific antigen relapse after radical prostatectomy for prostate cancer. A single-center experience

International Nuclear Information System (INIS)

Yoshida, Takahiro; Nakayama, Masashi; Suzuki, Osamu

2011-01-01

The aim of this study was to investigate the efficacy and prognostic factors of salvage radiotherapy for prostate-specific antigen relapse after radical prostatectomy for prostate cancer at a single center in Japan. A retrospective review of the medical records of 51 patients who underwent salvage radiotherapy for prostate-specific antigen relapse after radical prostatectomy was carried out. Salvage radiotherapy was undergone for the single indication of at least two consecutive prostate-specific antigen elevations >0.1 ng/ml. Salvage radiotherapy was delivered to the prostatic bed at a total dose of 60 or 64 Gy. Late toxicity was scored according to the Common Terminology Criteria for Adverse Events 3.0. A total dose of 60 and 64 Gy were administered to 26 and 25 patients, respectively. The median prostate-specific antigen level at the initiation of radiotherapy was 0.29 ng/ml (range, 0.11-1.10 ng/ml). With a median follow-up of 57.3 months (range, 9.9-134.0 months), the prostate-specific antigen relapse-free rate at 5 years was 50.7%. Multivariate analysis using Cox's proportional hazards regression model revealed that the Gleason score at radical prostatectomy ≥8 significantly predicted prostate-specific antigen relapse after salvage radiotherapy (hazard ratio 4.531; 95% confidence interval 1.413-14.535; P=0.011). The prostate-specific antigen relapse-free rate at 5 years in the Gleason score at radical prostatectomy ≤7 and at radical prostatectomy ≥8 was 62.7 and 15.4%, respectively. Salvage radiotherapy was effective for prostate-specific antigen relapse after radical prostatectomy with tolerable toxicities in Japanese patients. A high Gleason score seemed to be a poor prognostic factor. (author)

Salvage surgery for hypopharyngeal carcinoma and cervical esophageal carcinoma with local recurrence or residual tumor after chemoradiotherapy

International Nuclear Information System (INIS)

Takemura, Hirokazu; Hayashi, Ryuichi; Yamazaki, Mitsuo

2008-01-01

In this study, we present the treatment results of salvage surgery in 34 patients with residual primary tumor or local relapse tumor in the hypopharynx and cervical esophagus after radiotherapy (15 patients) or chemoradiotherapy (19 patients) at the Division of Head and Neck Surgery, National Cancer Center Hospital East between 1997 and 2006. All patients underwent total pharyngolaryngoesophagectomy (TPLE) as salvage surgery. Among these patients, postoperative complication was observed in 11 patients (32.4%). Fisher's exact test revealed no significant difference in postoperative complication rate between the radiotherapy (RT) group and chemoradiotherapy (CRT) group. Tumors in the neck recurred in 10 patients (55.6%) after surgical resection. The tumor recurrence control rate for cervical lymph nodes was 84.7% for patients with clinically N0 disease after CRT who had not undergone neck dissection. The median survival time was 392 days. We consider that salvage surgery can he safely performed by considering the necessity and method of operation, and the outcome of patients receiving CRT would he improved by salvage surgery. (author)

Salvage radiation therapy following radical prostatectomy. A national Danish study

DEFF Research Database (Denmark)

Ervandian, Maria; Høyer, Morten; Petersen, Stine Elleberg

2015-01-01

BACKGROUND: The purpose of this observational cohort study was to evaluate the outcome and prognostic factors following salvage radiotherapy (SRT) in a consecutive national cohort. MATERIAL AND METHODS: Between 2006 and 2010, 259 patients received SRT in Denmark. Patient- and cancer-related chara...

Experimental test of postfire management in pine forests: impact of salvage logging versus partial cutting and nonintervention on bird-species assemblages.

Science.gov (United States)

Castro, Jorge; Moreno-Rueda, Gregorio; Hódar, José A

2010-06-01

There is an intense debate about the effects of postfire salvage logging versus nonintervention policies on regeneration of forest communities, but scant information from experimental studies is available. We manipulated a burned forest area on a Mediterranean mountain to experimentally analyze the effect of salvage logging on bird-species abundance, diversity, and assemblage composition. We used a randomized block design with three plots of approximately 25 ha each, established along an elevational gradient in a recently burned area in Sierra Nevada Natural and National Park (southeastern Spain). Three replicates of three treatments differing in postfire burned wood management were established per plot: salvage logging, nonintervention, and an intermediate degree of intervention (felling and lopping most of the trees but leaving all the biomass). Starting 1 year after the fire, we used point sampling to monitor bird abundance in each treatment for 2 consecutive years during the breeding and winter seasons (720 censuses total). Postfire burned-wood management altered species assemblages. Salvage logged areas had species typical of open- and early-successional habitats. Bird species that inhabit forests were still present in the unsalvaged treatments even though trees were burned, but were almost absent in salvage-logged areas. Indeed, the main dispersers of mid- and late-successional shrubs and trees, such as thrushes (Turdus spp.) and the European Jay (Garrulus glandarius) were almost restricted to unsalvaged treatments. Salvage logging might thus hamper the natural regeneration of the forest through its impact on assemblages of bird species. Moreover, salvage logging reduced species abundance by 50% and richness by 40%, approximately. The highest diversity at the landscape level (gamma diversity) resulted from a combination of all treatments. Salvage logging may be positive for bird conservation if combined in a mosaic with other, less-aggressive postfire

Salvage Stereotactic Body Radiotherapy (SBRT) Following In-Field Failure of Initial SBRT for Spinal Metastases

Energy Technology Data Exchange (ETDEWEB)

Thibault, Isabelle; Campbell, Mikki [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Tseng, Chia-Lin [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada); Atenafu, Eshetu G. [Department of Biostatistics, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada); Letourneau, Daniel [Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada); Yu, Eugene [Department of Radiology, University Health Network, University of Toronto, Toronto, Ontario (Canada); Cho, B.C. John [Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada); Lee, Young K. [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Fehlings, Michael G. [Department of Radiology, University Health Network, University of Toronto, Toronto, Ontario (Canada); Sahgal, Arjun, E-mail: arjun.sahgal@sunnybrook.ca [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada)

2015-10-01

Purpose: We report our experience in salvaging spinal metastases initially irradiated with stereotactic body radiation therapy (SBRT), who subsequently progressed with imaging-confirmed local tumor progression, and were re-irradiated with a salvage second SBRT course to the same level. Methods and Materials: From a prospective database, 56 metastatic spinal segments in 40 patients were identified as having been irradiated with a salvage second SBRT course to the same level. In addition, 24 of 56 (42.9%) segments had initially been irradiated with conventional external beam radiation therapy before the first course of SBRT. Local control (LC) was defined as no progression on magnetic resonance imaging at the treated segment, and calculated according to the competing risk model. Overall survival (OS) was evaluated for each patient treated by use of the Kaplan-Meier method. Results: The median salvage second SBRT total dose and number of fractions was 30 Gy in 4 fractions (range, 20-35 Gy in 2-5 fractions), and for the first course of SBRT was 24 Gy in 2 fractions (range, 20-35 Gy in 1-5 fractions). The median follow-up time after salvage second SBRT was 6.8 months (range, 0.9-39 months), the median OS was 10.0 months, and the 1-year OS rate was 48%. A longer time interval between the first and second SBRT courses predicted for better OS (P=.02). The crude LC was 77% (43/56), the 1-year LC rate was 81%, and the median time to local failure was 3.0 months (range, 2.7-16.7 months). Of the 13 local failures, 85% (11/13) and 46% (6/13) showed progression within the epidural space and paraspinal soft tissues, respectively. Absence of baseline paraspinal disease predicted for better LC (P<.01). No radiation-induced vertebral compression fractures or cases of myelopathy were observed. Conclusion: A second course of spine SBRT, most often with 30 Gy in 4 fractions, for spinal metastases that failed initial SBRT is a feasible and efficacious salvage treatment option.

Implant salvage in breast reconstruction with severe peri-prosthetic infection.

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Meybodi, Farid; Sedaghat, Negin; French, James; Keighley, Caitlin; Mitchell, David; Elder, Elisabeth

2017-12-01

Although treatment of mild peri-prosthetic infection in implant-based breast reconstruction results in high rates of resolution, successful management of severe peri-prosthetic infection remains a significant challenge. In this case series, a protocol utilizing a novel dressing - negative pressure wound therapy with instillation (NPWTi) - for the management of severe peri-prosthetic infection in breast reconstruction patients is described. This is an operative technique involving: (i) explantation of the breast prosthesis and application of the NPWTi dressing to the implant pocket; (ii) change of the NPWTi dressing; (iii) intraoperative fluid/tissue cultures; and (iv) reimplantation of the breast prosthesis when cultures yield no growth. This protocol was utilized in six cases of severe peri-prosthetic infection in five patients with immediate breast reconstruction for breast cancer or risk-reducing surgery. Cultures of fluid/tissue grew typical and/or unusual organisms. Only one case did not yield an organism. The hospital length of stay upon completion of the protocol ranged from 7-16 days (mean, 12 days). Successful implant salvage was achieved in five of six cases. The protocol was aborted in one case to allow for completion of adjuvant chemotherapy. Early findings from this case series suggest that in cases of severe peri-prosthetic infection this novel operative protocol may result in successful implant salvage for breast reconstruction patients. Further studies are needed to more fully elaborate the role of NPWTi to achieve implant salvage in challenging cases of peri-prosthetic infection. © 2015 Royal Australasian College of Surgeons.

49 CFR 599.402 - Requirements and limitations for salvage auctions that are consigned trade-in vehicles under the...

Science.gov (United States)

2010-10-01

... that are consigned trade-in vehicles under the CARS program. 599.402 Section 599.402 Transportation... SAVE ACT PROGRAM Disposal of Trade-in Vehicle § 599.402 Requirements and limitations for salvage auctions that are consigned trade-in vehicles under the CARS program. (a) The salvage auction must: (1...

Dismal salvage of testicular torsion: A call to action! | Maranya ...

African Journals Online (AJOL)

... were not subjected to orchidopexy. There was no occurrence of torsion after orchidopexy. Conclusion: Testicular torsions were associated with low salvage rates. Increased public awareness coupled with clinician, parental, teacher, teenage and adult male education with respect to the consequences of acute scrotal pain ...

The serine protease inhibitor TLCK attenuates intrinsic death pathways in neurons upstream of mitochondrial demise.

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Reuther, C; Ganjam, G K; Dolga, A M; Culmsee, C

2014-11-01

It is well-established that activation of proteases, such as caspases, calpains and cathepsins are essential components in signaling pathways of programmed cell death (PCD). Although these proteases have also been linked to mechanisms of neuronal cell death, they are dispensable in paradigms of intrinsic death pathways, e.g. induced by oxidative stress. However, emerging evidence implicated a particular role for serine proteases in mechanisms of PCD in neurons. Here, we investigated the role of trypsin-like serine proteases in a model of glutamate toxicity in HT-22 cells. In these cells glutamate induces oxytosis, a form of caspase-independent cell death that involves activation of the pro-apoptotic protein BH3 interacting-domain death agonist (Bid), leading to mitochondrial demise and ensuing cell death. In this model system, the trypsin-like serine protease inhibitor Nα-tosyl-l-lysine chloromethyl ketone hydrochloride (TLCK) inhibited mitochondrial damage and cell death. Mitochondrial morphology alterations, the impairment of the mitochondrial membrane potential and ATP depletion were prevented and, moreover, lipid peroxidation induced by glutamate was completely abolished. Strikingly, truncated Bid-induced cell death was not affected by TLCK, suggesting a detrimental activity of serine proteases upstream of Bid activation and mitochondrial demise. In summary, this study demonstrates the protective effect of serine protease inhibition by TLCK against oxytosis-induced mitochondrial damage and cell death. These findings indicate that TLCK-sensitive serine proteases play a crucial role in cell death mechanisms upstream of mitochondrial demise and thus, may serve as therapeutic targets in diseases, where oxidative stress and intrinsic pathways of PCD mediate neuronal cell death.

Hedgehog Signaling Inhibitors as Anti-Cancer Agents in Osteosarcoma

International Nuclear Information System (INIS)

Ram Kumar, Ram Mohan; Fuchs, Bruno

2015-01-01

Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have not yet been fully elucidated and several evolutionary signaling pathways have been found to be linked with osteosarcoma pathogenesis, especially the hedgehog signaling (Hh) pathway. The present review will outline the importance and targeting the hedgehog signaling (Hh) pathway in osteosarcoma tumor biology. Available data also suggest that aberrant Hh signaling has pro-migratory effects and leads to the development of osteoblastic osteosarcoma. Activation of Hh signaling has been observed in osteosarcoma cell lines and also in primary human osteosarcoma specimens. Emerging data suggests that interference with Hh signal transduction by inhibitors may reduce osteosarcoma cell proliferation and tumor growth thereby preventing osteosarcomagenesis. From this perspective, we outline the current state of Hh pathway inhibitors in osteosarcoma. In summary, targeting Hh signaling by inhibitors promise to increase the efficacy of osteosarcoma treatment and improve patient outcome

[NF-κB signaling pathways and the future perspectives of bone disease therapy using selective inhibitors of NF-κB].

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Jimi, Eijiro; Fukushima, Hidefumi

2016-02-01

The transcriptional factor nuclear factor κB(NF-κB)regulates the expression of a wide variety of genes that are involved in immune and inflammatory responses, proliferation, and tumorigenesis. NF-κB consists of five members, such as p65(RelA), RelB, c-Rel, p50/p105(NF-κB1), and p52/p100(NF-κB2). There are two distinct NF-κB activation pathways, termed the classical and alternative NF-κB signaling pathways. Since mice lacking both p50 and p52 subunits developed typical osteopetrosis, due to total lack of osteoclasts, NF-κB is also important osteoclast differentiation. A selective NF-κB inhibitor blocked receptor activator of NF-κB ligand(RANKL)-induced osteoclastogenesis both in vitro and in vivo. Recent findings have shown that inactivation of NF-κB enhances osteoblast differentiation in vitro and bone formation in vivo. NF-κB is constitutively activated in many cancers including oral squamous cell carcinoma(OSCC), and is involved in the invasive characteristics of OSCC. A selective NF-κB inhibitor also prevented jaw bone destruction by OSCC by reduced osteoclast numbers in animal model. Thus the inhibition of NF-κB might useful for the treatment of bone diseases, such as arthritis, osteoporosis, periodontitis, and bone invasion by OSCC by inhibiting bone resorption and by stimulating bone formation.

Smad signaling pathway is a pivotal component of tissue inhibitor of metalloproteinases-3 regulation by transforming growth factor beta in human chondrocytes.

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Qureshi, Hamid Yaqoob; Ricci, Gemma; Zafarullah, Muhammad

2008-09-01

Transforming growth factor beta (TGF-beta1) promotes cartilage matrix synthesis and induces tissue inhibitor of metalloproteinases-3 (TIMP-3), which inhibits matrix metalloproteinases, aggrecanases and TNF-alpha-converting enzyme implicated in articular cartilage degradation and joint inflammation. TGF-beta1 activates Akt, ERK and Smad2 pathways in chondrocytes. Here we investigated previously unexplored roles of specific Smads in TGF-beta1 induction of TIMP-3 gene by pharmacological and genetic knockdown approaches. TGF-beta1-induced Smad2 phosphorylation and TIMP-3 protein expression could be inhibited by the Smad2/3 phosphorylation inhibitors, PD169316 and SB203580 and by Smad2-specific siRNA. Specific inhibitor of Smad3 (SIS3) and Smad3 siRNA abolished TGF-beta induction of TIMP-3. Smad2/3 siRNAs also down regulated TIMP-3 promoter-driven luciferase activities, suggesting transcriptional regulation. SiRNA-driven co-Smad4 knockdown abrogated TIMP-3 augmentation by TGF-beta. TIMP-3 promoter deletion analysis revealed that -828 deletion retains the original promoter activity while -333 and -167 deletions display somewhat reduced activity suggesting that most of the TGF-beta-responsive, cis-acting elements are found in the -333 fragment. Chromatin Immunoprecipitation (ChIP) analysis confirmed binding of Smad2 and Smad4 with the -940 and -333 promoter sequences. These results suggest that receptor-activated Smad2 and Smad3 and co-Smad4 critically mediate TGF-beta-stimulated TIMP-3 expression in human chondrocytes and TIMP-3 gene is a target of Smad signaling pathway.

Prevotella intermedia stimulates tissue-type plasminogen activator and plasminogen activator inhibitor-2 expression via multiple signaling pathways in human periodontal ligament cells.

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Guan, Su-Min; He, Jian-Jun; Zhang, Ming; Shu, Lei

2011-06-01

Prevotella intermedia is an important periodontal pathogen that induces various inflammatory and immune responses. In this study, we investigated the effects of P. intermedia on the plasminogen system in human periodontal ligament (hPDL) cells and explored the signaling pathways involved. Using semi-quantitative reverse transcription (RT)-PCR and quantitative real-time RT-qPCR, we demonstrated that P. intermedia challenge increased tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-2 expression in a concentration- and time-dependent manner, but exerted no influence on urokinase-type plasminogen activator and PAI-1mRNA expression in hPDL cells. Prevotella intermedia stimulation also enhanced tPA protein secretion as confirmed by enzyme-linked immunosorbent assay. Western blot results revealed that P. intermedia treatment increased phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase (p38). ERK, JNK and protein kinase C inhibitors significantly attenuated the P. intermedia-induced tPA and PAI-2 expression. Furthermore, p38 and phosphatidylinositol 3-kinase inhibitors markedly decreased PAI-2 expression, whereas they showed no or little inhibition on tPA expression. In contrast, inhibition of protein kinase A greatly enhanced the upregulatory effect of P. intermedia on tPA and PAI-2 expression. Our results suggest that P. intermedia may contribute to periodontal tissue destruction by upregulating tPA and PAI-2 expression in hPDL cells via multiple signaling pathways. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Adjuvant Versus Salvage Radiotherapy for Patients With Adverse Pathological Findings Following Radical Prostatectomy: A Decision Analysis

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Christopher J. D. Wallis MD

2017-05-01

Full Text Available Background: Patients undergoing surgery for prostate cancer who have adverse pathological findings experience high rates of recurrence. While there are data supporting adjuvant radiotherapy compared to a wait-and-watch strategy to reduce recurrence rates, there are no randomized controlled trials comparing adjuvant radiotherapy with the other standard of care, salvage radiotherapy (radiotherapy administered at the time of recurrence. Methods: We constructed a health state transition (Markov model employing two-dimensional Monte Carlo simulation using a lifetime horizon to compare the quality-adjusted survival associated with postoperative strategies using adjuvant or salvage radiotherapy. Prior to analysis, we calibrated and validated our model using the results of previous randomized controlled trials. We considered clinically important oncological health states from immediately postoperative to prostate cancer–specific death, commonly described complications from prostate cancer treatment, and other causes of mortality. Transition probabilities and utilities for disease states were derived from a literature search of MEDLINE and expert consensus. Results: Salvage radiotherapy was associated with an increased quality-adjusted life expectancy (QALE (58.3 months as compared with adjuvant radiotherapy (53.7 months, a difference of 4.6 months (standard deviation 8.8. Salvage radiotherapy had higher QALE in 53% of hypothetical cohorts. There was a minimal difference in overall life expectancy (-0.1 months. Examining recurrence rates, our model showed validity when compared with available randomized controlled data. Conclusions: A salvage radiotherapy strategy appears to provide improved QALE for patients with adverse pathological findings following radical prostatectomy, compared with adjuvant radiotherapy. As these findings reflect, population averages, specific patient and tumor factors, and patient preferences remain central for individualized

Gynecologic examination and cervical biopsies after (chemo) radiation for cervical cancer to identify patients eligible for salvage surgery

International Nuclear Information System (INIS)

Nijhuis, Esther R.; Zee, Ate G.J. van der; Hout, Bertha A. in 't; Boomgaard, Jantine J.; Hullu, Joanne A. de; Pras, Elisabeth; Hollema, Harry; Aalders, Jan G.; Nijman, Hans W.; Willemse, Pax H.B.; Mourits, Marian J.E.

2006-01-01

Purpose: The aim of this study was to evaluate efficacy of gynecologic examination under general anesthesia with cervical biopsies after (chemo) radiation for cervical cancer to identify patients with residual disease who may benefit from salvage surgery. Methods and Materials: In a retrospective cohort study data of all cervical cancer patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IB1 to IVA treated with (chemo) radiation between 1994 and 2001 were analyzed. Patients underwent gynecologic examination under anesthesia 8 to 10 weeks after completion of treatment. Cervical biopsy samples were taken from patients judged to be operable. In case of residual cancer, salvage surgery was performed. Results: Between 1994 and 2001, 169 consecutive cervical cancer patients received primary (chemo) radiation, of whom 4 were lost to follow-up. Median age was 56 years (interquartile range [IQR], 44-71) and median follow-up was 3.5 years (IQR, 1.5-5.9). In each of 111 patients a biopsy sample was taken, of which 90 (81%) showed no residual tumor. Vital tumor cells were found in 21 of 111 patients (19%). Salvage surgery was performed in 13 of 21 (62%) patients; of these patients, 5 (38%) achieved long-term, complete remission after salvage surgery (median follow-up, 5.2 years; range, 3.9-8.8 years). All patients with residual disease who did not undergo operation (8/21) died of progressive disease. Locoregional control was more often obtained in patients who underwent operation (7 of 13) than in patients who were not selected for salvage surgery (0 of 8 patients) (p < 0.05). Conclusions: Gynecologic examination under anesthesia 8 to 10 weeks after (chemo) radiation with cervical biopsies allows identification of those cervical cancer patients who have residual local disease, of whom a small but significant proportion may be salvaged by surgery

Yeast Interacting Proteins Database: YLR328W, YGR010W [Yeast Interacting Proteins Database

Lifescience Database Archive (English)

Full Text Available YLR328W NMA1 Nicotinic acid mononucleotide adenylyltransferase, involved in pathways... of NAD biosynthesis, including the de novo, NAD(+) salvage, and nicotinamide riboside salvage pathways Row... ORF YLR328W Bait gene name NMA1 Bait description Nicotinic acid mononucleotide adenylyltransferase, involved in pathways...otinamide riboside salvage pathways Rows with this bait as bait Rows with this bait as bait (2) Rows with th

Salvage Treatment for Recurrent Intracranial Germinoma After Reduced-Volume Radiotherapy: A Single-Institution Experience and Review of the Literature

International Nuclear Information System (INIS)

Hu, Yu-Wen; Huang, Pin-I; Wong, Tai-Tong; Ho, Donald Ming-Tak; Chang, Kai-Ping; Guo, Wan-Yuo; Chang, Feng-Chi; Shiau, Cheng-Yin; Liang, Muh-Lii; Lee, Yi-Yen

2012-01-01

Purpose: Intracranial germinomas (IGs) are highly curable with radiotherapy (RT). However, recurrence still occurs, especially when limited-field RT is applied, and the optimal salvage therapy remains controversial. Methods and Materials: Between January 1989 and December 2010, 14 patients with clinically or pathologically diagnosed recurrent IGs after RT were reviewed at our institution. Of these, 11 received focal-field RT, and the other 3 received whole-brain irradiation, whole-ventricle irradiation, and Gamma Knife radiosurgery as the respective first course of RT. In addition, we identified from the literature 88 patients with recurrent IGs after reduced-volume RT, in whom the details of salvage therapy were recorded. Results: The median time to recurrence was 30.3 months (range, 3.8–134.9 months). One patient did not receive further treatment and was lost during follow-up. Of the patients, 7 underwent salvage with craniospinal irradiation (CSI) plus chemotherapy (CT), 4 with CSI alone, 1 with whole-brain irradiation plus CT, and 1 with Gamma Knife radiosurgery. The median follow-up time was 105.1 months (range, 24.2–180.9 months). Three patients died without evidence of disease progression: two from second malignancies and one from unknown cause. The others remained disease free. The 3-year survival rate after recurrence was 83.3%. A total of 102 patients from our study and the literature review were analyzed to determine the factors affecting prognosis and outcomes. After recurrence, the 5-year survival rates were 71% and 92.9% for all patients and for those receiving salvage CSI, respectively. Univariate analysis showed that initial RT volume, initial RT dose, initial CT, and salvage RT type were significant prognostic predictors of survival. On multivariable analysis, salvage CSI was the most significant factor (p = 0.03). Conclusions: Protracted follow-up is recommended because late recurrence is not uncommon. CSI with or without CT is an effective

JAK inhibitors suppress t(8;21) fusion protein-induced leukemia

Science.gov (United States)

Lo, Miao-Chia; Peterson, Luke F.; Yan, Ming; Cong, Xiuli; Hickman, Justin H.; DeKelver, Russel C.; Niewerth, Denise; Zhang, Dong-Er

2014-01-01

Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein AML1-ETO and its alternatively spliced variant AML1-ETO9a (AE9a) enhance the JAK/STAT pathway via down-regulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML. PMID:23812420

Combining RNA interference and kinase inhibitors against cell signalling components involved in cancer

International Nuclear Information System (INIS)

O'Grady, Michael; Raha, Debasish; Hanson, Bonnie J; Bunting, Michaeline; Hanson, George T

2005-01-01

The transcription factor activator protein-1 (AP-1) has been implicated in a large variety of biological processes including oncogenic transformation. The tyrosine kinases of the epidermal growth factor receptor (EGFR) constitute the beginning of one signal transduction cascade leading to AP-1 activation and are known to control cell proliferation and differentiation. Drug discovery efforts targeting this receptor and other pathway components have centred on monoclonal antibodies and small molecule inhibitors. Resistance to such inhibitors has already been observed, guiding the prediction of their use in combination therapies with other targeted agents such as RNA interference (RNAi). This study examines the use of RNAi and kinase inhibitors for qualification of components involved in the EGFR/AP-1 pathway of ME180 cells, and their inhibitory effects when evaluated individually or in tandem against multiple components of this important disease-related pathway. AP-1 activation was assessed using an ME180 cell line stably transfected with a beta-lactamase reporter gene under the control of AP-1 response element following epidermal growth factor (EGF) stimulation. Immunocytochemistry allowed for further quantification of small molecule inhibition on a cellular protein level. RNAi and RT-qPCR experiments were performed to assess the amount of knockdown on an mRNA level, and immunocytochemistry was used to reveal cellular protein levels for the targeted pathway components. Increased potency of kinase inhibitors was shown by combining RNAi directed towards EGFR and small molecule inhibitors acting at proximal or distal points in the pathway. After cellular stimulation with EGF and analysis at the level of AP-1 activation using a β-lactamase reporter gene, a 10–12 fold shift or 2.5–3 fold shift toward greater potency in the IC 50 was observed for EGFR and MEK-1 inhibitors, respectively, in the presence of RNAi targeting EGFR. EGFR pathway components were qualified as

Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

Science.gov (United States)

Davies, L; Brown, T J; Haynes, S; Payne, K; Elliott, R A; McCollum, C

2006-11-01

To compare patient outcomes, resource use and costs to the NHS and NHS Blood Transfusion Authority (BTA) associated with cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion. Electronic databases covering the period 1996-2004 for systematic reviews and 1994-2004 for economic evidence. Existing systematic reviews were updated with data from selected randomised controlled trials (RCTs) that involved adults scheduled for elective non-urgent surgery. Any resource use or cost data were extracted for potential use in populating an economic model. Relative risks or weighted mean difference of each outcome for each intervention were assessed, taking into account the number of RCTs included in each outcome and intervention and the presence of any heterogeneity. This allowed indirect comparison of the relative effectiveness of each intervention when the intervention is compared with allogeneic blood transfusion. A decision analytic model synthesised clinical and economic data from several sources, to estimate the relative cost-effectiveness of cell salvage for people undergoing elective surgery with moderate to major expected blood loss. The perspective of the NHS and patients and a time horizon of 1 month were used. The economic model was developed from reviews of effectiveness and cost-effectiveness and clinical experts. Secondary analysis explored the robustness of the results to changes in the timing and costs of cell salvage equipment, surgical procedure, use of transfusion protocols and time horizon of analysis. Overall, 668 studies were identified electronically for the update of the two systematic reviews. This included five RCTs, of which two were cell salvage and three preoperative autologous donation (PAD). Five published systematic reviews were identified for antifibrinolytics, fibrin sealants and restrictive transfusion triggers, PAD plus erythropoietin, erythropoietin alone and acute normovolaemic haemodilution (ANH

Targeting the GPI biosynthetic pathway.

Science.gov (United States)

Yadav, Usha; Khan, Mohd Ashraf

2018-02-27

The GPI (Glycosylphosphatidylinositol) biosynthetic pathway is a multistep conserved pathway in eukaryotes that culminates in the generation of GPI glycolipid which in turn anchors many proteins (GPI-APs) to the cell surface. In spite of the overall conservation of the pathway, there still exist subtle differences in the GPI pathway of mammals and other eukaryotes which holds a great promise so far as the development of drugs/inhibitors against specific targets in the GPI pathway of pathogens is concerned. Many of the GPI structures and their anchored proteins in pathogenic protozoans and fungi act as pathogenicity factors. Notable examples include GPI-anchored variant surface glycoprotein (VSG) in Trypanosoma brucei, GPI-anchored merozoite surface protein 1 (MSP1) and MSP2 in Plasmodium falciparum, protein-free GPI related molecules like lipophosphoglycans (LPGs) and glycoinositolphospholipids (GIPLs) in Leishmania spp., GPI-anchored Gal/GalNAc lectin and proteophosphoglycans in Entamoeba histolytica or the GPI-anchored mannoproteins in pathogenic fungi like Candida albicans. Research in this active area has already yielded encouraging results in Trypanosoma brucei by the development of parasite-specific inhibitors of GlcNCONH 2 -β-PI, GlcNCONH 2 -(2-O-octyl)-PI and salicylic hydroxamic acid (SHAM) targeting trypanosomal GlcNAc-PI de-N-acetylase as well as the development of antifungal inhibitors like BIQ/E1210/gepinacin/G365/G884 and YW3548/M743/M720 targeting the GPI specific fungal inositol acyltransferase (Gwt1) and the phosphoethanolamine transferase-I (Mcd4), respectively. These confirm the fact that the GPI pathway continues to be the focus of researchers, given its implications for the betterment of human life.

Peroxisome Proliferator-Activated Receptor γ Induces the Expression of Tissue Factor Pathway Inhibitor-1 (TFPI-1 in Human Macrophages

Directory of Open Access Journals (Sweden)

G. Chinetti-Gbaguidi

2016-01-01

Full Text Available Tissue factor (TF is the initiator of the blood coagulation cascade after interaction with the activated factor VII (FVIIa. Moreover, the TF/FVIIa complex also activates intracellular signalling pathways leading to the production of inflammatory cytokines. The TF/FVIIa complex is inhibited by the tissue factor pathway inhibitor-1 (TFPI-1. Peroxisome proliferator-activated receptor gamma (PPARγ is a transcription factor that, together with PPARα and PPARβ/δ, controls macrophage functions. However, whether PPARγ activation modulates the expression of TFP1-1 in human macrophages is not known. Here we report that PPARγ activation increases the expression of TFPI-1 in human macrophages in vitro as well as in vivo in circulating peripheral blood mononuclear cells. The induction of TFPI-1 expression by PPARγ ligands, an effect shared by the activation of PPARα and PPARβ/δ, occurs also in proinflammatory M1 and in anti-inflammatory M2 polarized macrophages. As a functional consequence, treatment with PPARγ ligands significantly reduces the inflammatory response induced by FVIIa, as measured by variations in the IL-8, MMP-2, and MCP-1 expression. These data identify a novel role for PPARγ in the control of TF the pathway.

Extended Salvage Pelvic Lymph Node Dissection in Patients with Recurrent Prostate Cancer

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Daniar K. Osmonov

2014-01-01

Full Text Available Background. Treatment of patients with a biochemical recurrence (BCR of prostate cancer (PCa is generally difficult and without valid treatment options. Since 2004 we have been developing therapeutic possibilities for these patients. Methods. We retrospectively analyzed a cohort of 41 patients with a BCR of PCa and a mean followup of 40.3±20.8 months. Group 1 (n=10: salvage radical prostatectomy (sRP with SePLND (salvage extended pelvic lymph nodes dissection (initial treatment: combined brachytherapy. Group 2 (n=22: SePLND (initial treatment: radical prostatectomy (RP. Group 3 (n=9: SePLND (initial treatment: RP and adjuvant radiation therapy (RT. We observed PSA, PSA-velocity, localization of LNs and LNs+, BCR-free period, and BR (biochemical response. Results. Group 1: 60% with BCR-freedom (mean 27.2 months. Group 2: 63.6% with BCR-freedom (mean 17.5 months. Group 3: 33.3% with BCR-freedom (mean 17.6 months. In total, BCR-freedom was observed in 23 of 41 patients (56.1% after salvage surgery. 75.6% of all patients showed a BR. 765 LNs were removed and 14.8% of these were LN+. Conclusions. The BCR-free period and BR are comparable in all three groups. Sensibility to ADT can be reestablished and prolonged as a result of SePLND. Multicenter studies are needed for a reliable output.

Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Morris, M M; Dallow, K C; Zietman, A L; Althausen, A F; Heney, N M; McGovern, F J; Shipley, W U

1995-07-01

Purpose: To assess the ability of adjuvant irradiation to prevent PSA failure in cases of pT3N0 disease, and of salvage irradiation to durably suppress a rising PSA following radical prostatectomy. Methods and Materials: 62 patients treated by post-operative radiation therapy (60-64Gy in 1.8Gy fractions to the tumor bed) between 1988 and 1993 were evaluated. All had complete pre- and post-radiation PSA data. Median follow up was 3.2 years from time of surgery and 2.2 years from irradiation. 20 patients had Gleason grade 3 disease (moderately differentiated) and 41 Gleason 4-5 (poorly differentiated). 46 had positive inked surgical margins, 18 involved seminal vesicles and 5 had palpable recurrent disease. None had known nodal or metastatic disease. 32 patients underwent adjuvant treatment (undetectable PSA at time of irradiation) and 30 salvage (detectable PSA at time of irradiation). Kaplan-Meier life table analysis was employed. The endpoint studied was freedom from biochemical failure. This was defined as a rise in the PSA of greater than 10% (intra laboratory error <8%) or a previously undetectable PSA becoming detectable. Results: The overall actuarial freedom from biochemical failure at 4 years from radiotherapy was 59%. A significant difference was seen between those receiving adjuvant and those receiving salvage irradiation (71% vs 51%, p=0.03). Amongst those in the salvage group neither the PSA prior to surgery, the PSA at the time of irradiation, the seminal vesicle status, nor the Gleason score (3 vs 4-5) correlated significantly with outcome. The time interval between surgery and irradiation was, however, significant. Those being treated within 6 months fared better than those treated later (60% vs 36%, p=0.04). Further, those treated early were more likely to achieve an undetectable nadir PSA level (94% vs 71%). Conclusion: The addition of adjuvant irradiation appears to improve the 4 year biochemical disease-free survival of patients with poor

Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways

Energy Technology Data Exchange (ETDEWEB)

Zeng, Ke-Wu [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Li, Jun [Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029 (China); Dong, Xin; Wang, Ying-Hong; Ma, Zhi-Zhong; Jiang, Yong; Jin, Hong-Wei [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Tu, Peng-Fei, E-mail: pengfeitu@vip.163.com [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029 (China)

2013-11-15

Aldose reductase (AR) has a key role in several inflammatory diseases: diabetes, cancer and cardiovascular diseases. Therefore, AR inhibition seems to be a useful strategy for anti-inflammation therapy. In the central nervous system (CNS), microglial over-activation is considered to be a central event in neuroinflammation. However, the effects of AR inhibition in CNS inflammation and its underlying mechanism of action remain unknown. In the present study, we found that FMHM (a naturally derived AR inhibitor from the roots of Polygala tricornis Gagnep.) showed potent anti-neuroinflammatory effects in vivo and in vitro by inhibiting microglial activation and expression of inflammatory mediators. Mechanistic studies showed that FMHM suppressed the activity of AR-dependent phospholipase C/protein kinase C signaling, which further resulted in downstream inactivation of the IκB kinase/IκB/nuclear factor-kappa B (NF-κB) inflammatory pathway. Therefore, AR inhibition-dependent NF-κB inactivation negatively regulated the transcription and expression of various inflammatory genes. AR inhibition by FMHM exerted neuroprotective effects in lipopolysaccharide-induced neuron–microglia co-cultures. These findings suggested that AR is a potential target for neuroinflammation inhibition and that FMHM could be an effective agent for treating or preventing neuroinflammatory diseases. - Highlights: • FMHM is a natural-derived aldose reductase (AR) inhibitor. • FMHM inhibits various neuroinflammatory mediator productions in vitro and in vivo. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent NF-κB pathway. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent MAPK pathway. • FMHM protects neurons against inflammatory injury in microglia-neuron co-cultures.

Do indices of coronary conductance after reperfusion reflect the extent of salvaged myocardium?

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Shibata, Takahiro; Watanabe, Hisashi; Tsurusaki, Tetsushi; Minai, Kousuke; Ogawa, Takayuki; Iwano, Keiji; Tamura, Tetsutarou; Yoshida, Satoshi; Mutou, Makoto; Imai, Kamon; Horie, Toshinobu; Mochizuki, Seibu

2004-05-01

Existing indices of coronary conductance (hyperemic flow-versus-pressure slope index, FPSI, and zero flow pressure, Pzf) have been developed as measures of microcoronary resistance. These indices, however, refer to cases of normal hearts, and there are no reports studying these indices following acute myocardial infarction. In this study, we investigated whether FPSI and Pzf truly measure the extent of myocardial salvage after successful reperfusion therapy. We also developed a new index of zero pressure flow, Fzp. Nineteen patients who underwent successful reperfusion therapy to the proximal portion of the left anterior descending artery (LAD) were studied. After successful reperfusion therapy, a Doppler wire was placed into the LAD. Aortic pressure was recorded in real time. Results from the aortic pressure and flow meter were combined to produce FPSI, Pzf, and Fzp. All cases underwent a resting thallium (Tl) and BMIPP scintigram within five days of successful reperfusion therapy. Infarcted myocardium was estimated using a severity score calculated from the Tl scintigraphy (TlSS), and the BMIPP (BMIPPSS) was estimated using a severity score. Patients with a TlSS/BMIPPSS ratio of less than 0.4 were assigned to the successful salvage group (group S), while the others were assigned to the failed salvage group (group F). FPSI of group F was 1.91 +/- 0.26 m/sec and of group S was 0.92 +/- 0.43 m/sec (P < 0.01). Pzf of group F was 51 +/- 3 mmHg and of group S was 51 +/- 5 mmHg (NS). Fzp of group F was -98 +/- 16 cm/sec and of group S was -46 +/- 4 cm/sec (P < 0.05). FPSI and the new index of Fzp were useful in estimating the extent of myocardial salvage. Our results suggest that the Pzf index could not differentiate between the two groups.

Insulin signaling pathways in lepidopteran steroidogenesis

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Wendy eSmith

2014-02-01

Full Text Available Molting and metamorphosis are stimulated by the secretion of ecdysteroid hormones from the prothoracic glands. Insulin-like hormones have been found to enhance prothoracic gland activity, providing a mechanism to link molting to nutritional state. In silk moths (Bombyx mori, the prothoracic glands are directly stimulated by insulin and the insulin-like hormone bombyxin. Further, in Bombyx , the neuropeptide prothoracicotropic hormone (PTTH appears to act at least in part through the insulin-signaling pathway. In the prothoracic glands of Manduca sexta, while insulin stimulates the phosphorylation of the insulin receptor and Akt, neither insulin nor bombyxin II stimulate ecdysone secretion. Involvement of the insulin-signaling pathway in Manduca prothoracic glands was explored using two inhibitors of phosphatidylinositol-3-kinase (PI3K, LY294002 and wortmannin. PI3K inhibitors block the phosphorylation of Akt and 4EBP but have no effect on ecdysone secretion, or on the phosphorylation of the MAPkinase, ERK. Inhibitors that block phosphorylation of ERK, including the MEK inhibitor U0126, and high doses of the RSK inhibitor SL0101, effectively inhibit ecdysone secretion. The results highlight differences between the two lepidopteran insects most commonly used to directly study ecdysteroid secretion. In Bombyx, the PTTH and insulin-signaling pathways intersect; both insulin and PTTH enhance the phosphorylation of Akt and stimulate ecdysteroid secretion, and inhibition of PI3K reduces ecdysteroid secretion. By contrast, in Manduca, the action of PTTH is distinct from insulin. The results highlight species differences in the roles of translational regulators such as 4EBP, and members of the MAPkinase pathway such as ERK and RSK, in the effects of nutritionally-sensitive hormones such as insulin on ecdysone secretion and molting.

The outcome of rectal cancer after early salvage TME following TEM compared with primary TME: a case-matched study.

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Levic, K; Bulut, O; Hesselfeldt, P; Bülow, S

2013-08-01

Transanal endoscopic microsurgery (TEM) allows locally complete resection of early rectal cancer as an alternative to conventional radical surgery. In case of unfavourable histology after TEM, or positive resection margins, salvage surgery can be performed. However, it is unclear if the results are equivalent to primary treatment with total mesorectal excision (TME). The aim of this retrospective study was to determine whether there is a difference in outcome between patients who underwent early salvage resection with TME after TEM, and those who underwent primary TME for rectal cancer. From 1997 to 2011, early salvage surgery with TME after TEM was performed in 25 patients in our institution. These patients were compared with 25 patients who underwent primary TME, matched according to gender, age (±2 years), cancer stage and operative procedure. Data were obtained from the patients' charts and reviewed retrospectively. No patients received preoperative chemotherapy. Perioperative data and oncological outcome were analysed. The Mann-Whitney U-test and Fisher's exact test were used to compare the results between the two groups. There was no significant difference between the two groups in median operating time (P = 0.39), median blood loss (P = 0.19) or intraoperative complications (P = 1.00). The 30-day mortality was 8 % (n = 2) among patients who underwent salvage TME after TEM, and no patients died in the primary TME group (P = 0.49). There was no significant difference between two groups of patients in the median number of harvested lymph nodes (P = 0.34), median circumferential resection margin (CRM) (P = 0.99) or the completeness of the mesorectal fascia plane. No local recurrences occurred among the patients with salvage TME, and there were 2 patients (8 %) with local recurrences among the patients with primary TME (P = 0.49). Distant metastasis occurred in one patient (4 %) after salvage TME and in 3 patients (12 %) with primary TME (P = 0.61). The median

Oncological and functional outcomes of salvage renal surgery following failed primary intervention for renal cell carcinoma

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Fernando G. Abarzua-Cabezas

2015-02-01

Full Text Available Purpose To assess the oncologic and functional outcomes of salvage renal surgery following failed primary intervention for RCC. Materials and Methods We performed a retrospective review of patients who underwent surgery for suspected RCC during 2004-2012. We identified 839 patients, 13 of whom required salvage renal surgery. Demographic data was collected for all patients. Intraoperative and postoperative data included ischemic duration, blood loss and perioperative complications. Preoperative and postoperative assessments included abdominal CT or magnetic resonance imaging, chest CT and routine laboratory work. Estimated glomerular filtration rate (eGFR was calculated according to the Modification of Diet in Renal Disease equation. Results The majority (85% of the patients were male, with an average age of 64 years. Ten patients underwent salvage partial nephrectomy while 3 underwent salvage radical nephrectomy. Cryotherapy was the predominant primary failed treatment modality, with 31% of patients undergoing primary open surgery. Pre-operatively, three patients were projected to require permanent post-operative dialysis. In the remaining 10 patients, mean pre- and postoperative serum creatinine and eGFR levels were 1.35 mg/dL and 53.8 mL/min/1.73 m2 compared to 1.43 mg/dL and 46.6 mL/min/1.73 m2, respectively. Mean warm ischemia time in 10 patients was 17.4 min and for all patients, the mean blood loss was 647 mL. The predominant pathological stage was pT1a (8/13; 62%. Negative surgical margins were achieved in all cases. The mean follow-up was 32.9 months (3.5-88 months. Conclusion While salvage renal surgery can be challenging, it is feasible and has adequate surgical, functional and oncological outcomes.

Serum PSA Evaluations during salvage radiotherapy for post-prostatectomy biochemical failures as prognosticators for treatment outcomes

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Do, Tri; Dave, Giatri; Parker, Robert; Kagan, A. Robert

2001-01-01

Introduction: Serum prostate specific antigen (PSA) levels have proved to be sensitive markers for the diagnosis of prostate cancer. In addition, PSA levels are useful for detecting and monitoring prostate cancer progression after radiotherapy. Serum PSA evaluations during radiotherapy, however, have not been well documented. In this study, we investigate the prognostic value of PSA evaluations during salvage radiotherapy for prostatectomy failures. Methods: Forty-one patients with biochemical failures after prostatectomy treated with salvage radiotherapy consented to have their serum PSA levels evaluated at 30 Gy and 45 Gy of irradiation. All 41 patients had negative metastatic workup and pathologically uninvolved pelvic lymph nodes at the time of referral for salvage radiotherapy. Radiation therapy was delivered with 10-25 MV photons, with doses of 59.4-66.6 Gy. No patients received hormonal ablation therapy before irradiation. Results: The mean follow-up for all patients was 30.9 months. At last follow-up, 28/41 patients (68.3%) were free from biochemical failure, with 20 of 41 patients (48.8%) expressing undetectable PSA levels. Serum PSA evaluations at 30 Gy did not significantly predict for either biochemical (p=0.0917) or clinical (p=0.106) disease-free outcome. However, serum PSA evaluations at 45 Gy significantly predicted for both biochemical (p=0.0043) and clinical (p=0.0244) disease-free outcomes, with PSA elevations at 45 Gy significantly associated with poor outcomes. On univariate analysis of prognosticators for biochemical failures, the following were significant: an elevation in serum PSA levels at 45 Gy, detectable serum PSA immediately after prostatectomy, Gleason score 7-10, and serum PSA level >1 ng/ml before salvage radiotherapy. Conclusion: Evaluation of serum PSA level at 45 Gy of salvage radiotherapy for biochemical relapses after prostatectomy may serve as a significant prognosticator for both biochemical and clinical disease-free outcomes

mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.

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Costanza Bogani

Full Text Available BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN, usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. FINDINGS: Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001 and an ATP-competitive (PP242 mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib. mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with

Targeted therapies in the treatment of urothelial cancers.

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Aragon-Ching, Jeanny B; Trump, Donald L

2017-07-01

Progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years. However, the recent approval of immunotherapy with atezolizumab and nivolumab for second-line salvage therapy may usher in an era of more rapid improvement. Systemic treatment is suboptimal and is an area of substantial unmet medical need. The recent findings from The Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies. Promising results with treatment using vascular endothelial growth factor inhibitors such as ramucirumab, sunitinib or bevacizumab, and human epidermal growth factor receptor 2 targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials and are discussed later. Copyright © 2017 Elsevier Inc. All rights reserved.

Inhibitor specificity of recombinant and endogenous caspase-9.

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Ryan, Ciara A; Stennicke, Henning R; Nava, Victor E; Burch, Jennifer B; Hardwick, J Marie; Salvesen, Guy S

2002-01-01

Apoptosis triggered through the intrinsic pathway by radiation and anti-neoplastic drugs is initiated by the activation of caspase-9. To elucidate control mechanisms in this pathway we used a range of synthetic and natural reagents. The inhibitory potency of acetyl-Asp-Glu-Val-Asp-aldehyde ('Ac-DEVD-CHO'), benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone ('Z-VAD-FMK') and the endogenous caspase inhibitor X-chromosome-linked inhibitor of apoptosis protein ('XIAP') against recombinant caspase-9 were predictive of the efficacy of these compounds in a cell-free system. However, the viral proteins CrmA and p35, although potent inhibitors of recombinant caspase-9, had almost no ability to block caspase-9 in this system. These findings were also mirrored in cell expression studies. We hypothesize that the viral inhibitors CrmA and p35 are excluded from reacting productively with the natural form of active caspase-9 in vivo, making the potency of inhibitors highly context-dependent. This is supported by survival data from a mouse model of apoptosis driven by Sindbis virus expressing either p35 or a catalytic mutant of caspase-9. These results consolidate previous findings that CrmA is a potent inhibitor of caspase-9 in vitro, yet fails to block caspase-9-mediated cell death. PMID:12067274

A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors.

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El Meskini, Rajaa; Iacovelli, Anthony J; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L; Baran, Maureen; Householder, Deborah B; Van Dyke, Terry; Weaver Ohler, Zoë

2015-01-01

Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment. © 2015. Published by The Company of Biologists Ltd.

A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors

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Rajaa El Meskini

2015-01-01

Full Text Available Current therapies for glioblastoma multiforme (GBM, the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment.

Salvage prostate HDR brachytherapy combined with interstitial hyperthermia for local recurrence after radiation therapy failure

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Kukielka, A.M.; Hetnal, M.; Dabrowski, T.; Walasek, T.; Brandys, P.; Reinfuss, M. [Centre of Oncology, M. Sklodowska - Curie Institute, Krakow Branch, Department of Radiotherapy, Krakow (Poland); Nahajowski, D.; Kudzia, R.; Dybek, D. [Centre of Oncology, M. Sklodowska - Curie Institute, Krakow Branch, Department of Medical Physics, Department of Radiotherapy, Krakow (Poland)

2014-02-15

The aim of the present retrospective study is to evaluate toxicity and early clinical outcomes of interstitial hyperthermia (IHT) combined with high-dose rate (HDR) brachytherapy as a salvage treatment in patients with biopsy-confirmed local recurrence of prostate cancer after previous external beam radiotherapy. Between September 2008 and March 2013, 25 patients with local recurrence of previously irradiated prostate cancer were treated. The main eligibility criteria for salvage prostate HDR brachytherapy combined with interstitial hyperthermia were biopsy confirmed local recurrence and absence of nodal and distant metastases. All patients were treated with a dose of 30 Gy in 3 fractions at 21-day intervals. We performed 62 hyperthermia procedures out of 75 planned (83 %). The aim of the hyperthermia treatment was to heat the prostate to 41-43 C for 60 min. Toxicity for the organs of the genitourinary system and rectum was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE, v. 4.03). Determination of subsequent biochemical failure was based on the Phoenix definition (nadir + 2 ng/ml). The median age was 71 years (range 62-83 years), the median initial PSA level was 16.3 ng/ml (range 6.37-64 ng/ml), and the median salvage PSA level was 2.8 ng/ml (1.044-25.346 ng/ml). The median follow-up was 13 months (range 4-48 months). The combination of HDR brachytherapy and IHT was well tolerated. The most frequent complications were nocturia, weak urine stream, urinary frequency, hematuria, and urgency. Grade 2 rectal hemorrhage was observed in 1 patient. No grade 3 or higher complications were observed. The 2-year Kaplan-Meier estimate of biochemical control after salvage treatment was 74 %. The PSA in 20 patients decreased below the presalvage level, while 11 patients achieved a PSA nadir < 0.5 ng/ml. All patients are still alive. Of the 7 patients who experienced biochemical failure, bone metastases were found in 2 patients. IHT in combination

75 FR 54026 - Salvage and Marine Firefighting Requirements; Vessel Response Plans for Oil

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2010-09-03

... information for resource providers for each vessel with appropriate equipment and resources located in each... appropriate salvage and marine firefighting resources were identified and available for responding to...

Deubiquitinase inhibitor b-AP15 activates endoplasmic reticulum (ER) stress and inhibits Wnt/Notch1 signaling pathway leading to the reduction of cell survival in hepatocellular carcinoma cells.

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Ding, Youming; Chen, Xiaoyan; Wang, Bin; Yu, Bin; Ge, Jianhui

2018-04-15

b-AP15, a potent and selective inhibitor of the ubiquitin-specific peptidase 14 (USP14), displays in vitro and in vivo antitumor abilities on some types of cancer cells. However, the mechanism underlying its action is not well elucidated. The purposes of the present study are to observe the potential impacts of b-AP15 on cell survival of hepatocellular carcinoma cells and to investigate whether and how this compound inhibits some survival-promoting signaling pathways. We found that b-AP15 significantly decreased cell viability and increased cell apoptosis in a dose-dependent manner in hepatocellular carcinoma cells, along with the perturbation of cell cycle and the decreased expressions of cell cycle-related proteins. We also demonstrated that the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were enhanced by b-AP15 supplementation. The inhibition of ER stress/UPR only partly attenuated the cytotoxicity of b-AP15 on hepatocellular carcinoma cells. In addition, b-AP15 treatment inhibited Wnt/β-catenin and Notch1 signaling pathways, and suppressed phosphorylation of STAT3, Akt, and Erk1/2, which were not restored by the inhibition of ER stress/UPR. Furthermore, the expression levels of signaling molecules in Notch1 were reduced by specific inhibitor of Wnt/β-catenin pathway. Notably, either Wnt or Notch1 signaling inhibitor mitigated phosphorylation of STAT3, Akt, and Erk1/2, and mimicked the cytotoxicity of b-AP15 on hepatocellular carcinoma cells. These results clearly indicate that b-AP15 induced cytotoxic response to hepatocellular carcinoma cells by augmenting ER stress/UPR and inhibiting Wnt/Notch1 signaling pathways. This new finding provides a novel mechanism by which b-AP15 produces its antitumor therapeutic effects. Copyright © 2018 Elsevier B.V. All rights reserved.

Suggestion for the prostatic fossa clinical target volume in adjuvant or salvage radiotherapy after a radical prostatectomy

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Park, Jun Su; Park, Won; Pyo, Hong Ryull; Park, Byung Kwan; Park, Sung Yoon; Choi, Han Yong; Lee, Hyun Moo; Jeon, Seong Soo; Seo, Seong Il; Jeong, Byong Chang; Jeon, Hwang Gyun

2014-01-01

Background and purpose: To assess the location of recurrent tumors and suggest the optimal target volume in adjuvant or salvage radiotherapy (RT) after a radical prostatectomy (RP). Material and methods: From January 2000 to December 2012, 113 patients had been diagnosed with suspected recurrent prostate cancer by MRI scan and received salvage RT in the Samsung Medical Center. This study assessed the location of the suspected tumor recurrences and used the inferior border of the pubic symphysis as a point of reference. Results: There were 118 suspect tumor recurrences. The most common site of recurrence was the anastomotic site (78.8%), followed by the bladder neck (15.3%) and retrovesical area (5.9%). In the cranial direction, 106 (87.3%) lesions were located within 30 mm of the reference point. In the caudal direction, 12 lesions (10.2%) were located below the reference point. In the transverse plane, 112 lesions (94.9%) were located within 10 mm of the midline. Conclusions: A MRI scan acquired before salvage RT is useful for the localization of recurrent tumors and the delineation of the target volume. We suggest the optimal target volume in adjuvant or salvage RT after RP, which includes 97% of suspected tumor recurrences

Travel distance and use of salvage palliative chemotherapy in patients with metastatic colorectal cancer.

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Ahmed, Shahid; Iqbal, Mahjabeen; Le, Duc; Iqbal, Nayyer; Pahwa, Punam

2018-04-01

Salvage palliative chemotherapy in metastatic colorectal cancer has been associated with significant improvement in survival. However, not all patients receive all available therapies. Travel burden can affect patient access and use of future therapy. The present study aims to determine relationship between travel distance (TD) and salvage palliative chemotherapy in patients with metastatic colorectal cancer. A patient cohort diagnosed with metastatic colorectal cancer during 2006-2010 in the province of Saskatchewan, Canada was studied. Logistic regression analyses were performed to assess relationship between travel distance and subsequent line therapies. The median age of 264 eligible patients was 62 years [interquartile range (IQR): 53-72]. The patients who received salvage systemic therapy had a median distance to travel of 60.0 km (IQR: 4.7-144) compared with 88.1 km (IQR: 4.8-189) if they did not receive second- or third-line therapy (P=0.06). In multivariate analysis distance to the cancer center therapies. Our result revealed that travel distance to the cancer center greater than 100 km was associated less frequent use of second or subsequent line therapies in patients with metastatic colorectal cancer.

Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics

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Chelsea Jenkins

2012-01-01

Full Text Available The Fanconi Anemia (FA pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs. The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

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Knight, Louise A; Kurbacher, Christian M; Glaysher, Sharon; Fernando, Augusta; Reichelt, Ralf; Dexel, Susanne; Reinhold, Uwe; Cree, Ian A

2009-01-01

Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation

Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway.

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Chen, Dongshao; Lin, Xiaoting; Zhang, Cheng; Liu, Zhentao; Chen, Zuhua; Li, Zhongwu; Wang, Jingyuan; Li, Beifang; Hu, Yanting; Dong, Bin; Shen, Lin; Ji, Jiafu; Gao, Jing; Zhang, Xiaotian

2018-01-26

Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G 2 /M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.

The anaphase inhibitor of Saccharomyces cerevisiae Pds1p is a target of the DNA damage checkpoint pathway

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Cohen-Fix, O.; Koshland, D.

1997-01-01

Inhibition of DNA replication and physical DNA damage induce checkpoint responses that arrest cell cycle progression at two different stages. In Saccharomyces cerevisiae, the execution of both checkpoint responses requires the Mec1 and Rad53 proteins. This observation led to the suggestion that these checkpoint responses are mediated through a common signal transduction pathway. However, because the checkpoint-induced arrests occur at different cell cycle stages, the downstream effectors mediating these arrests are likely to be distinct. We have previously shown that the S. cerevisiae protein Pds1p is an anaphase inhibitor and is essential for cell cycle arrest in mitosis in the presence DNA damage. Herein we show that DNA damage, but not inhibition of DNA replication, induces the phosphorylation of Pds1p. Analyses of Pds1p phosphorylation in different checkpoint mutants reveal that in the presence of DNA damage, Pds1p is phosphorylated in a Mec1p- and Rad9p-dependent hut Rad53p-independent manner. Our data place Pds1p and Rad53p on parallel branches of the DNA damage checkpoint pathway. We suggest that Pds1p is a downstream target of the DNA damage checkpoint pathway and that it is involved in implementing the DNA damage checkpoint arrest specifically in mitosis

Is Angiosome-Targeted Angioplasty Effective for Limb Salvage and Wound Healing in Diabetic Foot? : A Meta-Analysis.

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Chae, Kum Ju; Shin, Jin Yong

2016-01-01

Given that the efficacy of employing angiosome-targeted angioplasty in the treatment of diabetic foot remains controversial, this study was conducted to examine its efficacy. We performed a systematic literature review and meta-analysis using core databases, extracting the treatment modality of angiosome-targeted angioplasty as the predictor variable, and limb salvage, wound healing, and revision rate as the outcome variables. We used the Newcastle-Ottawa Scale to assess the study quality, along with the Cochrane Risk of Bias Tool. We evaluated publication bias using a funnel plot. The search strategy identified 518 publications. After screening these, we selected four articles for review. The meta-analysis revealed that overall limb salvage and wound healing rates were significantly higher (Odds ratio = 2.209, 3.290, p = 0.001, pdiabetic foot was more effective than nonangiosome-targeted angioplasty with respect to wound healing and limb salvage.

Local Recurrence After Complete Clinical Response and Watch and Wait in Rectal Cancer After Neoadjuvant Chemoradiation: Impact of Salvage Therapy on Local Disease Control

Energy Technology Data Exchange (ETDEWEB)

Habr-Gama, Angelita, E-mail: gamange@uol.com.br [Angelita and Joaquim Gama Institute, São Paulo (Brazil); University of São Paulo School of Medicine, São Paulo (Brazil); Gama-Rodrigues, Joaquim [Angelita and Joaquim Gama Institute, São Paulo (Brazil); University of São Paulo School of Medicine, São Paulo (Brazil); São Julião, Guilherme P. [Angelita and Joaquim Gama Institute, São Paulo (Brazil); Colorectal Surgery Division, University of São Paulo School of Medicine, São Paulo (Brazil); Proscurshim, Igor; Sabbagh, Charles; Lynn, Patricio B. [Angelita and Joaquim Gama Institute, São Paulo (Brazil); Perez, Rodrigo O. [Angelita and Joaquim Gama Institute, São Paulo (Brazil); Ludwig Institute for Cancer Research, São Paulo Branch (Brazil)

2014-03-15

Purpose: To review the risk of local recurrence and impact of salvage therapy after Watch and Wait for rectal cancer with complete clinical response (cCR) after chemoradiation therapy (CRT). Methods and Materials: Patients with cT2-4N0-2M0 distal rectal cancer treated with CRT (50.4-54 Gy + 5-fluorouracil-based chemotherapy) and cCR at 8 weeks were included. Patients with cCR were enrolled in a strict follow-up program with no immediate surgery (Watch and Wait). Local recurrence-free survival was compared while taking into account Watch and Wait strategy alone and Watch and Wait plus salvage. Results: 90 of 183 patients experienced cCR at initial assessment after CRT (49%). When early tumor regrowths (up to and including the initial 12 months of follow-up) and late recurrences were considered together, 28 patients (31%) experienced local recurrence (median follow-up time, 60 months). Of those, 26 patients underwent salvage therapy, and 2 patients were not amenable to salvage. In 4 patients, local re-recurrence developed after Watch and Wait plus salvage. The overall salvage rate for local recurrence was 93%. Local recurrence-free survival at 5 years was 69% (all local recurrences) and 94% (after salvage procedures). Thirteen patients (14%) experienced systemic recurrence. The 5-year cancer-specific overall survival and disease-free survival for all patients (including all recurrences) were 91% and 68%, respectively. Conclusions: Local recurrence may develop in 31% of patients with initial cCR when early regrowths (≤12 months) and late recurrences are grouped together. More than half of these recurrences develop within 12 months of follow-up. Salvage therapy is possible in ≥90% of recurrences, leading to 94% local disease control, with 78% organ preservation.

Local Recurrence After Complete Clinical Response and Watch and Wait in Rectal Cancer After Neoadjuvant Chemoradiation: Impact of Salvage Therapy on Local Disease Control

International Nuclear Information System (INIS)

Habr-Gama, Angelita; Gama-Rodrigues, Joaquim; São Julião, Guilherme P.; Proscurshim, Igor; Sabbagh, Charles; Lynn, Patricio B.; Perez, Rodrigo O.

2014-01-01

Purpose: To review the risk of local recurrence and impact of salvage therapy after Watch and Wait for rectal cancer with complete clinical response (cCR) after chemoradiation therapy (CRT). Methods and Materials: Patients with cT2-4N0-2M0 distal rectal cancer treated with CRT (50.4-54 Gy + 5-fluorouracil-based chemotherapy) and cCR at 8 weeks were included. Patients with cCR were enrolled in a strict follow-up program with no immediate surgery (Watch and Wait). Local recurrence-free survival was compared while taking into account Watch and Wait strategy alone and Watch and Wait plus salvage. Results: 90 of 183 patients experienced cCR at initial assessment after CRT (49%). When early tumor regrowths (up to and including the initial 12 months of follow-up) and late recurrences were considered together, 28 patients (31%) experienced local recurrence (median follow-up time, 60 months). Of those, 26 patients underwent salvage therapy, and 2 patients were not amenable to salvage. In 4 patients, local re-recurrence developed after Watch and Wait plus salvage. The overall salvage rate for local recurrence was 93%. Local recurrence-free survival at 5 years was 69% (all local recurrences) and 94% (after salvage procedures). Thirteen patients (14%) experienced systemic recurrence. The 5-year cancer-specific overall survival and disease-free survival for all patients (including all recurrences) were 91% and 68%, respectively. Conclusions: Local recurrence may develop in 31% of patients with initial cCR when early regrowths (≤12 months) and late recurrences are grouped together. More than half of these recurrences develop within 12 months of follow-up. Salvage therapy is possible in ≥90% of recurrences, leading to 94% local disease control, with 78% organ preservation

Evaluation of acute ischemia in pre-procedure ECG predicts myocardial salvage after primary PCI in STEMI patients with symptoms >12hours

DEFF Research Database (Denmark)

Fakhri, Yama; Busk, Martin; Schoos, Mikkel Malby

2016-01-01

-presenters). The Anderson-Wilkin's score (AW-score) estimates the acuteness of myocardial ischemia from the electrocardiogram (ECG) in STEMI patients. We hypothesized that the AW-score is superior to symptom duration in identifying substantial salvage potential in late-presenters. METHODS: The AW-score (range 1......-4) was obtained from the pre-pPCI ECG in 55 late-presenters and symptoms 12-72 hours. Myocardial perfusion imaging was performed to assess area at risk before pPCI and after 30days to assess myocardial salvage index (MSI). We correlated both the AW-score and pain-to-balloon with MSI and determined the salvage...

Overlapping Bark Beetle Outbreaks, Salvage Logging and Wildfire Restructure a Lodgepole Pine Ecosystem

Directory of Open Access Journals (Sweden)

Charles C. Rhoades

2018-02-01

Full Text Available The 2010 Church’s Park Fire burned beetle-killed lodgepole pine stands in Colorado, including recently salvage-logged areas, creating a fortuitous opportunity to compare the effects of salvage logging, wildfire and the combination of logging followed by wildfire. Here, we examine tree regeneration, surface fuels, understory plants, inorganic soil nitrogen and water infiltration in uncut and logged stands, outside and inside the fire perimeter. Subalpine fir recruitment was abundant in uncut, unburned, beetle-killed stands, whereas lodgepole pine recruitment was abundant in cut stands. Logging roughly doubled woody fuel cover and halved forb and shrub cover. Wildfire consumed all conifer seedlings in uncut and cut stands and did not stimulate new conifer regeneration within four years of the fire. Aspen regeneration, in contrast, was relatively unaffected by logging or burning, alone or combined. Wildfire also drastically reduced cover of soil organic horizons, fine woody fuels, graminoids and shrubs relative to unburned, uncut areas; moreover, the compound effect of logging and wildfire was generally similar to wildfire alone. This case study documents scarce conifer regeneration but ample aspen regeneration after a wildfire that occurred in the later stage of a severe beetle outbreak. Salvage logging had mixed effects on tree regeneration, understory plant and surface cover and soil nitrogen, but neither exacerbated nor ameliorated wildfire effects on those resources.

Crystal Structures of the Helicobacter pylori MTAN Enzyme Reveal Specific Interactions between S-Adenosylhomocysteine and the 5'-Alkylthio Binding Subsite

Energy Technology Data Exchange (ETDEWEB)

Mishra, Vidhi [Univ. of Toledo, OH (United States); Ronning, Donald R. [Univ. of Toledo, OH (United States)

2012-11-13

The bacterial 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) enzyme is a multifunctional enzyme that catalyzes the hydrolysis of the N-ribosidic bond of at least four different adenosine-based metabolites: S-adenosylhomocysteine (SAH), 5'-methylthioadenosine (MTA), 5'-deoxyadenosine (5'-DOA), and 6-amino-6-deoxyfutalosine. These activities place the enzyme at the hub of seven fundamental bacterial metabolic pathways: S-adenosylmethionine (SAM) utilization, polyamine biosynthesis, the purine salvage pathway, the methionine salvage pathway, the SAM radical pathways, autoinducer-2 biosynthesis, and menaquinone biosynthesis. The last pathway makes MTAN essential for Helicobacter pylori viability. Although structures of various bacterial and plant MTANs have been described, the interactions between the homocysteine moiety of SAH and the 5'-alkylthiol binding site of MTAN have never been resolved. We have determined crystal structures of an inactive mutant form of H. pylori MTAN bound to MTA and SAH to 1.63 and 1.20 Å, respectively. The active form of MTAN was also crystallized in the presence of SAH, allowing the determination of the structure of a ternary enzyme–product complex resolved at 1.50 Å. These structures identify interactions between the homocysteine moiety and the 5'-alkylthiol binding site of the enzyme. This information can be leveraged for the development of species-specific MTAN inhibitors that prevent the growth of H. pylori.

Proteasome inhibitors activate autophagy involving inhibition of PI3K-Akt-mTOR pathway as an anti-oxidation defense in human RPE cells.

Directory of Open Access Journals (Sweden)

Bingrong Tang

Full Text Available The two major intracellular protein degradation systems, the ubiquitin-proteasome system (UPS and autophagy, work collaboratively in many biological processes including development, apoptosis, aging, and countering oxidative injuries. We report here that, in human retinal pigment epithelial cells (RPE, ARPE-19 cells, proteasome inhibitors, clasto-lactacystinβ-lactone (LA or epoxomicin (Epo, at non-lethal doses, increased the protein levels of autophagy-specific genes Atg5 and Atg7 and enhanced the conversion of microtubule-associated protein light chain (LC3 from LC3-I to its lipidative form, LC3-II, which was enhanced by co-addition of the saturated concentration of Bafilomycin A1 (Baf. Detection of co-localization for LC3 staining and labeled-lysosome further confirmed autophagic flux induced by LA or Epo. LA or Epo reduced the phosphorylation of the protein kinase B (Akt, a downstream target of phosphatidylinositol-3-kinases (PI3K, and mammalian target of rapamycin (mTOR in ARPE-19 cells; by contrast, the induced changes of autophagy substrate, p62, showed biphasic pattern. The autophagy inhibitor, Baf, attenuated the reduction in oxidative injury conferred by treatment with low doses of LA and Epo in ARPE-19 cells exposed to menadione (VK3 or 4-hydroxynonenal (4-HNE. Knockdown of Atg7 with siRNA in ARPE-19 cells reduced the protective effects of LA or Epo against VK3. Overall, our results suggest that treatment with low levels of proteasome inhibitors confers resistance to oxidative injury by a pathway involving inhibition of the PI3K-Akt-mTOR pathway and activation of autophagy.

Salvage surgery for local failures after stereotactic ablative radiotherapy for early stage non-small cell lung cancer

International Nuclear Information System (INIS)

Verstegen, Naomi E.; Maat, Alexander P. W. M.; Lagerwaard, Frank J.; Paul, Marinus A.; Versteegh, Michel I; Joosten, Joris J.; Lastdrager, Willem; Smit, Egbert F.; Slotman, Ben J.; Nuyttens, Joost J. M. E.; Senan, Suresh

2016-01-01

The literature on surgical salvage, i.e. lung resections in patients who develop a local recurrence following stereotactic ablative radiotherapy (SABR), is limited. We describe our experience with salvage surgery in nine patients who developed a local recurrence following SABR for early stage non-small cell lung cancer (NSCLC). Patients who underwent surgical salvage for a local recurrence following SABR for NSCLC were identified from two Dutch institutional databases. Complications were scored using the Dindo-Clavien-classification. Nine patients who underwent surgery for a local recurrence were identified. Median time to local recurrence was 22 months. Recurrences were diagnosed with CT- and/or 18FDG-PET-imaging, with four patients also having a pre-surgical pathological diagnosis. Extensive adhesions were observed during two resections, requiring conversion from a thoracoscopic procedure to thoracotomy during one of these procedures. Three patients experienced complications post-surgery; grade 2 (N = 2) and grade 3a (N = 1), respectively. All resection specimens showed viable tumor cells. Median length of hospital stay was 8 days (range 5–15 days) and 30-day mortality was 0 %. Lymph node dissection revealed mediastinal metastases in 3 patients, all of whom received adjuvant therapy. Our experience with nine surgical procedures for local recurrences post-SABR revealed two grade IIIa complications, and a 30-day mortality of 0 %, suggesting that salvage surgery can be safely performed after SABR

Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia?

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Avital F. Barak

2011-12-01

Full Text Available The outcome and quality of life of chronic myeloid leukemia (CML patients has remarkably changed with the treatment of tyrosine kinase inhibitors (TKIs. Currently, hematopoietic stem cell transplantation (HSCT is considered mainly as a third line salvage therapy in cases of TKIs resistance or intolerance. Here we describe a patient with chronic phase CML who developed both resistance and late occurrence of s severe thrombocytopenia on first and second generation TKIs and eventually underwent HSCT. Although the mechanism of the myelosuppression is not fully understood, we showed for the first time the development of dose dependent platelet antibodies in the presence of TKIs, suggesting the possibility of TKIs induced thrombocytopenia. Our case emphasizes that late development of severe myelosuppression during imatinib treatment is probably an important indication for consideration of early HSCT.

The SCOPIC clause as a major development in salvage law : The SCOPIC clause in the context of the Lloyd’s Open Form and the International Convention on Salvage

NARCIS (Netherlands)

Djadjev, Ilian

2015-01-01

The SCOPIC clause (Special Compensation P&I Club Clause) provides an alternative remuneration to salvors, which is computed differently to the awards provided in Article 13 and Article 14 of the International Convention on Salvage (1989). In essence, SCOPIC provides agreed tariff rates under the

Nicotinamide riboside kinase structures reveal new pathways to NAD+.

Directory of Open Access Journals (Sweden)

Wolfram Tempel

2007-10-01

Full Text Available The eukaryotic nicotinamide riboside kinase (Nrk pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+ by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize the distinctive carboxamide group of nicotinamide riboside. Indeed, nicotinic acid riboside is a specific substrate of human Nrk enzymes and is utilized in yeast in a novel biosynthetic pathway that depends on Nrk and NAD+ synthetase. Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+.

Percutaneous anterior C1/2 transarticular screw fixation: salvage of failed percutaneous odontoid screw fixation for odontoid fracture

OpenAIRE

Wu, Ai-Min; Jin, Hai-Ming; Lin, Zhong-Ke; Chi, Yong-Long; Wang, Xiang-Yang

2017-01-01

Background The objective of this study is to investigate the outcomes and safety of using percutaneous anterior C1/2 transarticular screw fixation as a salvage technique for odontoid fracture if percutaneous odontoid screw fixation fails. Methods Fifteen in 108 odontoid fracture patients (planned to be treated by percutaneous anterior odontoid screw fixation) were failed to introduce satisfactory odontoid screw trajectory. To salvage this problem, we chose the percutaneous anterior C1/2 trans...

Review of Maxillofacial Hardware Complications and Indications for Salvage

OpenAIRE

Hernandez Rosa, Jonatan; Villanueva, Nathaniel L.; Sanati-Mehrizy, Paymon; Factor, Stephanie H.; Taub, Peter J.

2015-01-01

From 2002 to 2006, more than 117,000 facial fractures were recorded in the U.S. National Trauma Database. These fractures are commonly treated with open reduction and internal fixation. While in place, the hardware facilitates successful bony union. However, when postoperative complications occur, the plates may require removal before bony union. Indications for salvage versus removal of the maxillofacial hardware are not well defined. A literature review was performed to identify instances w...

Physician Beliefs and Practices for Adjuvant and Salvage Radiation Therapy After Prostatectomy

International Nuclear Information System (INIS)

Showalter, Timothy N.; Ohri, Nitin; Teti, Kristopher G.; Foley, Kathleen A.; Keith, Scott W.; Trabulsi, Edouard J.; Lallas, Costas D.; Dicker, Adam P.; Hoffman-Censits, Jean; Pizzi, Laura T.; Gomella, Leonard G.

2012-01-01

Purpose: Despite results of randomized trials that support adjuvant radiation therapy (RT) after radical prostatectomy (RP) for prostate cancer with adverse pathologic features (APF), many clinicians favor selective use of salvage RT. This survey was conducted to evaluate the beliefs and practices of radiation oncologists (RO) and urologists (U) regarding RT after RP. Methods and Materials: We designed a Web-based survey of post-RP RT beliefs and policies. Survey invitations were e-mailed to a list of 926 RO and 591 U. APF were defined as extracapsular extension, seminal vesicle invasion, or positive surgical margin. Differences between U and RO in adjuvant RT recommendations were evaluated by comparative statistics. Multivariate analyses were performed to evaluate factors predictive of adjuvant RT recommendation. Results: Analyzable surveys were completed by 218 RO and 92 U (overallresponse rate, 20%). Adjuvant RT was recommended based on APF by 68% of respondents (78% RO, 44% U, p <0.001). U were less likely than RO to agree that adjuvant RT improves survival and/or biochemical control (p < 0.0001). PSA thresholds for salvage RT were higher among U than RO (p < 0.001). Predicted rates of erectile dysfunction due to RT were higher among U than RO (p <0.001). On multivariate analysis, respondent specialty was the only predictor of adjuvant RT recommendations. Conclusions: U are less likely than RO to recommend adjuvant RT. Future research efforts should focus on defining the toxicities of post-RP RT and on identifying the subgroups of patients who will benefit from adjuvant vs. selective salvage RT.

Physician Beliefs and Practices for Adjuvant and Salvage Radiation Therapy After Prostatectomy

Energy Technology Data Exchange (ETDEWEB)

Showalter, Timothy N., E-mail: timothy.showalter@jeffersonhospital.org [Department of Radiation Oncology, Jefferson Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Ohri, Nitin; Teti, Kristopher G. [Department of Radiation Oncology, Jefferson Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Foley, Kathleen A. [Strategic Consulting, Thomson Reuters Healthcare, Cambridge, MA (United States); Keith, Scott W. [Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Trabulsi, Edouard J.; Lallas, Costas D. [Department of Urology, Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Dicker, Adam P. [Department of Radiation Oncology, Jefferson Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Hoffman-Censits, Jean [Department of Medical Oncology, Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Pizzi, Laura T. [School of Pharmacy, Thomas Jefferson University, Philadelphia, PA (United States); Gomella, Leonard G. [Department of Urology, Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States)

2012-02-01

Purpose: Despite results of randomized trials that support adjuvant radiation therapy (RT) after radical prostatectomy (RP) for prostate cancer with adverse pathologic features (APF), many clinicians favor selective use of salvage RT. This survey was conducted to evaluate the beliefs and practices of radiation oncologists (RO) and urologists (U) regarding RT after RP. Methods and Materials: We designed a Web-based survey of post-RP RT beliefs and policies. Survey invitations were e-mailed to a list of 926 RO and 591 U. APF were defined as extracapsular extension, seminal vesicle invasion, or positive surgical margin. Differences between U and RO in adjuvant RT recommendations were evaluated by comparative statistics. Multivariate analyses were performed to evaluate factors predictive of adjuvant RT recommendation. Results: Analyzable surveys were completed by 218 RO and 92 U (overallresponse rate, 20%). Adjuvant RT was recommended based on APF by 68% of respondents (78% RO, 44% U, p <0.001). U were less likely than RO to agree that adjuvant RT improves survival and/or biochemical control (p < 0.0001). PSA thresholds for salvage RT were higher among U than RO (p < 0.001). Predicted rates of erectile dysfunction due to RT were higher among U than RO (p <0.001). On multivariate analysis, respondent specialty was the only predictor of adjuvant RT recommendations. Conclusions: U are less likely than RO to recommend adjuvant RT. Future research efforts should focus on defining the toxicities of post-RP RT and on identifying the subgroups of patients who will benefit from adjuvant vs. selective salvage RT.

Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin

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Jacquemont Céline

2012-04-01

Full Text Available Abstract Background Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia (FA pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin. Results Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor (Chembridge compound 5929407. Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib (proteasome inhibitor, CA-074-Me (cathepsin B inhibitor and 17-AAG (HSP90 inhibitor, synergized with cisplatin specifically in FA-proficient ovarian cancer cells (2008 + FANCF, but not in FA-deficient isogenic cells (2008. In addition, geldanamycin (HSP90 inhibitor and two CHK1 inhibitors (UCN-01 and SB218078 exhibited a significantly stronger synergism with cisplatin in FA

Surgical complications of salvage surgery following concurrent chemoradiotherapy for laryngeal cancer

International Nuclear Information System (INIS)

Furuta, Yasushi; Homma, Akihiro; Oridate, Nobuhiko

2007-01-01

Surgical complication rates of salvage laryngectomy after chemoradiotherapy (CRT) have been reported to be high. Wound complications after salvage laryngectomy following concurrent chemoradiotherapy (CCRT) were analyzed. Eighty-six patients who had undergone total laryngectomy for laryngeal cancer at Hokkaido University Hospital between 1990 and 2006 were divided into three groups according to preoperative treatments received: total laryngectomy (TL) group (n=35) without radiotherapy (RT) or CCRT, RT-TL group (n=17) with RT alone, CRT-TL group (n=34) with low-dose CCRT. Major wound complications were defined as major pharyngocutaneous fistulas which caused inpatient care for more than eight weeks or which were closed by surgery, bleeding that required surgical reintervention, and wound infection or skin necrosis that caused inpatient care for more than eight weeks. Minor complications were self-limited, managed with local wound care, and did not prolong inpatient care for more than eight weeks. We also analyzed wound complications of larynx preservation surgery after CCRT. Overall wound complications, both major and minor, were observed in 26% of the TL group, 35% of the RT-TL group, and 47% of the CRT-TL group. Major wound complications were observed in 11%, 18%, and 29%, respectively. A considerable but not statistically significant increase in the incidence of overall and major wound complications was observed between the TL and CRT-TL groups (p=0.082 and 0.078, respectively). Pharyngocutaneous fistulas were the most common complication, occurring in 14/86 (16%) of patients. Patients who developed pharyngocutaneous fistulas after CCRT tended to require surgical reintervention and longer periods before the initiation of oral intake. Wound complications were observed in 2/3 (67%) of patients who had undergone larynx preservation surgery. High incidences of wound complications and poor wound recovery in patients undergoing salvage laryngectomy following CCRT should

JAK inhibitors in autoinflammation.

Science.gov (United States)

Hoffman, Hal M; Broderick, Lori

2018-06-11

Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

Salvage Radiation Therapy Dose Response for Biochemical Failure of Prostate Cancer After Prostatectomy—A Multi-Institutional Observational Study

Energy Technology Data Exchange (ETDEWEB)

Pisansky, Thomas M., E-mail: pisansky.thomas@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Agrawal, Shree [Case Western Reserve University School of Medicine, Cleveland, Ohio (United States); Hamstra, Daniel A. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Koontz, Bridget F. [Department of Radiation Oncology, Duke Cancer Institute, Durham, North Carolina (United States); Liauw, Stanley L. [Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois (United States); Efstathiou, Jason A. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Michalski, Jeff M. [Department of Radiation Oncology, Washington University, St. Louis, Missouri (United States); Feng, Felix Y. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Abramowitz, Matthew C.; Pollack, Alan [Department of Radiation Oncology, University of Miami, Miami, Florida (United States); Anscher, Mitchell S. [Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia (United States); Moghanaki, Drew [Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia (United States); Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia (United States); Den, Robert B. [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Stephans, Kevin L. [Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Zietman, Anthony L. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Lee, W. Robert [Department of Radiation Oncology, Duke Cancer Institute, Durham, North Carolina (United States); Kattan, Michael W. [Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio (United States); and others

2016-12-01

Purpose: To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. Methods and Materials: Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of ≤2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. Results: With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of ≥7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of ≥66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. Conclusions: The use of salvage radiation doses of ≥66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint.

Salvage Radiation Therapy Dose Response for Biochemical Failure of Prostate Cancer After Prostatectomy—A Multi-Institutional Observational Study

International Nuclear Information System (INIS)

Pisansky, Thomas M.; Agrawal, Shree; Hamstra, Daniel A.; Koontz, Bridget F.; Liauw, Stanley L.; Efstathiou, Jason A.; Michalski, Jeff M.; Feng, Felix Y.; Abramowitz, Matthew C.; Pollack, Alan; Anscher, Mitchell S.; Moghanaki, Drew; Den, Robert B.; Stephans, Kevin L.; Zietman, Anthony L.; Lee, W. Robert; Kattan, Michael W.

2016-01-01

Purpose: To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. Methods and Materials: Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of ≤2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. Results: With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of ≥7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of ≥66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. Conclusions: The use of salvage radiation doses of ≥66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint.

Involvement of NO-cGMP pathway in anti-hyperalgesic effect of PDE5 inhibitor tadalafil in experimental hyperalgesia.

Science.gov (United States)

Otari, K V; Upasani, C D

2015-08-01

The association of elevated level of cyclic guanosine monophosphate (cGMP) with inhibition of hyperalgesia and involvement of nitric oxide (NO)-cGMP pathway in the modulation of pain perception was previously reported. Phosphodiesterases 5 (PDE5) inhibitors, sildenafil and tadalafil (TAD) used in erectile dysfunction, are known to act via the NO-cGMP pathway. TAD exerts its action by increasing the levels of intracellular cGMP. Hence, the present study investigated the effect of TAD 5, 10, or 20 mg/kg, per os (p.o.) or L-NAME 20 mg/kg, intraperitoneally (i.p.) and TAD (20 mg/kg, p.o.) in carrageenan- and diabetes-induced hyperalgesia in rats using hot plate test at 55 ± 2 °C. In carrageenan- and diabetes-induced hyperalgesia, TAD (10 and 20 mg/kg, p.o.) significantly increased paw withdrawal latencies (PWLs) as compared to the control group. L-NAME significantly decreased PWLs as compared to the normal group and aggravated the hyperalgesia. Moreover, significant difference in PWLs of L-NAME and TAD 20 was evident. Co-administration of L-NAME (20 mg/kg) with TAD (20 mg/kg) showed significant difference in PWLs as compared to the TAD (20 mg/kg), indicating L-NAME reversed and antagonized TAD-induced anti-hyperalgesia. This suggested an important role of NO-cGMP pathway in TAD-induced anti-hyperalgesic effect.

Inhibition of multiple pathogenic pathways by histone deacetylase inhibitor SAHA in a corneal alkali-burn injury model

Science.gov (United States)

Li, Xinyu; Zhou, Qinbo; Hanus, Jakub; Anderson, Chastain; Zhang, Hongmei; Dellinger, Michael; Brekken, Rolf; Wang, Shusheng

2013-01-01

Neovascularization (NV) in the cornea is a major cause of vision impairment and corneal blindness. Hemangiogenesis and lymphangiogenesis induced by inflammation underlie the pathogenesis of corneal NV. The current mainstay treatment, corticosteroid, treats the inflammation associated with corneal NV, but is not satisfactory due to such side effects as cataract and the increase in intraocular pressure. It is imperative to develop a novel therapy that specifically targets the hemangiogenesis, lymphangiogenesis and inflammation pathways underlying corneal NV. Histone deacetylase inhibitors (HDACi) have been in clinical trials for cancer and other diseases. In particular, HDACi suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) has been approved by the FDA for the treatment of cutaneous T-cell lymphoma. The functional mechanism of SAHA in cancer and especially in corneal NV remains unclear. Here, we show that topical application of SAHA inhibits neovascularization in an alkali-burn corneal injury model. Mechanistically, SAHA inhibits corneal NV by repressing hemangiogenesis, inflammation pathways and previously overlooked lymphangiogenesis. Topical SAHA is well tolerated on the ocular surface. In addition, the potency of SAHA in corneal NV appears to be comparable to the current steroid therapy. SAHA may possess promising therapeutic potential in alkali-burn corneal injury and other inflammatory neovascularization disorders. PMID:23186311

Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3.

Directory of Open Access Journals (Sweden)

Jennifer M Atkinson

Full Text Available It has previously been observed that a loss of β-catenin expression occurs with melanoma progression and that nuclear β-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/β-catenin pathway may provide benefit for melanoma patients. In order to further probe this concept we tested LY2090314, a potent and selective small-molecule inhibitor with activity against GSK3α and GSK3β isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOPFlash reporter activity, stabilized β-catenin and elevated the expression of Axin2, a Wnt responsive gene and marker of pathway activation. Cytotoxicity assays revealed that melanoma cell lines are very sensitive to LY2090314 in vitro (IC50 ~10 nM after 72hr of treatment in contrast to other solid tumor cell lines (IC50 >10 uM as evidenced by caspase activation and PARP cleavage. Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that β-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by β-catenin knockdown. We further demonstrate that in vivo, LY2090314 elevates Axin2 gene expression after a single dose and produces tumor growth delay in A375 melanoma xenografts with repeat dosing. The activity of LY2090314 in preclinical models suggests that the role of Wnt activators for the treatment of melanoma should be further explored.

Transcriptional changes associated with resistance to inhibitors of epidermal growth factor receptor revealed using metaanalysis

International Nuclear Information System (INIS)

Younis, Sidra; Javed, Qamar; Blumenberg, Miroslav

2015-01-01

EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways. Here we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors. The metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis. This metaanalysis suggests that ‘combination therapies’ can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding

Viable tumor in salvage neck dissections in head and neck cancer : Relation with initial treatment, change of lymph node size and human papillomavirus

NARCIS (Netherlands)

van den Bovenkamp, Karlijn; Dorgelo, Bart; Noordhuis, Maartje G; van der Laan, Bernard F A M; van der Vegt, Bert; Bijl, Hendrik P; Roodenburg, Jan L; van Dijk, Boukje A C; Oosting, Sjoukje F; Schuuring, Ed M D; Langendijk, Johannes A; Halmos, Gyorgy B; Plaat, Boudewijn E C

Objectives: To identify predictive factors for the presence of viable tumor and outcome in head and neck cancer patients who undergo therapeutic salvage neck dissections. Materials and Methods: Retrospective analysis of 76 salvage neck dissections after radiotherapy alone (n = 22), radiotherapy in

Reirradiation for recurrent head and neck cancer with salvage interstitial pulsed-dose-rate brachytherapy. Long-term results

Energy Technology Data Exchange (ETDEWEB)

Strnad, Vratislav; Lotter, Michael; Kreppner, Stephan; Fietkau, Rainer [University Hospital Erlangen, Dept. of Radiation Oncology, Erlangen (Germany)

2015-01-10

To assess the long-term results of protocol-based interstitial pulsed-dose-rate (PDR) brachytherapy as reirradiation combined with simultaneous chemotherapy and interstitial hyperthermia in selected patients with recurrent head and neck tumors. A total of 104 patients with biopsy-proven recurrent head and neck cancer were treated with interstitial PDR brachytherapy. Salvage surgery had also been undergone by 53/104 (51 %) patients (R1 or R2 resection in > 80 % of patients). Salvage brachytherapy alone was administered in 81 patients (78 %), with a median total dose of 56.7 Gy. Salvage brachytherapy in combination with external beam radiotherapy (EBRT) was performed in 23/104 patients (32 %), using a median total dose of D{sub REF} = 24 Gy. Simultaneously to PDR brachytherapy, concomitant chemotherapy was administered in 58/104 (55.8 %) patients. A single session of interstitial hyperthermia was also used to treat 33/104 (31.7 %) patients. The analysis was performed after a median follow-up of 60 months. Calculated according to Kaplan-Meier, local tumor control rates after 2, 5, and 10 years were 92.5, 82.4, and 58.9 %, respectively. Comparing results of salvage PDR brachytherapy with or without simultaneous chemotherapy, the 10-year local control rates were 76 vs. 39 % (p= 0014), respectively. No other patient- or treatment-related parameters had a significant influence on treatment results. Soft tissue necrosis or bone necrosis developed in 18/104 (17.3 %) and 11/104 (9.6 %) patients, respectively, but only 3 % of patients required surgical treatment. PDR interstitial brachytherapy with simultaneous chemotherapy is a very effective and, in experienced hands, also a safe treatment modality in selected patients with head and neck cancer in previously irradiated areas. (orig.) [German] Es erfolgte die Analyse der Langzeitergebnisse einer protokollbasierten interstitiellen Brachytherapie (Re-Bestrahlung) mit simultaner Chemotherapie und interstitieller Hyperthermie

Tissue factor pathway inhibitor in paediatric patients with nephrotic ...

African Journals Online (AJOL)

elevated TFPI blood levels could therefore be accounted for by excessive endothelial release of this inhibitor .... that diastolic blood pressure was higher in the proteinuria group than in either the remission or the control .... dilated veins around the umbilicus, renal biopsy findings of fibrin deposition inside the glomeruli and in ...

Accuracy of post-radiotherapy biopsy before salvage radical prostatectomy.

Science.gov (United States)

Meeks, Joshua J; Walker, Marc; Bernstein, Melanie; Kent, Matthew; Eastham, James A

2013-08-01

To determine whether post-radiotherapy (RT) biopsy (PRB) adequately predicts the presence, location, and histological features of cancer in the salvage radical prostatectomy (SRP) specimen. Before salvage treatment, a PRB is required to confirm the presence of locally recurrent or persistent cancer and to determine the extent and location of the prostate cancer. SRP was performed between 1998 and 2011 on 198 patients. All patients underwent a PRB. PRB and SRP specimens were evaluated by a genitourinary pathologist. Patients had external-beam RT alone (EBRT; 71%) or brachytherapy with or without EBRT (29%). Of the men undergoing SRP, 26 (14%) were clinical stage ≥T3, with 13% of PRBs with Gleason score ≥8. Cancer was unilateral in 120 (61%) biopsies, with contralateral or bilateral prostate cancer at SRP in 49%. In the SRP specimen, cancer was multifocal in 57%. Cancer was upgraded at SRP in 58% of men, with 20% having an increase in primary Gleason grade. The accuracy of PRB varied by region from 62% to 76%, with undetected cancers ranging from 12% to 26% and most likely to occur at the mid-gland. Radiation-recurrent prostate cancers were often multifocal, and biopsy missed up to 20% of tumours. More than half of the cancers were upgraded at SRP, and many that were unilateral on PRB were bilateral at SRP. © 2013 BJU International.

Development of an image-based screening system for inhibitors of the plastidial MEP pathway and of protein geranylgeranylation

Science.gov (United States)

Hartmann, Michael; Gas-Pascual, Elisabet; Hemmerlin, Andrea; Rohmer, Michel; Bach, Thomas J.

2015-01-01

In a preceding study we have recently established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, which involves expressing a dexamethasone-inducible GFP fused to the prenylable, carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL). By using pathway-specific inhibitors it was there demonstrated that inhibition of the methylerythritol phosphate (MEP) pathway with oxoclomazone and fosmidomycin, as well as inhibition of protein geranylgeranyl transferase type 1 (PGGT-1), shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA) pathway with mevinolin did not affect this localization. Furthermore, in this initial study complementation assays with pathway-specific intermediates confirmed that the precursors for the cytosolic isoprenylation of this fusion protein are predominantly provided by the MEP pathway. In order to optimize this visualization system from a more qualitative assay to a statistically trustable medium or a high-throughput screening system, we established now new conditions that permit culture and analysis in 96-well microtiter plates, followed by fluorescence microscopy. For further refinement, the existing GFP-BD-CVIL cell line was transformed with an estradiol-inducible vector driving the expression of a RFP protein, C-terminally fused to a nuclear localization signal (NLS-RFP). We are thus able to quantify the total number of viable cells versus the number of inhibited cells after various treatments. This approach also includes a semi-automatic counting system, based on the freely available image processing software. As a result, the time of image analysis as well as the risk of user-generated bias is reduced to a minimum. Moreover, there is no cross-induction of gene expression by dexamethasone and estradiol, which is an

High-dose-rate brachytherapy as salvage modality for locally recurrent prostate cancer after definitive radiotherapy. A systematic review

International Nuclear Information System (INIS)

Chatzikonstantinou, Georgios; Zamboglou, Nikolaos; Roedel, Claus; Tselis, Nikolaos; Zoga, Eleni; Strouthos, Iosif; Butt, Saeed Ahmed

2017-01-01

To review the current status of interstitial high-dose-rate brachytherapy as a salvage modality (sHDR BRT) for locally recurrent prostate cancer after definitive radiotherapy (RT). A literature search was performed in PubMed using ''high-dose-rate, brachytherapy, prostate cancer, salvage'' as search terms. In all, 51 search results published between 2000 and 2016 were identified. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control (BC) and toxicity scores. Eleven publications reported clinical outcome and toxicity with follow-up ranging from 4-191 months. A variety of dose and fractionation schedules were described, including 19.0 Gy in 2 fractions up to 42.0 Gy in 6 fractions. The 5-year BC ranged from 18-77%. Late grade 3 genitourinary and gastrointestinal toxicity was 0-32% and 0-5.1%, respectively. sHDR BRT appears as safe and effective salvage modality for the reirradiation of locally recurrent prostate cancer after definitive RT. (orig.) [de

Risk of hormone escape in a human prostate cancer model depends on therapy modalities and can be reduced by tyrosine kinase inhibitors.

Directory of Open Access Journals (Sweden)

Charlotte Guyader

tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.

Septic Shock following Prostate Biopsy: Aggressive Limb Salvage for Extremities after Pressor-Induced Ischemic Gangrene

Directory of Open Access Journals (Sweden)

Jocelyn Lu, BS

2017-09-01

Full Text Available Summary:. Vasopressors used to treat patients with septic shock can cause ischemic necrosis of appendages such as the ears and nose, as well as the extremities. Cases of quadruple-extremity necrosis have high morbidity and mortality, and a profound negative impact on quality of life. This case report details the successful limb salvage and return to function using free tissue transfer as a means to salvage bilateral lower extremities in a patient who suffered vasopressor-induced ischemia of upper and lower extremities after prostate biopsy–induced septic shock. Septic shock following transrectal ultrasound–guided prostate biopsy is a rare, yet life-threatening complication. Successful treatment included thorough planning and staging of therapies such as awaiting tissue demarcation and serial surgical debridement to adequately prepare the tissue bed for free tissue transfer. Adjunctive treatments such as hyperbaric oxygen therapy, negative-pressure wound therapy, and meticulous wound care played a crucial role in wound healing. This vigilant planning and coordinated care resulted in the successful lower extremity salvage, consisting of bilateral transmetatarsal amputations and free tissue transfer to both limbs. We present our long-term follow-up of a functional ambulatory patient after catastrophic, life-threatening infection and appropriate multidisciplinary care.

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway.

Science.gov (United States)

Bailly, A; Perrin, A; Bou Malhab, L J; Pion, E; Larance, M; Nagala, M; Smith, P; O'Donohue, M-F; Gleizes, P-E; Zomerdijk, J; Lamond, A I; Xirodimas, D P

2016-01-28

The ubiquitin-like molecule NEDD8 is essential for viability, growth and development, and is a potential target for therapeutic intervention. We found that the small molecule inhibitor of NEDDylation, MLN4924, alters the morphology and increases the surface size of the nucleolus in human and germline cells of Caenorhabditis elegans in the absence of nucleolar fragmentation. SILAC proteomics and monitoring of rRNA production, processing and ribosome profiling shows that MLN4924 changes the composition of the nucleolar proteome but does not inhibit RNA Pol I transcription. Further analysis demonstrates that MLN4924 activates the p53 tumour suppressor through the RPL11/RPL5-Mdm2 pathway, with characteristics of nucleolar stress. The study identifies the nucleolus as a target of inhibitors of NEDDylation and provides a mechanism for p53 activation upon NEDD8 inhibition. It also indicates that targeting the nucleolar proteome without affecting nucleolar transcription initiates the required signalling events for the control of cell cycle regulators.

Advanced basal cell carcinoma, the hedgehog pathway, and treatment options – role of smoothened inhibitors

Directory of Open Access Journals (Sweden)

Fecher LA

2015-11-01

Full Text Available Leslie A Fecher,1,3 William H Sharfman2 1Department of Internal Medicine and Dermatology, Indiana University Health Simon Cancer Center, Indianapolis, IN, USA; 2The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 3Department of Internal Medicine and Dermatology, University of Michigan, MI, USA Abstract: Cutaneous basal cell carcinoma (BCC is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449, a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery. Keywords: basal cell carcinoma, hedgehog, smoothened, vismodegib, Gorlin, basal cell nevus syndrome

Risk factors for local failure requiring salvage neurosurgery after radiosurgery for brain metastases

International Nuclear Information System (INIS)

Weltman, Eduardo; Hanriot, Rodrigo de Morais; Prisco, Flavio Eduardo; Nadalin, Wladimir; Brandt, Reynaldo Andre; Moreira, Frederico Rafael

2004-01-01

Objective: the aim of this study is to select the risk factors for local failure requiring salvage neurosurgery in patients with brain metastases treated with stereotactic radiosurgery in a single institution. Methods: the follow-up of 123 patients, with 255 brain metastases treated with radiosurgery at the Radiation Oncology Department of the Hospital Israelita Albert Einstein from July 1993 to August 2001, was retrospectively analyzed. The criteria for salvage neurosurgery were tumor volume enlargement, or tumor persistence leading to severe neurological symptoms, life threatening situation or critical steroid dependence. We considered the case as local failure when the histopathologic evaluation showed morphologically preserved cancer cells (tumor recurrence, persistence or progression). We applied the Fisher's exact test to evaluate the statistical correlation between local failure and primary tumor histology, volume of the brain metastases, prescribed radiosurgery dose, and whole brain radiotherapy. Results: fourteen of 123 patients (11%) underwent salvage neurosurgery. Histology showed preserved cancer cells with necrosis and/or bleeding in 11 cases (9% of the total accrual), and only necrosis with or without bleeding (without preserved cancer cells) in three cases. The primary tumor histology among the 11 patients considered with active neoplasia was malignant melanoma in five cases (21% of the patients with melanoma), breast adenocarcinoma in three (16% of the patients with breast cancer), and other histology in the remaining three. Breast cancer diagnosis, non-elective whole brain irradiation, volume of the brain metastases, and the prescribed radiosurgery dose did not correlate with the risk of local failure. Patients treated with elective whole brain radiotherapy showed fewer local failures, when compared to all patients receiving whole brain radiotherapy, and to the patients not receiving this treatment, with incidence of failure in 4%,7% and 14

Regeneration response to tornado and salvage harvesting in a bottomland forest

Science.gov (United States)

John L. Nelson; John W. Groninger; Loretta L. Battaglia; Charles M. Ruffner

2010-01-01

A direct hit from an F4 tornado on May 2003, followed by a partial salvage logging operation at Mermet Lake State Conservation Area on the Ohio River bottoms of southern IL have provided a rare opportunity to assess the responses of a bottomland hardwood forest to severe wind and soil disturbances. The study area encompasses 700 acres and is representative of many...

Outcome analysis of salvage radiotherapy for occult cervical cancer found after simple hysterectomy

International Nuclear Information System (INIS)

Koh, Hyeon-Kang; Jeon, Wan; Kim, Hak-Jae; Wu, Hong-Gyun; Kim, Kyubo; Chie, Eui-Kyu; Ha, Sung-W.

2013-01-01

The objective was to analyze the outcomes of the patients, who received salvage radiotherapy for incidentally discovered cervical cancer following simple hysterectomy, and to identify the influence of intracavitary radiotherapy on treatment outcomes. Data from 117 patients with occult cervical cancer who underwent simple hysterectomy followed by salvage radiotherapy from September 1979 to November 2010 were collected. All the patients received external beam radiotherapy with (n=45) or without (n=72) intracavitary radiotherapy. Local control, disease-free survival, overall survival and treatment-related toxicity were investigated. The median follow-up time was 75 months. The 5- and 10-year local control/disease-free survival/overall survival rates were 93/87/87% and 90/84/83%, respectively. Among 98 patients who had no residual disease and negative resection margin on surgical specimens, 32 (33%) received intracavitary radiotherapy and 66 (67%) did not. There were no differences in patient and tumor characteristics between patients treated with and without intracavitary radiotherapy. The 5-year local control rate for the non-intracavitary radiotherapy group was 93 versus 94% for the intracavitary radiotherapy group (P=0.564); the disease-free survival rate was 88 versus 94% (P=0.894); the overall survival rate was 95 versus 85% (P=0.106), respectively. Among all patients, there were 5% of Grade 3 or higher late toxicities. Patients with occult invasive cervical cancer discovered following simple hysterectomy could be treated safely and effectively with salvage radiotherapy. For patients with no residual disease and negative resection margin, intracavitary radiotherapy could be omitted. (author)

Novel histone deacetylase inhibitor AR-42 exhibits antitumor activity in pancreatic cancer cells by affecting multiple biochemical pathways.

Directory of Open Access Journals (Sweden)

Yi-Jin Chen

Full Text Available Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer.Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model.AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33, which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo.AR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by

National survey on the current status of salvage radiotherapy on holidays by the JASTRO committee for future scope

International Nuclear Information System (INIS)

Nagata, Yasushi; Ashino, Yasuo

2002-01-01

Recently, the impact of the overall treatment time on local tumor control has been reported by several authors. However, we in Japan have a long radiotherapy break because of the two large national holiday seasons in April-May and December-January. Therefore, a national survey on the current status of salvage radiotherapy on holidays was performed in 2001. Fifty-three % of the all institutes performed salvage radiotherapy on holidays. However, there are several problems to be solved, and a national consensus and an authorized proposal by the JASTRO are waited. (author)

Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials.

Science.gov (United States)

Rodon, Jordi; DeSantos, Victoria; Ferry, Robert Jean; Kurzrock, Razelle

2008-09-01

The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone-IGF-IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling associated with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, >25 molecules with the same goal are at different stages of development. Here, we review the clinical and preclinical experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the biomarkers explored in the first clinical trials, the strategies that have been explored thus far, and the clinical trials that are going to explore their role in cancer treatment.

High-dose-rate brachytherapy as salvage modality for locally recurrent prostate cancer after definitive radiotherapy. A systematic review

Energy Technology Data Exchange (ETDEWEB)

Chatzikonstantinou, Georgios; Zamboglou, Nikolaos; Roedel, Claus; Tselis, Nikolaos [J.W. Goethe University of Frankfurt, Department of Radiotherapy and Oncology, Frankfurt am Main (Germany); Zoga, Eleni [Sana Klinikum Offenbach, Department of Radiotherapy and Oncology, Offenbach am Main (Germany); Strouthos, Iosif [Medical Center - University of Freiburg, Department of Radiotherapy and Oncology, University of Freiburg, Freiburg (Germany); Butt, Saeed Ahmed [Sana Klinikum Offenbach, Department of Medical Physics and Engineering, Offenbach am Main (Germany)

2017-09-15

To review the current status of interstitial high-dose-rate brachytherapy as a salvage modality (sHDR BRT) for locally recurrent prostate cancer after definitive radiotherapy (RT). A literature search was performed in PubMed using ''high-dose-rate, brachytherapy, prostate cancer, salvage'' as search terms. In all, 51 search results published between 2000 and 2016 were identified. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control (BC) and toxicity scores. Eleven publications reported clinical outcome and toxicity with follow-up ranging from 4-191 months. A variety of dose and fractionation schedules were described, including 19.0 Gy in 2 fractions up to 42.0 Gy in 6 fractions. The 5-year BC ranged from 18-77%. Late grade 3 genitourinary and gastrointestinal toxicity was 0-32% and 0-5.1%, respectively. sHDR BRT appears as safe and effective salvage modality for the reirradiation of locally recurrent prostate cancer after definitive RT. (orig.) [German] Zusammenfassende Darstellung relevanter Literatur zur interstitiellen High-Dose-Rate-Brachytherapie als Salvage-Modalitaet (sHDR-BRT) bei der Behandlung des lokal rezidivierten Prostatakarzinoms nach vorausgegangener definitiver Radiotherapie (RT). In der PubMed-Datenbank wurde eine Literaturrecherche mit den Suchbegriffen ''high-dose-rate, brachytherapy, prostate cancer, salvage'' durchgefuehrt. Zwischen den Jahren 2000 und 2016 wurden 51 Publikationen identifiziert. Die biochemische Kontrolle (BC) sowie das assoziierte Toxizitaetsprofil waren onkologische Hauptpunkte in der Analyse der beruecksichtigten Literatur. Von onkologischen Ergebnissen und Toxizitaeten berichteten 11 Publikationen bei einer medianen Nachbeobachtungszeit von 4-191 Monaten. Eine Variabilitaet von Dosis- und Fraktionierungsregimen wurde beschrieben mit totalen physikalischen Dosen von 19,0 Gy in 2 Fraktionen bis zu 42,0 Gy in 6 Fraktionen

Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

KAUST Repository

Ramadan, Ahmed M Ali

2011-06-26

The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

KAUST Repository

Ramadan, Ahmed M Ali; Eissa, Hala F.; El-Domyati, Fotouh M.; Saleh, Osama Mesilhy; Ibrahim, Nasser E.; Salama, M. I.; Mahfouz, Magdy M.; Bahieldin, Ahmed M.

2011-01-01

The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

Evaluating the 'next generation' of cell salvage--will it make a difference?

Science.gov (United States)

Yarham, Gemma; Clements, Ann; Oliver, Martin; Morris, Christopher; Cumberland, Tom; Bryan, Megan; Jekler, Sasa; Johns, Kathy; Mulholland, John

2011-07-01

Donor blood supplies are diminishing, becoming more costly and these transfusions lead to higher mortality in cardiac patients. The transfusion risks and the literature highlight the need for an alternative similar to cell salvage to be routinely considered. The Xtra is the first cell saver to be launched since 2001 and will undoubtedly initiate evolution towards the 'next generation' of cell savers. It is also the first to be launched in a new era where the demand for electronic perfusion data management (EPDM) has grown. The user interface (UI) was easy to use. The increased data entry options improved the quality of the recordable data. The integrated data management system (DMS) was comprehensive. Data was easy to manage and enabled central data compilation, which reduces repeated data, the risk of inconsistent data inventory and provides the potential for research and analyses. The haematocrit of the processed blood is a key quality indicator for cell salvage. The comparison of the manufacturer's integrated protocol, Popt, to our team's own protocol showed that Popt delivered a higher haematocrit on its '1st bowl' (59.1% compared to 57.3%) and its 'total process' end product haematocrit was 0.68% higher. The Popt cycle took an average of 330s, whereas our own settings completed in just over 300s. The Xtra is a device which will lead the evolution of 'next generation' cell saver technology. The user interface and data management system provide export options and the ability to record the level of data required for good EPDM. This is essential to 'future proof' cell salvage technology. The manufacturer's integrated protocol achieved a higher end product haematocrit than our perfusion team's best practice. The design of the Xtra is contemporary, but the DMS equips this cell saver for the new era that faces both Perfusion and Cardiac Surgery.

Salvage brachytherapy for local recurrences of prostate cancer treated previously with radiotherapy.

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Gawkowska-Suwinska, Marzena; Fijałkowski, Marek; Białas, Brygida; Szlag, Marta; Kellas-Ślęczka, Sylwia; Nowicka, Elżbieta; Behrendt, Katarzyna; Plewicki, Grzegorz; Smolska-Ciszewska, Beata; Giglok, Monika; Zajusz, Aleksander; Owczarek, Grzegorz

2009-12-01

The aim of the study was to analyze early effects and toxicity of salvage high dose rate brachytherapy for local recurrences of adenocarcinoma of the prostate after external beam radiotherapy (EBRT). In MCS Memorial Institute of Oncology in Gliwice a research programme on salvage HDR brachytherapy for local recurrences of prostate cancer treated previously with EBRT has been ongoing since February 2008. The treatment consisted of 3 fractions of 10 Gy each given every 14 days. Maximal urethral doses were constrained to be ≤ 120% of the prescribed dose. Maximal bladder and rectum doses were constrained to be ≤ 70% of the prescribed dose. Fifteen eligible patients were treated and analyzed from February 2008. All patients completed the treatment without major complications. The most common early complications were: macroscopic haematuria, pain in lower part of the abdomen, and transient dysuria. During the first week after the procedure a transient increase in IPSS score was noticed. The Foley catheter was removed on day 2 to 5. No complications after spinal anaesthesia were observed. Acute toxicity according to EORTC/RTOG was low. For bladder EORTC/RTOG score ranged from 0 to 2. Only in two patients grade 1 toxicity for rectum was observed. The follow-up ranged from 3 to 9 months. In one patient grade 2 rectal toxicity was observed, and one had urethral stricture. Other patients did not have any other significant late toxicity of the treatment. Two patients developed bone metastases. Salvage brachytherapy for localized prostate cancer (3 × 10 Gy every 14 days) seems to be a safe and well tolerated procedure. A significant decline in prostate-specific antigen (PSA) level is seen in patients with hormone-responsive cancer. Long-term efficiency and toxicity of the procedure are yet to be established.

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma.

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Zecena, Helma; Tveit, Daniel; Wang, Zi; Farhat, Ahmed; Panchal, Parvita; Liu, Jing; Singh, Simar J; Sanghera, Amandeep; Bainiwal, Ajay; Teo, Shuan Y; Meyskens, Frank L; Liu-Smith, Feng; Filipp, Fabian V

2018-04-04

Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. The cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Downregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors. The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance

Effects of multiple interacting disturbances and salvage logging on forest carbon stocks

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Bradford, J.B.; Fraver, S.; Milo, A.M.; D'Amato, A.W.; Palik, B.; Shinneman, D.J.

2012-01-01

Climate change is anticipated to increase the frequency of disturbances, potentially impacting carbon stocks in terrestrial ecosystems. However, little is known about the implications of either multiple disturbances or post-disturbance forest management activities on ecosystem carbon stocks. This study quantified how forest carbon stocks responded to stand-replacing blowdown and wildfire, both individually and in combination with and without post-disturbance salvage operations, in a sub-boreal jack pine ecosystem. Individually, blowdown or fire caused similar decreases in live carbon and total ecosystem carbon. However, whereas blowdown increased carbon in down woody material and forest floor, fire increased carbon in standing snags, a difference that may have consequences for long-term carbon cycling patterns. Fire after the blowdown caused substantial additional reduction in ecosystem carbon stocks, suggesting that potential increases in multiple disturbance events may represent a challenge for sustaining ecosystem carbon stocks. Salvage logging, as examined here, decreased carbon stored in snags and down woody material but had no significant effect on total ecosystem carbon stocks.

Effect of fractalkine, IP-10 and different signal pathway inhibitors on NK cells in the tumor microenvironment

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Zhao-zhen WU

2015-07-01

Full Text Available Objective　To investigate the inducing effects of chemokines [fractalkine (FKN, IP-10] and different signal pathway inhibitors on NK cells in the tumor microenvironment (TME. Methods　Immunohistochemistry was performed using antibodies for CD56 and DAP10 respectively on human breast carcinoma. Murine macrophages (RAW 264.7 and breast cancer cells (4T1 were co-cultivated at a 1:4 ratio to imitate the TME with NK cells (KY-1 set as the object. RT-PCR was used to determine the mRNA expressions of CD16, NKG2D and NK1.1, and the content of CD107a in the supernatants was determined by ELISA. 10ng/ml FKN and 10ng/ml IP-10 were added into the TME, NK1.1+CD16+KY-1 cells were counted with flow cytometry, migration and adhesion assays were used to assess the related function of KY-1 cells. 4T1 cells were incubated in 10nmol/L of rapamycin, 30μmol/L of LY294002, 500ng/μl of andrographolide and 2mmol/L of wortmannin, the 4T1 tumor supernatants (TSNs were harvested separately and used to incubate RAW 264.7 for 48h, then the expressions of Rae1α and H60a mRNA in 4T1, RAW 264.7 and their mixture were determined by RT-PCR. Results　The related indicators of KY-1 cells such as NK1.1+ number, chemotaxis rate, and adhesion function decreased obviously in TME, and the above indices increased after the addition of FKN and IP-10, and some signal pathway inhibitors indirectly promoted NK cells' function in TME, and among them rapamycin was the most efficient one (P<0.05. Conclusion　FKN and IP-10 may up-regulate the number and function of NK cells in TME, and rapamycin can promote NK cells' killing function by inducing high expression of NKG2DLs (Rae1, H60a on tumor cells. DOI: 10.11855/j.issn.0577-7402.2015.07.07

Salvage radiotherapy with or without concurrent chemotherapy for pelvic recurrence after hysterectomy alone for early-stage uterine cervical cancer

Energy Technology Data Exchange (ETDEWEB)

Kim, Sang-Won [Ajou University School of Medicine, Department of Radiation Oncology, Yeongtong-gu, Suwon, Gyeonggi-do (Korea, Republic of); Konyang University School of Medicine, Department of Radiation Oncology, Daejeon (Korea, Republic of); Chun, Mison; Oh, Young-Taek [Ajou University School of Medicine, Department of Radiation Oncology, Yeongtong-gu, Suwon, Gyeonggi-do (Korea, Republic of); Ryu, Hee-Sug; Chang, Suk-Joon; Kong, Tae Wook [Ajou University School of Medicine, Department of Obstetrics and Gynecology, Yeongtong-gu, Suwon, Gyeonggi-do (Korea, Republic of); Lee, Eun Ju [Ajou University School of Medicine, Department of Radiology, Yeongtong-gu, Suwon, Gyeonggi-do (Korea, Republic of); Lee, Yong Hee [Ajou University School of Medicine, Department of Pathology, Yeongtong-gu, Suwon, Gyeonggi-do (Korea, Republic of)

2017-07-15

Treatment outcomes of patients with pelvic recurrence after hysterectomy alone for uterine cervical cancer who received salvage radiotherapy (RT) with or without concurrent chemotherapy were investigated. Salvage RT for recurrent cervical cancer confined to the pelvic cavity after hysterectomy alone was received by 33 patients. The median interval between initial hysterectomy and recurrence was 26 months. Whole-pelvic irradiation was delivered to median dose of 45 Gy, followed by a boost with a median dose of 16 Gy to the gross tumor volume. Cisplatin-based concurrent chemotherapy was administered to 29 patients. The median follow-up period was 53 months for surviving patients. Most patients (97.0%) completed salvage RT of ≥45 Gy. Complete response (CR) was achieved in 23 patients (69.7%). Pelvic sidewall involvement and evaluation with positron-emission tomography-computed tomography were significantly associated with CR. The 5-year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 62.7, 79.5, 72.5, and 60.1%, respectively. Initial International Federation of Gynecology and Obstetrics stage, pelvic sidewall involvement, and CR status were significant factors for PFS and OS rates in multivariate analysis. The incidence of severe acute and late toxicities (≥grade 3) was 12.1 and 3.0%, respectively. Aggressive salvage RT with or without concurrent chemotherapy for recurrent cervical cancer confined to the pelvic cavity was feasible, with promising treatment outcomes and acceptable toxicities. However, even more intensive novel treatment strategies should be investigated for patients with unfavorable prognostic factors. (orig.) [German] Untersuchung der Behandlungsergebnisse von Patientinnen mit Beckenrezidiv nach alleiniger Hysterektomie bei Zervixkarzinom, die eine Salvage-Radiotherapie (RT) mit oder ohne begleitende Chemotherapie erhalten hatten. Insgesamt 33 Patientinnen erhielten

Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer

NARCIS (Netherlands)

Paller, C.J.; Wissing, M.D.; Mendonca, J.; Sharma, A.; Kim, E.; Kim, H.S.; Kortenhorst, M.S.Q.; Gerber, S.; Rosen, M.; Shaikh, F.; Zahurak, M.L.; Rudek, M.A.; Hammers, H.; Rudin, C.M.; Carducci, M.A.; Kachhap, S.K.

2014-01-01

Histone deacetylase inhibitors (HDACIs) are being tested in clinical trials for the treatment of solid tumors. While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes/pathways are downregulated by HDACIs. This provides opportunities for combination

An ecosystem services approach to the ecological effects of salvage logging: valuation of seed dispersal.

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Leverkus, Alexandro B; Castro, Jorge

2017-06-01

Forest disturbances diminish ecosystem services and boost disservices. Because post-disturbance management intends to recover the greatest possible value, selling timber often prevails over other considerations. Ecological research has shown diverse effects of salvage logging, yet such research has focused on the biophysical component of post-disturbance ecosystems and lacks the link with human well-being. Here we bridge that gap under the ecosystem services framework by assessing the impact of post-fire management on a non-timber value. By employing the replacement cost method, we calculated the value of the post-fire natural regeneration of Holm oaks in southern Spain under three post-fire management options by considering the cost of planting instead. The value of this ecosystem service in non-intervention areas doubled that of salvage-logged stands due to the preference for standing dead trees by the main seed disperser. Still, most of the value resulted from the resprouting capacity of oaks. The value of this and other ecosystem services should be added to traditional cost/benefit analyses of post-disturbance management. We thus call for a more holistic approach to salvage logging research, one that explicitly links ecological processes with human well-being through ecosystem services, to better inform decision-makers on the outcomes of post-disturbance management. © 2017 by the Ecological Society of America.

Short-time effect of salvage harvesting on microbial soil properties in a Mediterranean area affected by a wildfire: preliminary results

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Moltó, Jorge; Mataix-Solera, Jorge; Arcenegui, Victoria; Morugan, Alicia; Girona, Antonio; Garcia-orenes, Fuensanta

2014-05-01

In the Mediterranean region, wildfires are considered one of the main ecological factors, which, in addition to and in relation to changes in soil use, may cause soil loss and degradation, one of the most important environmental problems that humanity must face up to. As is well known, the soil-plant system is one of the key factors determining ecological recovery after the occurrence of a wildfire. Traditionally, a variety of forestry practices have been implemented on spanish sites after the incidence of a wildfire. Among them stands out the complete extraction of the burned wood, which consist in getting rid of the branches and other wooden debris using small controlled bonfires, splintering or mechanical extraction. This set of post-fire management practices is known as salvage logging or salvage harvesting. Despite the remarkable relevance and influence that this conjunction of techniques has on land management after a wildfire, very little experimental research focused on assessing the impact of salvage logging on the vegetal community has been done. Furthermore, even less research inquiring into the mode and grade of incidence that the salvage logging produces on soil properties has taken place. The aim of this research is to assess the effects that the salvage harvesting has on different soil microbial properties and other related properties. The study area is located in the Natural Park of the "Sierra de Mariola" in the province of Alicante, southeastern Spain. This location was affected by a wildfire whose extension reached more than 500 Ha in July 2012. Different post-fire treatments were proposed by the authorities, including salvage harvesting in some areas. Two different treatments were distinguished for the study, "control" (without any kind of burned wood removal) and "harvest" (where salvage logging was carried out), in each area three 4 m2 sampling plots were set up. These two treatments were established on the same slope with the same orography

Molecular cloning of a novel glucuronokinase/putative pyrophosphorylase from zebrafish acting in an UDP-glucuronic acid salvage pathway.

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Roman Gangl

Full Text Available In animals, the main precursor for glycosaminoglycan and furthermore proteoglycan biosynthesis, like hyaluronic acid, is UDP-glucuronic acid, which is synthesized via the nucleotide sugar oxidation pathway. Mutations in this pathway cause severe developmental defects (deficiency in the initiation of heart valve formation. In plants, UDP-glucuronic acid is synthesized via two independent pathways. Beside the nucleotide sugar oxidation pathway, a second minor route to UDP-glucuronic acid exist termed the myo-inositol oxygenation pathway. Within this myo-inositol is ring cleaved into glucuronic acid, which is subsequently converted to UDP-glucuronic acid by glucuronokinase and UDP-sugar pyrophosphorylase. Here we report on a similar, but bifunctional enzyme from zebrafish (Danio rerio which has glucuronokinase/putative pyrophosphorylase activity. The enzyme can convert glucuronic acid into UDP-glucuronic acid, required for completion of the alternative pathway to UDP-glucuronic acid via myo-inositol and thus establishes a so far unknown second route to UDP-glucuronic acid in animals. Glucuronokinase from zebrafish is a member of the GHMP-kinase superfamily having unique substrate specificity for glucuronic acid with a Km of 31 ± 8 µM and accepting ATP as the only phosphate donor (Km: 59 ± 9 µM. UDP-glucuronic acid pyrophosphorylase from zebrafish has homology to bacterial nucleotidyltransferases and requires UTP as nucleosid diphosphate donor. Genes for bifunctional glucuronokinase and putative UDP-glucuronic acid pyrophosphorylase are conserved among some groups of lower animals, including fishes, frogs, tunicates, and polychaeta, but are absent from mammals. The existence of a second pathway for UDP-glucuronic acid biosynthesis in zebrafish likely explains some previous contradictory finding in jekyll/ugdh zebrafish developmental mutants, which showed residual glycosaminoglycans and proteoglycans in knockout mutants of UDP

Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors.

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Mark Merchant

Full Text Available Mitogen-activated protein kinase (MAPK pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and

Inhibitors of pan PI3K signaling synergize with BRAF or MEK inhibitors to prevent BRAF-mutant melanoma cell growth

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Melanie eSweetlove

2015-06-01

Full Text Available BRAF and MEK inhibitors have improved outcomes for patients with BRAF-mutant melanoma, but their efficacy is limited by both intrinsic and acquired resistance. Activation of the PI3K pathway can mediate resistance to these agents, providing a strong rationale for combination therapy in melanoma. Here, a panel of 9 low passage human metastatic melanoma cell lines with BRAF mutations were tested in cell proliferation and protein expression assays for sensitivity to inhibitors of MEK (selumetinib and BRAF (vemurafenib as single agents and in combination with inhibitors of pan-PI3K (ZSTK474, pan-PI3K/mTOR (BEZ235, individual PI3K isoforms (p110α, A66; p110β, TGX-221; p110γ, AS-252424; p110δ, idelalisib, or mTORC1/2 (KU-0063794. Selumetinib and vemurafenib potently inhibited cell proliferation in all cell lines, especially in those that expressed low levels of pAKT. ZSTK474 and BEZ235 also inhibited cell proliferation in all cell lines and enhanced the antitumor activity of selumetinib and vemurafenib in the majority of lines by either interacting synergistically or additively to increase potency or by inducing cytotoxicity by significantly increasing the magnitude of cell growth inhibition. Furthermore, ZSTK474 or BEZ235 combined with selumetinib to produce robust inhibition of pERK, pAKT and pS6 expression and synergistic inhibition of NZM20 tumor growth. The inhibitors of individual PI3K isoforms or mTORC1/2 were less effective at inhibiting cell proliferation either as single agents or in combination with selumetinib or vemurafenib, although KU-0063794 synergistically interacted with vemurafenib and increased the magnitude of cell growth inhibition with selumetinib or vemurafenib in certain cell lines. Overall, these results suggest that the sensitivity of BRAF-mutant melanoma cells to BRAF or MEK inhibitors is at least partly mediated by activation of the PI3K pathway and can be enhanced by combined inhibition of the BRAF/MEK and PI3K

Use of Intra-Arterial Chemotherapy and Embolization Before Limb Salvage Surgery for Osteosarcoma of the Lower Extremity

International Nuclear Information System (INIS)

Zhang Huojun; Yang Jijin; Lu Jianping; Lai Chaojen; Sheng Jin; Li Yuxiao; Hao Qiang; Zhang Shunmin; Gupta, Sanjay

2009-01-01

We report our experience with the use of intra-arterial chemotherapy and embolization before limb salvage surgery in patients with osteosarcoma of the lower extremity. We evaluated the effect of this procedure on the degree of tumor necrosis and on the amount of blood loss during surgery. We reviewed the medical records of all patients who received intra-arterial chemotherapy and embolization before undergoing limb salvage surgery for osteosarcoma of the lower extremity at our institution between January 2003 and April 2008. Patient demographic, tumor characteristics, treatment details, postembolization complications, and surgical and pathological findings were recorded for each patient. We evaluated the operative time, estimated blood loss (EBL), and volume of blood transfusion during surgery and in the postoperative period in all patients in the study group. The same parameters were recorded for 65 other patients with lower extremity osteosarcoma who underwent limb salvage operation at our institution without undergoing preoperative intervention. The study included 47 patients (25 males and 22 females). Angiography showed that the tumors were hypervascular. Intra-arterial chemotherapy and embolization were performed successfully, resulting in a substantial reduction or complete disappearance of tumor stain in all patients. No major complications were encountered. At the time of surgery, performed 3-7 days after embolization, a fibrous edematous band around the tumor was observed in 43 of the 47 patients, facilitating surgery. The goal of limb salvage was achieved successfully in all cases. Percentage tumor necrosis induced by treatment ranged from 70.2% to 94.2% (average, 82.9%). EBL during surgery, EBL from drains in the postoperative period, total EBL, and transfusion volumes were significantly lower in the 47 study patients compared to the 65 patients who underwent surgery without preoperative treatment with intra-arterial chemotherapy and embolization. The

Gemcitabine, dexamethasone, and cisplatin (GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-cell lymphoma and Hodgkin lymphoma.

Science.gov (United States)

Moccia, Alden A; Hitz, Felicitas; Hoskins, Paul; Klasa, Richard; Power, Maryse M; Savage, Kerry J; Shenkier, Tamara; Shepherd, John D; Slack, Graham W; Song, Kevin W; Gascoyne, Randy D; Connors, Joseph M; Sehn, Laurie H

2017-02-01

The optimal choice of salvage therapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) remains unknown. Based on promising results of phase II trials, the preferred salvage regimen in British Columbia since 2002 has been the out-patient regimen, gemcitabine, dexamethasone, and cisplatin (GDP). We conducted a retrospective analysis including all patients with relapsed/refractory DLBCL or HL who received GDP as salvage therapy between September 2002 and June 2010. We identified 235 patients: 152 DLBCL, 83 HL. Overall response rates were 49% and 71% for patients with DLBCL and HL, respectively. Within the transplant-eligible population, 52% of patients with DLBCL and 96% of patients with HL proceeded to stem cell transplantation. The 2-year progression-free survival and overall survival were 21% and 28% in the DLBCL cohort, and 58% and 85% in the HL group. GDP is an effective and well-tolerated out-patient salvage regimen for relapsed/refractory DLBCL and HL.

Environmental assessment for the salvage/demolition of 200 West Area, 200 East Area, and 300 Area steam plants

International Nuclear Information System (INIS)

1996-10-01

This environmental assessment has been prepared to assess potential environmental impacts associated with the US Department of Energy's proposed action: the salvage/demolition of the 200 West Area, 200 East Area, and 300 Area Steam Plants and steam distribution piping. Impact information will be used by the US Department of Energy, Richland Operations Office Manager, to determine if the proposed action is a major federal action significantly affecting the quality of the human environment. If the proposed action is determined to be major and significant, an environmental impact statement will be prepared. If the proposed action is determined not to be major and significant, a Finding of No Significant Impact (FONSI) will be issued and the action can proceed. The proposed action involves the salvage and demolition of the 200 West Area, 200 East Are, and 300 Area steam plants and their associated steam distribution piping, equipment, and ancillary facilities. Activities include the salvaging and recycling of all materials, wastes, and equipment where feasible, with waste minimization efforts utilized

Salvage therapies in relapsed and/or refractory myeloma: what is current and what is the future?

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Thumallapally N

2016-08-01

Full Text Available Nishitha Thumallapally,1 Hana Yu,1 Divya Asti,1 Adarsh Vennepureddy,1 Terenig Terjanian2 1Department of Internal Medicine, 2Division of Hematology and Oncology, Staten Island University Hospital, New York, NY, USA Abstract: The treatment landscape for multiple myeloma (MM is evolving with our understanding of its pathophysiology. However, given the inevitable cohort heterogeneity in salvage therapy, response to treatment and overall prognoses tend to vary widely, making meaningful conclusions about treatment efficacy difficult to derive. Despite the hurdles in current research, progress is underway toward more targeted therapeutic approaches. Several new drugs with novel mechanism of action and less toxic profile have been developed in the past decade, with the potential for use as single agents or in synergy with other treatment modalities in MM therapy. As our discovery of these emerging therapies progresses, so too does our need to reshape our knowledge on knowing how to apply them. This review highlights some of the recent landmark changes in MM management with specific emphasis on salvage drugs available for relapsed and refractory MM and also discusses some of the upcoming cutting-edge therapies that are currently in various stages of clinical development. Keywords: multiple myeloma, novel drugs, relapsed and refractory myeloma, salvage chemotherapy 

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

DEFF Research Database (Denmark)

van Imhoff, Gustaaf W; McMillan, Andrew; Matasar, Matthew J

2017-01-01

Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Pat...

An economic assessment of mountain pine beetle timber salvage in the west

Science.gov (United States)

Jeffrey P. Prestemon; Karen L. Abt; Kevin M. Potter; Frank H. Koch

2013-01-01

The mountain pine beetle has killed lodgepole pine and other species of pines in the western United States in an ongoing epidemic. The most heavily affected states are in the interior West: Colorado, Idaho, Montana, and Wyoming, with smaller losses elsewhere. Timber salvage is one response to the epidemic, which could generate revenues for affected landowners and...

Effect of a hydrophilic and a hydrophobic statin on cardiac salvage after ST-elevated acute myocardial infarction - a pilot study.

Science.gov (United States)

Chitose, Tadasuke; Sugiyama, Seigo; Sakamoto, Kenji; Shimomura, Hideki; Yamashita, Takuro; Hokamaki, Jun; Tsunoda, Ryusuke; Shiraishi, Shinya; Yamashita, Yasuyuki; Ogawa, Hisao

2014-11-01

Early statin therapy after acute coronary syndrome reduces atherothrombotic vascular events. This study aimed to compare the effects of hydrophilic and hydrophobic statins on myocardial salvage and left ventricular (LV) function in patients with ST-elevated myocardial infarction (STEMI). Seventy-five STEMI patients who had received emergency reperfusion therapy were enrolled and randomized into the hydrophilic statin group (rosuvastatin; 5 mg/day, n = 38) and hydrophobic statin group (atorvastatin; 10 mg/day, n = 37) for 6 months. LV ejection fraction (LVEF), and B-type natriuretic peptide (BNP) and co-enzyme Q10 (CoQ10) levels were measured at baseline and the end of treatment. The myocardial salvage index was assessed by single photon emission computed tomography with (123-)I-β-methyl-iodophenylpentadecanoic acid (ischemic area-at-risk at onset of STEMI: AAR) and (201-)thallium scintigraphy (area-at-infarction at 6 months: AAI) [myocardial salvage index = (AAR-AAI) × 100/AAR (%)]. Onset-to-balloon time and maximum creatine phosphokinase levels were comparable between the groups. After 6 months, rosuvastatin (-37.6% ± 17.2%) and atorvastatin (-32.4% ± 22.4%) equally reduced low-density lipoprotein-cholesterol (LDL-C) levels (p = 0.28). However, rosuvastatin (+3.1% ± 5.9%, p < 0.05), but not atorvastatin (+1.6% ± 5.7%, p = 0.15), improved LVEF. Rosuvastatin reduced BNP levels compared with atorvastatin (-53.3% ± 48.8% versus -13.8% ± 82.9%, p < 0.05). The myocardial salvage index was significantly higher in the rosuvastatin group than the atorvastatin group (78.6% ± 29.1% versus 52.5% ± 38.0%, p < 0.05). CoQ10/LDL-C levels at 6 months were increased in the rosuvastatin group (+23.5%, p < 0.01) and percent changes in CoQ10/LDL-C were correlated with the myocardial salvage index (r = 0.56, p < 0.01). Rosuvastatin shows better beneficial effects on myocardial salvage than atorvastatin in STEMI patients, including long-term cardiac function, associated with

Involvement of caspase-dependent and -independent apoptotic pathways in cisplatin-induced apoptosis

Science.gov (United States)

Liu, Lei; Zhang, Yingjie; Wang, Xianwang

2009-02-01

Cisplatin, an efficient anticancer agent, can trigger multiple apoptotic pathways in cancer cells. However, the signal transduction pathways in response to cisplatin-based chemotherapy are complicated, and the mechanism is not fully understood. In current study, we showed that, during cisplatin-induced apoptosis of human lung adenocarcinoma cells, both the caspase-dependent and -independent pathways were activated. Herein, we reported that after cisplatin treatment, the activities of caspase-9/-3 were sharply increased; pre-treatment with Z-LEHD-fmk (inhibitor of caspase-9), Z-DEVD-fmk (inhibitor of caspase-3), and Z-VAD-fmk (a pan-caspase inhibitor) increased cell viability and decreased apoptosis, suggesting that caspase-mediated apoptotic pathway was activated following cisplatin treatment. Confocal imaging of the cells transfected with AIF-GFP demonstrated that AIF release occurred about 9 h after cisplatin treatment. The event proceeded progressively over time, coinciding with a nuclear translocation and lasting for more than 2 hours. Down-regulation of AIF by siRNA also significantly increased cell viability and decreased apoptosis, these results suggested that AIF-mediated caspase-independent apoptotic pathway was involved in cispatin-induced apoptosis. In conclusion, the current study demonstrated that both caspase-dependent and -independent apoptotic pathways were involved in cisplatin-induced apoptosis in human lung adenocarcinoma cells.

PI3K inhibitors as new cancer therapeutics: implications for clinical trial design

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Massacesi C

2016-01-01

Full Text Available Cristian Massacesi,1 Emmanuelle Di Tomaso,2 Patrick Urban,3 Caroline Germa,4 Cornelia Quadt,5 Lucia Trandafir,1 Paola Aimone,3 Nathalie Fretault,1 Bharani Dharan,4 Ranjana Tavorath,4 Samit Hirawat4 1Novartis Oncology, Paris, France; 2Novartis Institutes for BioMedical Research Inc, Cambridge, MA, USA; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5Novartis Pharmaceuticals KK, Tokyo, Japan Abstract: The PI3K–AKT–mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120 and the PI3Kα-selective inhibitor alpelisib (BYL719, currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited, nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described. Keywords: PI3K�

In vitro effects of heparin and tissue factor pathway inhibitor on factor VII assays. possible implications for measurements in vivo after heparin therapy

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Bladbjerg, E-M; Larsen, L F; Ostergaard, P

2000-01-01

The coagulant activity of blood coagulation factor VII (FVII:C) can be lowered by changes in lifestyle and by therapeutic intervention, e.g. heparin infusion. The question is, however, whether FVII:C determined ex vivo is a valid measure of the FVII activity in vivo. We measured plasma FVII......:C, activated FVII (FVIIa), FVII protein (FVII:Ag), tissue factor pathway inhibitor (TFPI), triglycerides, and free fatty acids (FFA) before and 15 min after infusion of a bolus of unfractionated heparin (50 IU/kg body weight) in 12 healthy subjects. Additionally, we conducted in vitro experiments...

Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.

Directory of Open Access Journals (Sweden)

Christina Gavegnano

2017-12-01

Full Text Available Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit γ-C receptor cytokine (IL-15-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of γ-C cytokine (IL-2, IL-7 and IL-15 ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies.

Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors.

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Thangavelu, Bharani; Bhansali, Pravin; Viola, Ronald E

2015-10-15

Aspartate-β-semialdehyde dehydrogenase (ASADH) lies at the first branch point in the aspartate metabolic pathway which leads to the biosynthesis of several essential amino acids and some important metabolites. This pathway is crucial for many metabolic processes in plants and microbes like bacteria and fungi, but is absent in mammals. Therefore, the key microbial enzymes involved in this pathway are attractive potential targets for development of new antibiotics with novel modes of action. The ASADH enzyme family shares the same substrate binding and active site catalytic groups; however, the enzymes from representative bacterial and fungal species show different inhibition patterns when previously screened against low molecular weight inhibitors identified from fragment library screening. In the present study several approaches, including fragment based drug discovery (FBDD), inhibitor docking, kinetic, and structure-activity relationship (SAR) studies have been used to guide ASADH inhibitor development. Elaboration of a core structure identified by FBDD has led to the synthesis of low micromolar inhibitors of the target enzyme, with high selectivity introduced between the Gram-negative and Gram-positive orthologs of ASADH. This new set of structures open a novel direction for the development of inhibitors against this validated drug-target enzyme. Copyright © 2015 Elsevier Ltd. All rights reserved.

Deoxynucleoside salvage in fission yeast allows rescue of ribonucleotide reductase deficiency but not Spd1-mediated inhibition of replication

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Fleck, Oliver; Fahnøe, Ulrik; Løvschal, Katrine Vyff

2017-01-01

In fission yeast, the small, intrinsically disordered protein S-phase delaying protein 1 (Spd1) blocks DNA replication and causes checkpoint activation at least in part, by inhibiting the enzyme ribonucleotide reductase, which is responsible for the synthesis of DNA. The CRL4(Cdt2) E3 ubiquitin...... ligase mediates degradation of Spd1 and the related protein Spd2 at S phase of the cell cycle. We have generated a conditional allele of CRL4(Cdt2), by expressing the highly unstable substrate-recruiting protein Cdt2 from a repressible promoter. Unlike Spd1, Spd2 does not regulate deoxynucleotide...... triphosphate (dNTP) pools; yet we find that Spd1 and Spd2 together inhibit DNA replication upon Cdt2 depletion. To directly test whether this block of replication was solely due to insufficient dNTP levels, we established a deoxy-nucleotide salvage pathway in fission yeast by expressing the human nucleoside...

Nicotinamide clearance by Pnc1 directly regulates Sir2-mediated silencing and longevity.

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Gallo, Christopher M; Smith, Daniel L; Smith, Jeffrey S

2004-02-01

The Saccharomyces cerevisiae Sir2 protein is an NAD(+)-dependent histone deacetylase (HDAC) that functions in transcriptional silencing and longevity. The NAD(+) salvage pathway protein, Npt1, regulates Sir2-mediated processes by maintaining a sufficiently high intracellular NAD(+) concentration. However, another NAD(+) salvage pathway component, Pnc1, modulates silencing independently of the NAD(+) concentration. Nicotinamide (NAM) is a by-product of the Sir2 deacetylase reaction and is a natural Sir2 inhibitor. Pnc1 is a nicotinamidase that converts NAM to nicotinic acid. Here we show that recombinant Pnc1 stimulates Sir2 HDAC activity in vitro by preventing the accumulation of NAM produced by Sir2. In vivo, telomeric, rDNA, and HM silencing are differentially sensitive to inhibition by NAM. Furthermore, PNC1 overexpression suppresses the inhibitory effect of exogenously added NAM on silencing, life span, and Hst1-mediated transcriptional repression. Finally, we show that stress suppresses the inhibitory effect of NAM through the induction of PNC1 expression. Pnc1, therefore, positively regulates Sir2-mediated silencing and longevity by preventing the accumulation of intracellular NAM during times of stress.

Assimilation of NAD(+) precursors in Candida glabrata.

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Ma, Biao; Pan, Shih-Jung; Zupancic, Margaret L; Cormack, Brendan P

2007-10-01

The yeast pathogen Candida glabrata is a nicotinamide adenine dinucleotide (NAD(+)) auxotroph and its growth depends on the environmental supply of vitamin precursors of NAD(+). C. glabrata salvage pathways defined in this article allow NAD(+) to be synthesized from three compounds - nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). NA is salvaged through a functional Preiss-Handler pathway. NAM is first converted to NA by nicotinamidase and then salvaged by the Preiss-Handler pathway. Salvage of NR in C. glabrata occurs via two routes. The first, in which NR is phosphorylated by the NR kinase Nrk1, is independent of the Preiss-Handler pathway. The second is a novel pathway in which NR is degraded by the nucleosidases Pnp1 and Urh1, with a minor role for Meu1, and ultimately converted to NAD(+) via the nicotinamidase Pnc1 and the Preiss-Handler pathway. Using C. glabrata mutants whose growth depends exclusively on the external NA or NR supply, we also show that C. glabrata utilizes NR and to a lesser extent NA as NAD(+) sources during disseminated infection.

Preliminary evaluation of the Accident Response Mobile Manipulation System for accident site salvage operations

International Nuclear Information System (INIS)

Trujillo, J.M.; Morse, W.D.; Jones, D.P.

1994-01-01

This paper describes and evaluates operational experiences with the Accident Response Mobile Manipulation System (ARMMS) during simulated accident site salvage operations which might involve nuclear weapons. The ARMMS is based upon a teleoperated mobility platform with two Schilling Titan 7F Manipulators

Improvement of limb salvage procedure using intraoperative radiotherapy for osteosarcoma

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Hirano, Toru; Iwasaki, Katsuo; Kamishiro,; Toshiyuki,; Hayashi, Yasuyuki [Nagasaki Univ. (Japan). School of Medicine

1992-10-01

Clinical outcome of limb salvage procedure combined with intraoperative irradiation was investigated in 6 patients with osteosarcoma in the distal part of femur (n=4) and proximal part of tibia (n=2). They ranged in age from 12 to 54 years, with a mean of 22.5. First, a lesion was separated from the surrounding soft tissue with curatively wide margin. Osteotomy was performed at the portion of diaphysis. After irradiation field was setted up by lifting the lesion, and was exposed to doses ranging from 60 Gy to 85 Gy of intraoperative irradiation, soft tissue and fragile tumor tissue, excluding joint capsule and ligament, were removed as soon as possible. Finally, bone was jointed by means of inner fixation or bone grafting. They had a median follow-up of one year and four months after surgery. Although superficial wound infection and delayed wound adhesion were encountered as postoperative complications in one and two patients, respectively, these were all healed. None of the patients had local recurrence. The ability of salvaged limb was excellent in one, good in 3, and fair in 2 patients. Because both of the two patients with sarcoma in the proximal part of tibia had excellent and good limb ability, this procedure was considered useful especially for sarcoma in the proximal part of tibia. (N.K.).

Improvement of limb salvage procedure using intraoperative radiotherapy for osteosarcoma

International Nuclear Information System (INIS)

Hirano, Toru; Iwasaki, Katsuo; Kamishiro; Toshiyuki; Hayashi, Yasuyuki

1992-01-01

Clinical outcome of limb salvage procedure combined with intraoperative irradiation was investigated in 6 patients with osteosarcoma in the distal part of femur (n=4) and proximal part of tibia (n=2). They ranged in age from 12 to 54 years, with a mean of 22.5. First, a lesion was separated from the surrounding soft tissue with curatively wide margin. Osteotomy was performed at the portion of diaphysis. After irradiation field was setted up by lifting the lesion, and was exposed to doses ranging from 60 Gy to 85 Gy of intraoperative irradiation, soft tissue and fragile tumor tissue, excluding joint capsule and ligament, were removed as soon as possible. Finally, bone was jointed by means of inner fixation or bone grafting. They had a median follow-up of one year and four months after surgery. Although superficial wound infection and delayed wound adhesion were encountered as postoperative complications in one and two patients, respectively, these were all healed. None of the patients had local recurrence. The ability of salvaged limb was excellent in one, good in 3, and fair in 2 patients. Because both of the two patients with sarcoma in the proximal part of tibia had excellent and good limb ability, this procedure was considered useful especially for sarcoma in the proximal part of tibia. (N.K.)

Kynurenine Pathway Metabolism is Involved in the Maintenance of the Intracellular NAD Concentration in Human Primary Astrocytes

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Ross Grant

2010-01-01

Full Text Available Efficient synthesis of NAD + is critical to maintaining cell viability in all organs of the body. However, little is known of the pathway(s by which cells of the central nervous system produce NAD + . The aim of this study was to investigate the relationship, between tryptophan degradation via the kynurenine pathway (KP and de novo NAD + synthesis in human astrocytes, a major cell type within the brain. In this study we observed that inhibition of single enzymes of the KP resulted in significant decreases in NAD + levels in astroglial cells after a 24 hr period. We also observed that astrocytes cultured in media deficient in tryptophan, nicotinic acid and nicotinamide resulted in a 50% decrease in NAD + levels after 24 hrs. This decrease in NAD + was partially restored by supplementation of the culture media with either tryptophan or kynurenine, or nicotinic acid or with supply of the salvage pathway precursor nicotinamide.

Kynurenine Pathway Metabolism is Involved in the Maintenance of the Intracellular NAD+ Concentration in Human Primary Astrocytes

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Grant, Ross; Nguyen, Susan; Guillemin, Gilles

2010-01-01

Efficient synthesis of NAD+ is critical to maintaining cell viability in all organs of the body. However, little is known of the pathway(s) by which cells of the central nervous system produce NAD+. The aim of this study was to investigate the relationship, between tryptophan degradation via the kynurenine pathway (KP) and de novo NAD+ synthesis in human astrocytes, a major cell type within the brain. In this study we observed that inhibition of single enzymes of the KP resulted in significant decreases in NAD+ levels in astroglial cells after a 24 hr period. We also observed that astrocytes cultured in media deficient in tryptophan, nicotinic acid and nicotinamide resulted in a 50% decrease in NAD+ levels after 24 hrs. This decrease in NAD+ was partially restored by supplementation of the culture media with either tryptophan or kynurenine, or nicotinic acid or with supply of the salvage pathway precursor nicotinamide. PMID:22084595

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

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Avanzi, Mauro P; Chen, Amanda; He, Wu; Mitchell, W Beau

2012-11-01

Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes. Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy. Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization. Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways. © 2012 American Association of Blood Banks.

Time interval between primary radiotherapy and salvage laryngectomy: a predictor of pharyngocutaneous fistula formation.

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Scotton, William J; Nixon, I J; Pezier, T F; Cobb, R; Joshi, A; Urbano, T Guerrero; Oakley, R; Jeannon, J P; Simo, R S

2014-08-01

Salvage laryngectomy (SL) is associated with high levels of morbidity. Rates of pharyngocutaneous fistulae (PCF) are as high as 35 % in some series. Patients at highest risk of such complications may be candidates for altered surgical management in terms of additional tissue transfer, or delayed tracheoesophageal puncture. This study investigates the relationship between the time from primary radiotherapy (RT) to salvage surgery and the development of PCF. 26 consecutive patients who underwent SL between 2000 and 2010 were identified from our institutional database. Demographic, staging, treatment and complication data were collected. Subgroup analysis was performed using the Student's t test or Mann-Whitney U test for continuous variables and either Chi-squared test or Fisher's Exact test for categorical variables. 26 patients underwent SL between October 2003 and July 2010. Of these, 15 (58 %) developed a PCF. On analysis of the time between pre-operative RT and surgery, a significant difference was seen, with a mean time of 19.5 months in those who developed a PCF versus 47.0 months in those who did not (p = 0.02). Patient characteristics, treatment, and pathology results were comparable between the two groups. There was no significant difference in distribution of the other covariates between the PCF and non-PCF groups. We reported a high rate of PCF and identified an association between PCF and a short time from primary treatment to salvage surgery. Identifying factors associated with higher rates of post-operative morbidity allows surgeons to adapt surgical planning in an attempt to minimize rates of PCF.

Rates and Durability of Response to Salvage Radiation Therapy Among Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma

International Nuclear Information System (INIS)

Tseng, Yolanda D.; Chen, Yu-Hui; Catalano, Paul J.; Ng, Andrea

2015-01-01

Purpose: To evaluate the response rate (RR) and time to local recurrence (TTLR) among patients who received salvage radiation therapy for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) and investigate whether RR and TTLR differed according to disease characteristics. Methods and Materials: A retrospective review was performed for all patients who completed a course of salvage radiation therapy between January 2001 and May 2011 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Separate analyses were conducted for patients treated with palliative and curative intent. Predictors of RR for each subgroup were assessed using a generalized estimating equation model. For patients treated with curative intent, local control (LC) and progression-free survival were estimated with the Kaplan-Meier method; predictors for TTLR were evaluated using a Cox proportional hazards regression model. Results: Salvage radiation therapy was used to treat 110 patients to 121 sites (76 curative, 45 palliative). Salvage radiation therapy was given as part of consolidation in 18% of patients treated with curative intent. Median dose was 37.8 Gy, with 58% and 36% of curative and palliative patients, respectively, receiving 39.6 Gy or higher. The RR was high (86% curative, 84% palliative). With a median follow-up of 4.8 years among living patients, 5-year LC and progression-free survival for curative patients were 66% and 34%, respectively. Refractory disease (hazard ratio 3.3; P=.024) and lack of response to initial chemotherapy (hazard ratio 4.3; P=.007) but not dose (P=.93) were associated with shorter TTLR. Despite doses of 39.6 Gy or higher, 2-year LC was only 61% for definitive patients with refractory disease or disease that did not respond to initial chemotherapy. Conclusions: Relapsed or refractory aggressive NHL is responsive to salvage radiation therapy, and durable LC can be achieved in some cases. However, refractory disease is associated with a

The cost of post-operative shed blood salvage after total knee arthroplasty: an analysis of 1,093 consecutive procedures

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Muñoz, Manuel; Ariza, Daniel; Campos, Arturo; Martín-Montañez, Elisa; Pavía, José

2013-01-01

Background Requirements for allogeneic red cell transfusion after total knee arthroplasty are still high (20–50%), and salvage and reinfusion of unwashed, filtered post-operative shed blood is an established method for reducing transfusion requirements following this operation. We performed a cost analysis to ascertain whether this alternative is likely to be cost-effective. Materials and methods Data from 1,093 consecutive primary total knee arthroplasties, managed with (reinfusion group, n=763) or without reinfusion of unwashed salvaged blood (control group, n=330), were retrospectively reviewed. The costs of low-vacuum drains, shed blood collection canisters (Bellovac ABT®, Wellspect HealthCare and ConstaVac CBC II®, Stryker), shed blood reinfusion, acquisition and transfusion of allogeneic red cell concentrate, haemoglobin measurements, and prolonged length of hospital stay were used for the blood management cost analysis. Results Patients in the reinfusion group received 152±64 mL of red blood cells from postoperatively salvaged blood, without clinically relevant incidents, and showed a lower allogeneic transfusion rate (24.5% vs 8.5%, for the control and reinfusion groups, respectively; p =0.001). There were no differences in post-operative infection rates. Patients receiving allogeneic transfusions stayed in hospital longer (+1.9 days [95% CI: 1.2 to 2.6]). As reinfusion of unwashed salvaged blood reduced the allogeneic transfusion rate, both reinfusion systems may provide net savings in different cost scenarios (€ 4.6 to € 106/patient for Bellovac ABT, and € −51.9 to € 49.9/patient for ConstaVac CBCII). Discussion Return of unwashed salvaged blood after total knee arthroplasty seems to save costs in patients with pre-operative haemoglobin between 12 and 15 g/dL. It is not cost-saving in patients with a pre-operative haemoglobin >15 g/dL, whereas in those with a pre-operative haemoglobin cost-saving, its efficacy could be increased by

A cell wall-bound adenosine nucleosidase is involved in the salvage of extracellular ATP in Solanum tuberosum.

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Riewe, David; Grosman, Lukasz; Fernie, Alisdair R; Zauber, Henrik; Wucke, Cornelia; Geigenberger, Peter

2008-10-01

Extracellular ATP (eATP) has recently been demonstrated to play a crucial role in plant development and growth. To investigate the fate of eATP within the apoplast, we used intact potato (Solanum tuberosum) tuber slices as an experimental system enabling access to the apoplast without interference of cytosolic contamination. (i) Incubation of intact tuber slices with ATP led to the formation of ADP, AMP, adenosine, adenine and ribose, indicating operation of apyrase, 5'-nucleotidase and nucleosidase. (ii) Measurement of apyrase, 5'-nucleotidase and nucleosidase activities in fractionated tuber tissue confirmed the apoplastic localization for apyrase and phosphatase in potato and led to the identification of a novel cell wall-bound adenosine nucleosidase activity. (iii) When intact tuber slices were incubated with saturating concentrations of adenosine, the conversion of adenosine into adenine was much higher than adenosine import into the cell, suggesting a potential bypass of adenosine import. Consistent with this, import of radiolabeled adenine into tuber slices was inhibited when ATP, ADP or AMP were added to the slices. (iv) In wild-type plants, apyrase and adenosine nucleosidase activities were found to be co-regulated, indicating functional linkage of these enzymes in a shared pathway. (v) Moreover, adenosine nucleosidase activity was reduced in transgenic lines with strongly reduced apoplastic apyrase activity. When taken together, these results suggest that a complete ATP salvage pathway is present in the apoplast of plant cells.

Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial.

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Bøtker, Hans Erik; Kharbanda, Rajesh; Schmidt, Michael R; Bøttcher, Morten; Kaltoft, Anne K; Terkelsen, Christian J; Munk, Kim; Andersen, Niels H; Hansen, Troels M; Trautner, Sven; Lassen, Jens Flensted; Christiansen, Evald Høj; Krusell, Lars R; Kristensen, Steen D; Thuesen, Leif; Nielsen, Søren S; Rehling, Michael; Sørensen, Henrik Toft; Redington, Andrew N; Nielsen, Torsten T

2010-02-27

Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage. 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266. 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0.75 (IQR 0.50-0.93, n=73) in the remote conditioning group versus 0.55 (0.35-0.88, n=69) in the control group, with median difference of 0.10 (95% CI 0.01-0.22; p=0.0333); mean salvage index was 0.69 (SD 0.27) versus 0.57 (0.26), with mean difference of 0.12 (95% CI 0.01-0.21; p=0.0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group). Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote

Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

International Nuclear Information System (INIS)

Narayan, Vivek; Vapiwala, Neha; Mick, Rosemarie; Subramanian, Pearl; Christodouleas, John P.; Bekelman, Justin E.; Deville, Curtiland; Rajendran, Ramji; Haas, Naomi B.

2017-01-01

Purpose: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. Methods and Materials: We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Results: Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Conclusions: Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.

Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy.

Science.gov (United States)

Narayan, Vivek; Vapiwala, Neha; Mick, Rosemarie; Subramanian, Pearl; Christodouleas, John P; Bekelman, Justin E; Deville, Curtiland; Rajendran, Ramji; Haas, Naomi B

2017-02-01

In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

Energy Technology Data Exchange (ETDEWEB)

Narayan, Vivek [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Vapiwala, Neha [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Mick, Rosemarie [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Subramanian, Pearl [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Christodouleas, John P.; Bekelman, Justin E.; Deville, Curtiland; Rajendran, Ramji [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Haas, Naomi B., E-mail: naomi.haas@uphs.upenn.edu [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

2017-02-01

Purpose: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. Methods and Materials: We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Results: Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Conclusions: Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.

Modeling nest survival of cavity-nesting birds in relation to postfire salvage logging

Science.gov (United States)

Vicki Saab; Robin E. Russell; Jay Rotella; Jonathan G. Dudley

2011-01-01

Salvage logging practices in recently burned forests often have direct effects on species associated with dead trees, particularly cavity-nesting birds. As such, evaluation of postfire management practices on nest survival rates of cavity nesters is necessary for determining conservation strategies. We monitored 1,797 nests of 6 cavity-nesting bird species: Lewis'...

Joint inhibition of TOR and JNK pathways interacts to extend the lifespan of Brachionus manjavacas (Rotifera).

Science.gov (United States)

Snell, Terry W; Johnston, Rachel K; Rabeneck, Brett; Zipperer, Cody; Teat, Stephanie

2014-04-01

The TOR kinase pathway is central in modulating aging in a variety of animal models. The target of rapamycin (TOR) integrates a complex network of signals from growth conditions, nutrient availability, energy status, and physiological stresses and matches an organism's growth rate to the resource environment. Important remaining problems are the identification of the pathways that interact with TOR and their characterization as additive or synergistic. One of the most versatile stress sensors in metazoans is the Jun-N-terminal kinase (JNK) signaling pathway. JNK is an evolutionarily conserved stress-activated protein kinase that is induced by a range of stressors, including UV irradiation, reactive oxygen species, DNA damage, heat, and bacterial antigens. JNK is thought to interact with the TOR pathway, but its effects on TOR are poorly understood. We used the rotifer Brachionus manjavacas as a model animal to probe the regulation of TOR and JNK pathways and explore their interaction. The effect of various chemical inhibitors was examined in life table and stressor challenge experiments. A survey of 12 inhibitors revealed two, rapamycin and JNK inhibitor, that significantly extended lifespan of B. manjavacas. At 1 μM concentration, exposure to rapamycin or JNK inhibitor extended mean rotifer lifespan by 35% and maximum lifespan by 37%. Exposure to both rapamycin and JNK inhibitor simultaneously extended mean rotifer lifespan by 65% more than either alone. Exposure to a combination of rapamycin and JNK inhibitors conveyed greater protection to starvation, UV and osmotic stress than either inhibitor alone. RNAi knockdown of TOR and JNK gene expression was investigated for its ability to extend rotifer lifespan. RNAi knockdown of the TOR gene resulted in 29% extension of the mean lifespan compared to control and knockdown of the JNK gene resulted in 51% mean lifespan extension. In addition to the lifespan, we quantified mitochondria activity using the fluorescent

Limb salvage and reconstruction following a zebra attack

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Jacob T. Carlson

2017-06-01

Full Text Available Animal bites are fairly rare events but can cause devastating traumatic injuries to the victim. In addition to the soft tissue, vascular, and orthopedic trauma inflicted by these occurrences, bite injuries also have the potential to introduce an inoculum of microbes, which may progress to an infection if not treated properly and expeditiously.We present the case of a healthy male who sustained multiple bite wounds from a domestic zebra to his left upper extremity. This attack caused severe damage, including devascularization of the arm at the brachial artery, disruption of the distal biceps and brachialis, stripping of the forearm nerves, and shearing of the overlying soft tissue. The patient was taken emergently to the operating room for revascularization of the extremity utilizing a vein bypass graft. The soft tissue injuries were addressed with numerous irrigation and debridement procedures, during which coverage of the vein bypass graft was obtained using a variety of techniques, including skin flaps, musculocutaneous advancements, and the application of an acellular dermal matrix (AlloDerm and a collagen-glycosaminoglycan matrix (Integra.Wound cultures obtained intra-operatively during the irrigation and debridement procedures were notable for the growth of multiple microbes, including Rhodococcus spp., which have been documented to cause infection in immunocompromised patients. The patient in this case was treated with a prolonged course of antibiotics, and wound cultures negative for microbial growth were eventually obtained prior to final closure of his wound. The patient then underwent successful biceps reconstruction with a pedicled latissimus dorsi muscle transfer. This case documents the extraordinary multidisciplinary approach provided in the salvage, management, and eventual reconstruction of a mangled left upper extremity that had sustained devastating traumatic injuries resulting from a rather unusual source. Keywords: Zebra

The effector AWR5 from the plant pathogen Ralstonia solanacearum is an inhibitor of the TOR signalling pathway.

Science.gov (United States)

Popa, Crina; Li, Liang; Gil, Sergio; Tatjer, Laura; Hashii, Keisuke; Tabuchi, Mitsuaki; Coll, Núria S; Ariño, Joaquín; Valls, Marc

2016-06-03

Bacterial pathogens possess complex type III effector (T3E) repertoires that are translocated inside the host cells to cause disease. However, only a minor proportion of these effectors have been assigned a function. Here, we show that the T3E AWR5 from the phytopathogen Ralstonia solanacearum is an inhibitor of TOR, a central regulator in eukaryotes that controls the switch between cell growth and stress responses in response to nutrient availability. Heterologous expression of AWR5 in yeast caused growth inhibition and autophagy induction coupled to massive transcriptomic changes, unmistakably reminiscent of TOR inhibition by rapamycin or nitrogen starvation. Detailed genetic analysis of these phenotypes in yeast, including suppression of AWR5-induced toxicity by mutation of CDC55 and TPD3, encoding regulatory subunits of the PP2A phosphatase, indicated that AWR5 might exert its function by directly or indirectly inhibiting the TOR pathway upstream PP2A. We present evidence in planta that this T3E caused a decrease in TOR-regulated plant nitrate reductase activity and also that normal levels of TOR and the Cdc55 homologues in plants are required for R. solanacearum virulence. Our results suggest that the TOR pathway is a bona fide T3E target and further prove that yeast is a useful platform for T3E function characterisation.

Postoperative blood salvage versus allogeneic blood transfusion in total knee and hip arthroplasty: a literature review.

Science.gov (United States)

Leigheb, Massimiliano; Pogliacomi, Francesco; Bosetti, Michela; Boccafoschi, Francesca; Sabbatini, Maurizio; Cannas, Mario; Grassi, Federico

2016-04-15

We aimed to compare Postoperative Blood Salvage (PBS) with Allogeneic Blood Transfusion (ABT) in patients undergoing Total Hip and Knee Arthroplasty (THA, TKA).  A bibliographic research was carried out in order to review the literature dedicated to postoperative blood salvage in major orthopaedic surgery, excluding papers dealing exclusively with preoperative autologous donation, intraoperative blood salvage and ABT. PBS and ABT were compared according to complications, costs and duration of hospitalization. PBS effectiveness in reducing ABT was also assessed. PBS system is useful for reducing the complication rate and the length of hospital stay if compared to ABT. Costs for the reinfusion of unwashed shed blood, washed blood, and allogeneic transfusion are controversial among the different authors. Several papers demonstrate that PBS significantly reduces the need of postoperative ABT in both THA and TKA, while there is low evidence that PBS does not affect the risk of surgical wound complications. To reduce potential risks related to PBS, including non-hemolytic febrile reaction, the reinfusion of saved blood should begin within 4-6 hours after the start of collection through the wound drainage. According to literature, PBS appears to be a valid alternative to ABT, which is the standard treatment for postoperative anemia in THA and TKA. Contraindications to PBS must be ruled out before recommending it to patients undergoing major orthopaedic procedures.

Salvage High-intensity Focused Ultrasound for the Recurrent Prostate Cancer after Radiotherapy

International Nuclear Information System (INIS)

Shoji, S.; Nakano, M.; Omata, T.; Harano, Y.; Nagata, Y.; Uchida, T.; Usui, Y.; Terachi, T.

2010-01-01

To investigate the use of minimally invasive high-intensity focused ultrasound (HIFU) as a salvage therapy in men with localized prostate cancer recurrence following external beam radiotherapy (EBRT), brachytherapy or proton therapy. A review of 20 cases treated using the Sonablate registered 500 HIFU device, between August 28, 2002 and September 1, 2009, was carried out. All men had presumed organ-confined, histologically confirmed recurrent prostate adenocarcinoma following radiation therapy. All men with presumed, organ-confined, recurrent disease following EBRT in 8 patients, brachytherapy in 7 patients or proton therapy in 5 patients treated with salvage HIFU were included. The patients were followed for a mean (range) of 16.0 (3-80) months. Biochemical disease-free survival (bDFS) rates in patients with low-intermediate and high risk groups were 86% and 50%, respectively. Side-effects included urethral stricture in 2 of the 16 patients (13%), urinary tract infection or dysuria syndrome in eight (26%), and urinary incontinence in one (6%). Recto-urethral fistula occurred in one patient (6%). Transrectal HIFU is an effective treatment for recurrence after radiotherapy especially in patients with low- and intermediate risk groups.

Comprehensive suppression of all apoptosis-induced proliferation pathways as a proposed approach to colorectal cancer prevention and therapy.

Directory of Open Access Journals (Sweden)

Michael Bordonaro

Full Text Available Mutations in the WNT/beta-catenin pathway are present in the majority of all sporadic colorectal cancers (CRCs, and histone deacetylase inhibitors induce apoptosis in CRC cells with such mutations. This apoptosis is counteracted by (1 the signaling heterogeneity of CRC cell populations, and (2 the survival pathways induced by mitogens secreted from apoptotic cells. The phenomena of signaling heterogeneity and apoptosis-induced survival constitute the immediate mechanisms of resistance to histone deacetylase inhibitors, and probably other chemotherapeutic agents. We explored the strategy of augmenting CRC cell death by inhibiting all survival pathways induced by the pro-apoptotic agent LBH589, a histone deacetylase inhibitor: AKT, JAK/STAT, and ERK signaling. The apoptosis-enhancing ability of a cocktail of synthetic inhibitors of proliferation was compared to the effects of the natural product propolis. We utilized colorectal adenoma, drug-sensitive and drug-resistant colorectal carcinoma cells to evaluate the apoptotic potential of the combination treatments. The results suggest that an effective approach to CRC combination therapy is to combine apoptosis-inducing drugs (e.g., histone deacetylase inhibitors, such as LBH589 with agents that suppress all compensatory survival pathways induced during apoptosis (such as the cocktail of inhibitors of apoptosis-associated proliferation. The same paradigm can be applied to a CRC prevention approach, as the apoptotic effect of butyrate, a diet-derived histone deacetylase inhibitor, is augmented by other dietary agents that modulate survival pathways (e.g., propolis and coffee extract. Thus, dietary supplements composed by fermentable fiber, propolis, and coffee extract may effectively counteract neoplastic growth in the colon.

The vascularised fibular graft for limb salvage after bone tumour surgery A MULTICENTRE STUDY

NARCIS (Netherlands)

Hilven, P. H.; Bayliss, L.; Cosker, T.; Dijkstra, P. D. S.; Jutte, P. C.; Lahoda, L. U.; Schaap, G. R.; Bramer, J. A. M.; van Drunen, G. K.; Strackee, S. D.; van Vooren, J.; Gibbons, M.; Giele, H.; van de Sande, M. A. J.

2015-01-01

Vascularised fibular grafts (VFGs) are a valuable surgical technique in limb salvage after resection of a tumour. The primary objective of this multicentre study was to assess the risk factors for failure and complications for using a VFG after resection of a tumour. The study involved 74

Homologous Recombination in Protozoan Parasites and Recombinase Inhibitors

Directory of Open Access Journals (Sweden)

Andrew A. Kelso

2017-09-01

Full Text Available Homologous recombination (HR is a DNA double-strand break (DSB repair pathway that utilizes a homologous template to fully repair the damaged DNA. HR is critical to maintain genome stability and to ensure genetic diversity during meiosis. A specialized class of enzymes known as recombinases facilitate the exchange of genetic information between sister chromatids or homologous chromosomes with the help of numerous protein accessory factors. The majority of the HR machinery is highly conserved among eukaryotes. In many protozoan parasites, HR is an essential DSB repair pathway that allows these organisms to adapt to environmental conditions and evade host immune systems through genetic recombination. Therefore, small molecule inhibitors, capable of disrupting HR in protozoan parasites, represent potential therapeutic options. A number of small molecule inhibitors were identified that disrupt the activities of the human recombinase RAD51. Recent studies have examined the effect of two of these molecules on the Entamoeba recombinases. Here, we discuss the current understandings of HR in the protozoan parasites Trypanosoma, Leishmania, Plasmodium, and Entamoeba, and we review the small molecule inhibitors known to disrupt human RAD51 activity.

DNA damage response pathway in radioadaptive response.

Science.gov (United States)

Sasaki, Masao S; Ejima, Yosuke; Tachibana, Akira; Yamada, Toshiko; Ishizaki, Kanji; Shimizu, Takashi; Nomura, Taisei

2002-07-25

Radioadaptive response is a biological defense mechanism in which low-dose ionizing irradiation elicits cellular resistance to the genotoxic effects of subsequent irradiation. However, its molecular mechanism remains largely unknown. We previously demonstrated that the dose recognition and adaptive response could be mediated by a feedback signaling pathway involving protein kinase C (PKC), p38 mitogen activated protein kinase (p38MAPK) and phospholipase C (PLC). Further, to elucidate the downstream effector pathway, we studied the X-ray-induced adaptive response in cultured mouse and human cells with different genetic background relevant to the DNA damage response pathway, such as deficiencies in TP53, DNA-PKcs, ATM and FANCA genes. The results showed that p53 protein played a key role in the adaptive response while DNA-PKcs, ATM and FANCA were not responsible. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), mimicked the priming irradiation in that the inhibitor alone rendered the cells resistant against the induction of chromosome aberrations and apoptosis by the subsequent X-ray irradiation. The adaptive response, whether it was afforded by low-dose X-rays or wortmannin, occurred in parallel with the reduction of apoptotic cell death by challenging doses. The inhibitor of p38MAPK which blocks the adaptive response did not suppress apoptosis. These observations indicate that the adaptive response and apoptotic cell death constitute a complementary defense system via life-or-death decisions. The p53 has a pivotal role in channeling the radiation-induced DNA double-strand breaks (DSBs) into an adaptive legitimate repair pathway, where the signals are integrated into p53 by a circuitous PKC-p38MAPK-PLC damage sensing pathway, and hence turning off the signals to an alternative pathway to illegitimate repair and apoptosis. A possible molecular mechanism of adaptive response to low-dose ionizing irradiation has been discussed in relation to

The Influence of findings of coronary artery on myocardial salvage in acute myocardial infarction

International Nuclear Information System (INIS)

Itano, Midoriko; Naruse, Hitoshi; Morita, Masato; Kawamoto, Hideo; Yamamoto, Juro; Fukutake, Naoshige; Ohyanagi, Mitsumasa; Iwasaki, Tadaaki; Fukuchi, Minoru

1992-01-01

201 Tl stress myocardial scintigraphy was performed in convalescent patients with acute myocardial infarction, to evaluate the influence of stenosis and collateral circulation of coronary artery in acute phase, on myocardial salvage in chronic phase. In 14 cases of unsuccessful coronary revascularization (complete occlusion), a complete defect of thallium imaging in chronic phase was seen in only one case of four cases with good collateral circulation, while eight of 10 cases with poor collateral circulation. In 16 cases with collateral circulation, six cases showed a complete defect, although the target vessel had improved to less than 75% of stenosis. However, in cases of good collateral circulation, no case showed a complete defect when the target vessel had improved to less than 75% of stenosis. The myocardial salvage is quite possible (p<0.05), when the coronary angiography in acute phase showed the forward flow (99% or 90% of stenosis) before coronary revascularization and/or good collateral circulation (Rentrop 2deg or 3deg). (author)

Th17 Inhibitors in Active Psoriatic Arthritis

DEFF Research Database (Denmark)

Naik, Girish S; Ming, Wai K; Magodoro, Itai M

2018-01-01

BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α...

Natural recovery and leaf water potential after fire influenced by salvage logging and induced drought stress

Directory of Open Access Journals (Sweden)

D. Moya

2013-01-01

Full Text Available Salvage logging is one of the most common emergency actions in the short-term management after a fire. Several studies have been carried out and some obtained positive results which incite to carry it out but other, found negative effects on seedling establishment and regeneration. In addition, climatic changes will have large impacts on vegetation productivity and resilience since the regional models for south-eastern Spain predicts a rainfall decrease of about 20% and temperature increase of 4.5 ºC. Our aim was to determine how short-term forest management and induced drought affect the ecosystem recovery in Aleppo pine stands naturally recovered after a fire.In summer 2009, a mid-high severity fire burned 968 ha of Aleppo pine (Pinus halepensis Mill. forest in south-eastern Spain. Six months later, a salvage logging was carried out. The Aleppo pine recruitment was negligible. During summer 2010, twelve square plots (2m x 2m were set in the three scenarios: control, salvaged and drought induced. The surface cover and soil water availability for three dominant understory species were recorded in four field campaigns: Spring-2010, Fall-2010, Spring-2011 and Fall-2011.The season, management and the target species showed significant differences in growing and water stress. In general, Esparto grass showed lower water stress, mainly in Fall, a higher increase of total coverage. Both effects were showing their highest values in non-salvaged areas and no drought. Changes in leaf water potential and soil water content after the drought season influence the survival and development of individuals.Our results indicate that soil water content and ecosystem response can be modified by short-term silvicultural treatments. Therefore, management after fire could cause opposite effects to those initially foreseen, since they depend on fire severity, and type of ecosystem management response. So, their application must be evaluated and assessed before

DMPD: Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 16982211 Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. Wullaer...vg) (.html) (.csml) Show Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. PubmedID 1698221...1 Title Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. Author

The Impact of use of Double Set-up on Infection Rates in Revision Total Knee Replacement and Limb Salvage Procedures

Directory of Open Access Journals (Sweden)

Jennifer Waterman

2015-03-01

Full Text Available A retrospective analysis was performed to determine the impact of utilizing a double set-up procedure on reducing infection rates revision total knee and limb salvage procedures in patients with known joint infection.  Eighteen cases fit selection criteria.  The recurrence rate of infection was 5.5% which is less than reported recent literature review.   This suggests the use of a double set-up in combination with other infection reducing protocols may help further reduce recurrent infection.  Keywords: double set-up, infection, revision total knee arthroplasty, limb-salvage

Physiological and morphological responses of pine and willow saplings to post-fire salvage logging

Science.gov (United States)

Millions, E. L.; Letts, M. G.; Harvey, T.; Rood, S. B.

2015-12-01

With global warming, forest fires may be increasing in frequency, and post-fire salvage logging may become more common. The ecophysiological impacts of this practice on tree saplings remain poorly understood. In this study, we examined the physiological and morphological impacts of increased light intensity, due to post-fire salvage logging, on the conifer Pinus contorta (pine) and deciduous broadleaf Salix lucida (willow) tree and shrub species in the Crowsnest Pass region of southern Alberta. Photosynthetic gas-exchange and plant morphological measurements were taken throughout the summer of 2013 on approximately ten year-old saplings of both species. Neither species exhibited photoinhibition, but different strategies were observed to acclimate to increased light availability. Willow saplings were able to slightly elevate their light-saturated rate of net photosynthesis (Amax) when exposed to higher photosynthetic photon flux density (PPFD), thus increasing their growth rate. Willow also exhibited increased leaf inclination angles and leaf mass per unit area (LMA), to decrease light interception in the salvage-logged plot. By contrast, pine, which exhibited lower Amax and transpiration (E), but higher water-use efficiency (WUE = Amax/E) than willow, increased the rate at which electrons were moved through and away from the photosynthetic apparatus in order to avoid photoinhibition. Acclimation indices were higher in willow saplings, consistent with the hypothesis that species with short-lived foliage exhibit greater acclimation. LMA was higher in pine saplings growing in the logged plot, but whole-plant and branch-level morphological acclimation was limited and more consistent with a response to decreased competition in the logged plot, which had much lower stand density.

Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

Science.gov (United States)

Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

2011-02-10

Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

External and internal hemipelvectomy for sarcomas of the pelvic girdle : consequences of limb-salvage treatment

NARCIS (Netherlands)

Ham, SJ; Veth, RPH; van Horn, [No Value; Eisma, WH; Hoekstra, HJ; Schraffordt Koops, H.

1997-01-01

The outcome of different Limb-saving treatment modalities for pelvic girdle sarcoma is controversial. The oncological and functional results after 11 external and 10 internal hemipelvectomies and the consequences of limb-salvage treatment were studied in 21 consecutive patients with primary bone (19

A PKA survival pathway inhibited by DPT-PKI, a new specific cell permeable PKA inhibitor, is induced by T. annulata in parasitized B-lymphocytes.

Science.gov (United States)

Guergnon, Julien; Dessauge, Frederic; Traincard, François; Cayla, Xavier; Rebollo, Angelita; Bost, Pierre Etienne; Langsley, Gordon; Garcia, Alphonse

2006-08-01

T. annulata, an intracellular pathogenic parasite of the Aplicomplexa protozoan family infects bovine B-lymphocytes and macrophages. Parasitized cells that become transformed survive and proliferate independently of exogenous growth factors. In the present study, we used the isogenic non parasitized BL3 and parasitized TBL3 B cell lines, as a model to evaluate the contribution of two-major PI3-K- and PKA-dependent anti-apoptotic pathways in the survival of T. annulata parasitized B lymphocytes. We found that T. annulata increases PKA activity, induces over-expression of the catalytic subunit and down-regulates the pro-survival phosphorylation state of Akt/PKB. Consistent with a role of PKA activation in survival, two pharmacological inhibitors H89 and KT5720 ablate PKA-dependent survival of parasitized cells. To specifically inhibit PKA pro-survival pathways we linked the DPTsh1 peptide shuttle sequence to PKI(5-24) and we generated DPT-PKI, a cell permeable PKI. DPT-PKI specifically inhibited PKA activity in bovine cell extracts and, as expected, also inhibited the PKA-dependent survival of T. annulata parasitized TBL3 cells. Thus, parasite-dependent constitutive activation of PKA in TBL3 cells generates an anti-apoptotic pathway that can protect T. annulata-infected B cells from apoptosis. These results also indicate that DPT-PKI could be a powerful tool to inhibit PKA pathways in other cell types.

77 FR 19177 - Beaverhead-Deerlodge National Forest, Jefferson Ranger District, Montana, Boulder River Salvage...

Science.gov (United States)

2012-03-30

... statement. SUMMARY: The project proposes to salvage by clearcut harvest dead and lodgepole pine infested or... Need for Action The purpose and need for this project is to harvest merchantable wood products from..., before the value of the wood deteriorates; reduce stand density in lodgepole pine and Douglas-fir stands...

Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor

DEFF Research Database (Denmark)

Bladbjerg, E-M; Skouby, S O.; Andersen, L F

2002-01-01

BACKGROUND: Long-term hormone replacement therapy (HRT) reduces cardiovascular risk, but an early increased risk was reported in women with coronary heart disease. In such women the arterial intima can express tissue factor, and changes in coagulation factor VII (factor VII) and tissue factor...... pathway inhibitor (TFPI) may be deleterious. METHODS: We measured factor VII clotting activity, activated factor VII, and concentrations of factor VII and TFPI during 12 months in healthy post-menopausal women randomized to: (i). cyclic oral estrogen/progestin (n = 25); (ii). long-cycle oral estrogen......: No variations were observed in the reference group. There was a substantial decrease in TFPI concentrations in the HRT groups irrespective of the type of progestin. In women receiving long-cycle treatment, all factor VII measures increased during the unopposed estrogen periods, and the increase was reversed...

Molecular regulation of MICA expression after HDAC inhibitor treatment of cancer cells

DEFF Research Database (Denmark)

Jensen, Helle

and NKG2D-ligands are upregulated on the surface of abnormal cells. We have previously shown that cancer cells can be stimulated to express the NKG2D-ligands MICA/B after exposure to HDAC-inhibitors (HDAC-i), an occurrence that is not observed in healthy cells. Here we characterize the molecular signal...... pathways that lead to MICA expression after HDAC-inhibitor treatment of cancer cells. Chelating Calcium with Bapta-AM or EGTA potently inhibited HDAC-inhibitor and CMV mediated MICA/B expression. It was further observed that ER Calcium stores were depleted after HDAC-inhibitor treatment. NF-kB activity can...

Acrolein increases 5-lipoxygenase expression in murine macrophages through activation of ERK pathway.

Science.gov (United States)

Kim, Chae E; Lee, Seung J; Seo, Kyo W; Park, Hye M; Yun, Jung W; Bae, Jin U; Bae, Sun S; Kim, Chi D

2010-05-15

Episodic exposure to acrolein-rich pollutants has been linked to acute myocardial infarction, and 5-lipoxygenase (5-LO) is involved in the production of matrix metalloproteinase-9 (MMP-9), which destabilizes atherosclerotic plaques. Thus, the present study determined the effect of acrolein on 5-LO/leukotriene B(4) (LTB(4)) production in murine macrophages. Stimulation of J774A.1 cells with acrolein led to increased LTB(4) production in association with increased 5-LO expression. Acrolein-evoked 5-LO expression was blocked by pharmacological inhibition of the ERK pathway, but not by inhibitors for JNK and p38 MAPK pathways. In line with these results, acrolein exclusively increased the phosphorylation of ERK among these MAPK, suggesting a role for the ERK pathway in acrolein-induced 5-LO expression with subsequent production of LTB(4). Among the receptor tyrosine kinases including epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR), acrolein-evoked ERK phosphorylation was attenuated by AG1478, an EGFR inhibitor, but not by AG1295, a PDGFR inhibitor. In addition, acrolein-evoked 5-LO expression was also inhibited by inhibition of EGFR pathway, but not by inhibition of PDGFR pathway. These observations suggest that acrolein has a profound effect on the 5-LO pathway via an EGFR-mediated activation of ERK pathway, leading to acute ischemic syndromes through the generation of LTB(4), subsequent MMP-9 production and plaque rupture.

Acrolein increases 5-lipoxygenase expression in murine macrophages through activation of ERK pathway

International Nuclear Information System (INIS)

Kim, Chae E.; Lee, Seung J.; Seo, Kyo W.; Park, Hye M.; Yun, Jung W.; Bae, Jin U.; Bae, Sun S.; Kim, Chi D.

2010-01-01

Episodic exposure to acrolein-rich pollutants has been linked to acute myocardial infarction, and 5-lipoxygenase (5-LO) is involved in the production of matrix metalloproteinase-9 (MMP-9), which destabilizes atherosclerotic plaques. Thus, the present study determined the effect of acrolein on 5-LO/leukotriene B 4 (LTB 4 ) production in murine macrophages. Stimulation of J774A.1 cells with acrolein led to increased LTB 4 production in association with increased 5-LO expression. Acrolein-evoked 5-LO expression was blocked by pharmacological inhibition of the ERK pathway, but not by inhibitors for JNK and p38 MAPK pathways. In line with these results, acrolein exclusively increased the phosphorylation of ERK among these MAPK, suggesting a role for the ERK pathway in acrolein-induced 5-LO expression with subsequent production of LTB 4 . Among the receptor tyrosine kinases including epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR), acrolein-evoked ERK phosphorylation was attenuated by AG1478, an EGFR inhibitor, but not by AG1295, a PDGFR inhibitor. In addition, acrolein-evoked 5-LO expression was also inhibited by inhibition of EGFR pathway, but not by inhibition of PDGFR pathway. These observations suggest that acrolein has a profound effect on the 5-LO pathway via an EGFR-mediated activation of ERK pathway, leading to acute ischemic syndromes through the generation of LTB 4 , subsequent MMP-9 production and plaque rupture.

[F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography after limb salvage surgery: post-surgical appearance, attenuation correction and local complications

Energy Technology Data Exchange (ETDEWEB)

Gelfand, Michael J.; Sharp, Susan E. [Cincinnati Children' s Hospital Medical Center, Department of Radiology, Nuclear Medicine Division, Cincinnati, OH (United States)

2015-08-15

Metal endoprostheses and internal fixation devices cause significant artifacts on CT after limb salvage surgery; positron emission tomography (PET) images should be evaluated for artifacts. (1) To describe [F-18]2-fluoro-2-deoxyglucose (FDG) PET uptake patterns after limb salvage surgery. (2) To determine whether metal endoprostheses and fixation hardware cause significant artifacts on CT attenuation-corrected PET that interfere with diagnostic use of PET/CT after limb salvage surgery. We reviewed 92 studies from 18 patients ages 5-21 years. Diagnoses were osteogenic sarcoma in 14, Ewing sarcoma in 3, and malignant peripheral nerve sheath tumor originating in bone in 1. Nine patients had distal femur/knee endoprostheses, five had lower-extremity bone allografts secured by large metal plates and four had upper-extremity limb salvage procedures. Maximum standardized uptake value was calculated at lower-extremity soft-tissue-endoprosthesis interfaces. In 15 patients with PET/CT imaging, the first PET/CT scan after limb salvage surgery was reviewed for metal artifacts on CT images and for artifacts at locations on PET corresponding to the CT metal artifacts. Increased FDG uptake was consistently present at soft-tissue interfaces with endoprostheses, allografts and internal fixation devices, with little or no FDG uptake at cemented endoprosthesis-bone interfaces. Maximum standardized uptake value at margins of femur/knee endoprostheses ranged from 1.4 to 5.7. In four patients with distal femur/knee endoprostheses, minimal artifact was noted on attenuation-corrected PET images, but image interpretation was not affected. In the other 11 patients who had CT attenuation correction, we detected no artifacts caused by the attenuation correction. CT attenuation correction did not cause artifacts that affected interpretation of attenuation-corrected PET images. (orig.)

[F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography after limb salvage surgery: post-surgical appearance, attenuation correction and local complications

International Nuclear Information System (INIS)

Gelfand, Michael J.; Sharp, Susan E.

2015-01-01

Metal endoprostheses and internal fixation devices cause significant artifacts on CT after limb salvage surgery; positron emission tomography (PET) images should be evaluated for artifacts. (1) To describe [F-18]2-fluoro-2-deoxyglucose (FDG) PET uptake patterns after limb salvage surgery. (2) To determine whether metal endoprostheses and fixation hardware cause significant artifacts on CT attenuation-corrected PET that interfere with diagnostic use of PET/CT after limb salvage surgery. We reviewed 92 studies from 18 patients ages 5-21 years. Diagnoses were osteogenic sarcoma in 14, Ewing sarcoma in 3, and malignant peripheral nerve sheath tumor originating in bone in 1. Nine patients had distal femur/knee endoprostheses, five had lower-extremity bone allografts secured by large metal plates and four had upper-extremity limb salvage procedures. Maximum standardized uptake value was calculated at lower-extremity soft-tissue-endoprosthesis interfaces. In 15 patients with PET/CT imaging, the first PET/CT scan after limb salvage surgery was reviewed for metal artifacts on CT images and for artifacts at locations on PET corresponding to the CT metal artifacts. Increased FDG uptake was consistently present at soft-tissue interfaces with endoprostheses, allografts and internal fixation devices, with little or no FDG uptake at cemented endoprosthesis-bone interfaces. Maximum standardized uptake value at margins of femur/knee endoprostheses ranged from 1.4 to 5.7. In four patients with distal femur/knee endoprostheses, minimal artifact was noted on attenuation-corrected PET images, but image interpretation was not affected. In the other 11 patients who had CT attenuation correction, we detected no artifacts caused by the attenuation correction. CT attenuation correction did not cause artifacts that affected interpretation of attenuation-corrected PET images. (orig.)

The Histone Deacetylase Inhibitors MS-275 and SAHA Suppress the p38 Mitogen-Activated Protein Kinase Signaling Pathway and Chemotaxis in Rheumatoid Arthritic Synovial Fibroblastic E11 Cells

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Hai-Shu Lin

2013-11-01

Full Text Available MS-275 (entinostat and SAHA (vorinostat, two histone deacetylase (HDAC inhibitors currently in oncological trials, have displayed potent anti-rheumatic activities in rodent models of rheumatoid arthritis (RA. To further elucidate their anti-inflammatory mechanisms, the impact of MS-275 and SAHA on the p38 mitogen-activated protein kinase (MAPK signaling pathway and chemotaxis was assessed in human rheumatoid arthritic synovial fibroblastic E11 cells. MS-275 and SAHA significantly suppressed the expression of p38α  MAPK, but induced the expression of MAPK phosphatase-1 (MKP-1, an endogenous suppressor of p38α  in E11 cells. At the same time, the association between p38α and MKP-1 was up-regulated and consequently, the activation (phosphorylation of p38α  was inhibited. Moreover, MS-275 and SAHA suppressed granulocyte chemotactic protein-2 (GCP-2, monocyte chemotactic protein-2 (MCP-2 and macrophage migration inhibitory factor (MIF in E11 cells in a concentration-dependent manner. Subsequently, E11-driven migration of THP-1 and U937 monocytes was inhibited. In summary, suppression of the p38 MAPK signaling pathway and chemotaxis appear to be important anti-rheumatic mechanisms of action of these HDAC inhibitors.

PHOTOBIOMODULATION-MEDIATED PATHWAY DIAGNOSTICS

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TIMON CHENG-YI LIU

2013-01-01

Full Text Available Cellular pathways are ordinarily diagnosed with pathway inhibitors, related gene regulation, or fluorescent protein markers. They are also suggested to be diagnosed with pathway activation modulation of photobiomodulation (PBM in this paper. A PBM on a biosystem function depends on whether the biosystem is in its function-specific homeostasis (FSH. An FSH, a negative feedback response for the function to be performed perfectly, is maintained by its FSH-essential subfunctions and its FSH-non-essential subfunctions (FNSs. A function in its FSH or far from its FSH is called a normal or dysfunctional function. A direct PBM may self-adaptatively modulate a dysfunctional function until it is normal so that it can be used to discover the optimum pathways for an FSH to be established. An indirect PBM may self-adaptatively modulate a dysfunctional FNS of a normal function until the FNS is normal, and the normal function is then upgraded so that it can be used to discover the redundant pathways for a normal function to be upgraded.

Isotype-specific inhibition of the phosphatidylinositol-3-kinase pathway in hematologic malignancies

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Castillo JJ

2014-02-01

Full Text Available Jorge J Castillo,1 Meera Iyengar,2 Benjamin Kuritzky,2 Kenneth D Bishop2 1Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, 2Division of Hematology and Oncology, Rhode Island Hospital, Providence, RI, USA Abstract: In the last decade, the advent of biological targeted therapies has revolutionized the management of several types of cancer, especially in the realm of hematologic malignancies. One of these pathways, and the center of this review, is the phosphatidylinositol-3-kinase (PI3K pathway. The PI3K pathway seems to play an important role in the pathogenesis and survival advantage in hematologic malignancies, such as leukemia, lymphoma, and myeloma. The objectives of the present review, hence, are to describe the current knowledge on the PI3K pathway and its isoforms, and to summarize preclinical and clinical studies using PI3K inhibitors, focusing on the advances made in hematologic malignancies. Keywords: phosphatidylinositol-3-kinase pathway, inhibitors, leukemia, lymphoma, myeloma

Treatment and Prognosis of Isolated Local Relapse after Stereotactic Body Radiotherapy for Clinical Stage I Non-Small-Cell Lung Cancer: Importance of Salvage Surgery.

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Hamaji, Masatsugu; Chen, Fengshi; Matsuo, Yukinori; Ueki, Nami; Hiraoka, Masahiro; Date, Hiroshi

2015-11-01

Many efforts have been made to detect local relapse (LR) in the follow-up after stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) although limited data are available on its treatment and prognosis. We aimed to characterize treatment options and clarify long-term outcomes of isolated LR after SBRT for patients with clinical stage I NSCLC. We reviewed our institutional database in search of patients with isolated LR after SBRT for clinical stage I NSCLC at our institution between 1999 and 2013. Patient characteristics were compared with Mann-Whitney U test, χ2 test, or Fisher's exact test as appropriate. Survival outcomes were estimated with Kaplan-Meier method. Potential prognostic factors were investigated using Cox proportional hazard model. Of 308 patients undergoing SBRT for clinical stage I NSCLC, 49 patients were identified to have isolated LR. Twelve patients underwent salvage surgery, none underwent radiotherapy, and eight patients received chemotherapy, whereas 29 patients received best supportive care. No patient characteristic except operability was significantly related with patient selection for LR treatments. Five-year overall survival (OS) rate of the whole cohort was 47.9% from SBRT and 25.7% from LR. Salvage surgery was associated with improved OS after LR (p = 0.014), and 5-year OS for patients undergoing salvage surgery was 79.5% from LR. It was confirmed that our patient selection for salvage surgery for isolated LR was associated with favorable survival outcomes. Operability based on multidisciplinary conferences, rather than measurable patient characteristics, is essential for appropriate patient selection for salvage surgery.

Focal salvage iodine-125 brachytherapy for prostate cancer recurrences after primary radiotherapy: A retrospective study regarding toxicity, biochemical outcome and quality of life

International Nuclear Information System (INIS)

Peters, Max; Maenhout, Metha; Voort van Zyp, Jochem R.N. van der; Moerland, Marinus A.; Moman, Maaike R.; Steuten, Lotte M.G.; Deursen, Marijke J.H. van; Vulpen, Marco van

2014-01-01

Purpose: Whole-gland salvage for recurrent prostate cancer (PCa) shows high failure and toxicity rates. Early and adequate localization of recurrences enables focal salvage, thereby potentially improving functional outcomes, while maintaining cancer control. Materials and methods: Retrospective analysis yielded 20 focal salvage I125 brachytherapy patients for locally recurrent PCa after primary radiotherapy. Tumor was defined by multiparametric MRI and correspondence with transrectal biopsies. Dose data were obtained intra-operatively. The tumor was prescribed ⩾144 Gy. Toxicity was scored by the Common Terminology Criteria for Adverse Events version 4 (CTCAE-4). Biochemical failure (BF) was defined using the Phoenix criteria (PSA-nadir + 2.0 ng/ml). Quality of life (QoL) was measured by SF-36 Health Survey and European Organization of Research and Treatment of Cancer (EORTC) C30+3 and PR25 questionnaires. Results: With a median follow-up of 36 months (range 10–45), six patients experienced BF, of which three had no initial response. Grade 3 genitourinary (GU) toxicity occurred in one patient (a urethral stricture). The five previously potent patients retained erectile function. QoL remained decreased with regard to urinary symptoms. Conclusion: Focal salvage I125 brachytherapy showed one grade 3 GU toxicity in the 20 treated patients. Biochemical response and QoL were acceptable

Smoothened inhibitors in the treatment of advanced basal cell carcinomas.

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Kunstfeld, Rainer

2014-03-01

The Hedgehog pathway has been identified as a key element in the development of many forms of cancer. Smoothened (Smo) inhibitors are known to beneficially interfere with the Hedgehog pathway and are currently under investigation as anticancer drugs for many tumor entities. Reviewed here are the most recent developments in clinical research on Smo inhibitors for the treatment of advanced basal cell carcinoma (BCC). When reviewing the literature of the past 12 months, it is striking to see the rapid evolution of the field. Compounds that have been presented as powerful new drug candidates 12 months ago have now been discontinued, whereas new ones have emerged. Reports on 13 drug candidates have been identified: one marketed, vismodegib, eight currently under development (phase I-II) and four for which clinical investigation for BCC is currently not being pursued. Smo inhibitors are a promising drug class for the treatment of BCC. To date, most candidates are in early stage development and are expected to enter the market in approximately 5-8 years, if successful.

Salvage radical prostatectomy after external radiotherapy for prostate cancer: Indications, morbidity and results. Review from CCAFU prostate section

International Nuclear Information System (INIS)

Paparel, P.; Soulie, M.; Mongiat-Artus, P.; Cornud, F.; Borgogno, C.; Les membres du sous-comite prostate du CCAFU

2010-01-01

Local recurrence after external radiotherapy for prostate cancer occurs in 30 to 50 % and is often diagnosed by a rising PSA. The absence of local control after radiotherapy is a risk factor of metastases and specific mortality. There are several therapeutic options to treat these patients: surveillance, hormonotherapy and salvage therapies (radical prostatectomy, cysto-prostatectomy, brachytherapy, high intensity focused ultrasound [HIFU] and cryotherapy). Hormonotherapy is not a curative treatment and after a couple of years, the disease will progress again. Local salvage therapies are the only treatment to have the potential to cure these patients with the condition of very strict inclusion criteria. Among these therapies, only radical prostatectomy demonstrated his efficacy with a follow-up of 10 years on specific survival and survival without biological progression respectively from 70 to 77 % and from 30 to 43 %. During last decade, morbidity of RP has strongly decreased with a percentage of rectal and ureteral injury at 3 %. Nevertheless, percentage of urinary incontinence remains high from 29 to 50 %. Salvage mini-invasive therapies (cryotherapy, HIFU and cryotherapy) are under constant evolution due to progress of technology. Functional and oncological results are better with last generation devices but need to be evaluated and compared with radical prostatectomy. (authors)

Inhibitors of the proteasome suppress homologous DNA recombination in mammalian cells.

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Murakawa, Yasuhiro; Sonoda, Eiichiro; Barber, Louise J; Zeng, Weihua; Yokomori, Kyoko; Kimura, Hiroshi; Niimi, Atsuko; Lehmann, Alan; Zhao, Guang Yu; Hochegger, Helfrid; Boulton, Simon J; Takeda, Shunichi

2007-09-15

Proteasome inhibitors are novel antitumor agents against multiple myeloma and other malignancies. Despite the increasing clinical application, the molecular basis of their antitumor effect has been poorly understood due to the involvement of the ubiquitin-proteasome pathway in multiple cellular metabolisms. Here, we show that treatment of cells with proteasome inhibitors has no significant effect on nonhomologous end joining but suppresses homologous recombination (HR), which plays a key role in DNA double-strand break (DSB) repair. In this study, we treat human cells with proteasome inhibitors and show that the inhibition of the proteasome reduces the efficiency of HR-dependent repair of an artificial HR substrate. We further show that inhibition of the proteasome interferes with the activation of Rad51, a key factor for HR, although it does not affect the activation of ATM, gammaH2AX, or Mre11. These data show that the proteasome-mediated destruction is required for the promotion of HR at an early step. We suggest that the defect in HR-mediated DNA repair caused by proteasome inhibitors contributes to antitumor effect, as HR plays an essential role in cellular proliferation. Moreover, because HR plays key roles in the repair of DSBs caused by chemotherapeutic agents such as cisplatin and by radiotherapy, proteasome inhibitors may enhance the efficacy of these treatments through the suppression of HR-mediated DNA repair pathways.

Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.

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Cristina Puy

Full Text Available Factor (F XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIα, in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIα, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIα by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin.Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPIα proteolysis was analyzed by western blot. TFPIα activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPIα by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIα by FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma.Our data suggest that SCP is a cofactor for TFPIα inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP.

BRAFV600E Negatively Regulates the AKT Pathway in Melanoma Cell Lines

OpenAIRE

Chen, Brenden; Tardell, Christine; Higgins, Brian; Packman, Kathryn; Boylan, John F.; Niu, Huifeng

2012-01-01

Cross-feedback activation of MAPK and AKT pathways is implicated as a resistance mechanism for cancer therapeutic agents targeting either RAF/MEK or PI3K/AKT/mTOR. It is thus important to have a better understanding of the molecular resistance mechanisms to improve patient survival benefit from these agents. Here we show that BRAFV600E is a negative regulator of the AKT pathway. Expression of BRAFV600E in NIH3T3 cells significantly suppresses MEK inhibitor (RG7167) or mTORC1 inhibitor (rapamy...

The use of expanded microporous polytetrafluoroethylene for limb salvage: a preliminary report.

Science.gov (United States)

Campbell, C D; Brooks, D H; Webster, M W; Bahnson, H T

1976-05-01

Initial laboratory and clinical evaluations of a new prosthetic material, expanded microporous polytetrafluoroethylene (PTFE), for small vessel replacement is promising and encourages further clinical trial. Frequently the autogenous saphenous vein is not available for bypass procedures, and alternative arterial substitutes have not proved reliable for replacement of small vessels. In this study, 15 patients with impending loss of limb and no available saphenous vein underwent revascularization of the lower extremity with expanded microporous PTFE grafts. Thirteen of 15 patients now demonstrate viable extremities with a resulting over-all early patency and limb salvage rate of 87 percent for this series. Follow-up ranges from one to 8 months. Seven patients had diabetes mellitus and eight had atherosclerotic heart disease. Nine grafts crossed the knee joint. In all patients arterial runoff was poor. Six patients had previous femoropopliteal bypasses, five with autogenous veins and one with Dacron velour. Two patients had multiple previous operations that failed, first with autogenous vein and later with fabric grafts. The current limb salvage and patency rate of 87 percent in high-risk patients suggests that expanded PTFE may be the prosthesis of choice when an autogenous vein is not available and possibly an equally good substitute when the venous autograft is available.

Control of the classical and the MBL pathway of complement activation

DEFF Research Database (Denmark)

Petersen, Steen Vang; Thiel, S; Jensen, L

2000-01-01

and the influence of high ionic strength on the complexes indicate that the activation and control of the MBL pathway differ from that of the classical pathway. MBL deficiency is linked to various clinical manifestations such as recurrent infections, severe diarrhoea, and recurrent miscarriage. On the other hand...... incubation at 37 degrees C in physiological buffer, the associated inhibitors as well as MASP-1, MASP-2, and MAp19 dissociated from MBL, whereas only little dissociation of the complex occurred in buffer with high ionic strength (1 M NaCl). The difference in sensitivity to various inhibitors...

Original Article Did salvage ICE chemotherapy improve the outcome in primary resistant/relapsing stage Ill/TV neuroblastoma

International Nuclear Information System (INIS)

Abdel Rahman, M.; Zekri, W.Z.K.; Moussa, E.A.M.; El Debawy, E.; Mostafa, N.E.; Yones, A.; Ezzat, S.; Rayan, A.

2011-01-01

Neuroblastoma is the most common extracranial and deadly solid tumor in children. It accounts for 15% of the deaths from cancer in the pediatric age group. Approximately half of the newly diagnosed children are at h igh risk o f treatment failure. The aim of this study is to evaluate the response rate of salvage chemotherapy by the ICE (Ifosfamide, Carboplatin, and Etoposide) regimen when administered to previously treated primary refractory or progressive high risk neuroblastoma patients. Patients and methods: Sixty-six patients from the National Cancer Institute (NCI), Cairo University and the Children Cancer Hospital Egypt (CCHE) received salvage chemotherapy (ICE) either due to primary resistance in 51/66 (77.2%) or due to disease progression on primary chemotherapy in 15/66 (22.8%). Results: They were 40 males (60.6%) and 26 females (39.4%). Patients' age ranged between 3 months and 12.5 years. The most common tumor site was suprarenal, followed by retroperitoneal mass. Two patients (3%)'died from chemotherapy toxicity during ICE administration. Evaluation of tumor response in the remaining 64 patients showed the following: CR/PR in 24 patients (36.5%), SD in 11 patients (16.6%), and PD in 29 patients (43.9%). Fourteen patients (21.2%) were considered eligible for auto BMT, while 50/64 patients (78.8%) failed this second line (salvage) chemotherapy and had palliative lines of therapy. By the end of the study (May 2010), 47/66 (71.2%) of the patients were still alive, while 19/66 (28.8%) were dead. Two out of 14 patients (14.2%) who underwent HSCT died from post transplantation disease progression, while 12/14 (85.8%) were in CCR. Conclusion: Chemotherapy by ICE for primary resistant or progressive stage III/IV NB seems well tolerated. With a 36.6% response rate, 18% CCR, and 3% treatment mortality rate, it could be considered a good salvage therapy in the category of patients who are condemned for palliation

Escape from Human Immunodeficiency Virus Type 1 (HIV-1 Entry Inhibitors

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Carol D. Weiss

2012-12-01

Full Text Available The human immunodeficiency virus (HIV enters cells through a series of molecular interactions between the HIV envelope protein and cellular receptors, thus providing many opportunities to block infection. Entry inhibitors are currently being used in the clinic, and many more are under development. Unfortunately, as is the case for other classes of antiretroviral drugs that target later steps in the viral life cycle, HIV can become resistant to entry inhibitors. In contrast to inhibitors that block viral enzymes in intracellular compartments, entry inhibitors interfere with the function of the highly variable envelope glycoprotein as it continuously adapts to changing immune pressure and available target cells in the extracellular environment. Consequently, pathways and mechanisms of resistance for entry inhibitors are varied and often involve mutations across the envelope gene. This review provides a broad overview of entry inhibitor resistance mechanisms that inform our understanding of HIV entry and the design of new inhibitors and vaccines.

Re-irradiation of the chest wall for local breast cancer recurrence. Results of salvage brachytherapy with hyperthermia

Energy Technology Data Exchange (ETDEWEB)

Auoragh, A. [University Hospital Erlangen, Department of Radiation Oncology, Erlangen (Germany); Hospital Fuerth, Department of Radiation Oncology, Fuerth (Germany); Strnad, V.; Ott, O.J.; Fietkau, R. [University Hospital Erlangen, Department of Radiation Oncology, Erlangen (Germany); Beckmann, M.W. [University Hospital Erlangen, Department of Gynecology and Obstetrics, Erlangen (Germany)

2016-09-15

Following mastectomy and adjuvant external beam radiation therapy in patients with breast cancer, the incidence of local or locoregional recurrence is approximately 9 % (2-20 %). Alongside the often limited possibilities of surgical treatment, radiation therapy combined with superficial hyperthermia is the most effective local therapy. In the present work, a retrospective analysis of salvage brachytherapy combined with superficial hyperthermia for chest wall recurrences is presented. Between 2004 and 2011, 18 patients with a total of 23 target volumes resulting from chest wall recurrences after previously mastectomy and external beam radiation therapy (median 56 Gy, range 50-68 Gy) were treated with superficial brachytherapy as salvage treatment: 8 patients (44 %) had macroscopic tumor, 3 (17 %) had microscopic tumor (R1), and 7 (39 %) had undergone R0 resection and were treated due to risk factors. A dose of 50 Gy was given (high-dose rate [HDR] and pulsed-dose rate [PDR] procedures). In all, 5 of 23 patients (22 %) received additional concurrent chemotherapy, and in 20 of 23 (87 %) target volumes additional superficial hyperthermia was carried out twice weekly. The 5-year local recurrence-free survival was 56 %, the disease-free survival was 28 %, and a 5-year overall survival was 22 %. Late side effects Common Toxicity Criteria (CTC) grade 3 were reported in 17 % of the patients: 2 of 18 (11 %) had CTC grade 3 fibrosis, and 1 of 18 (6 %) had a chronic wound healing disorder. Re-irradiation as salvage brachytherapy with superficial hyperthermia for chest wall recurrences is a feasible and safe treatment with good local control results and acceptable late side effects. (orig.) [German] Nach einer Mastektomie und adjuvanter Strahlentherapie bei Patientinnen mit Mammakarzinom kommt es bei 9 % (2-20 %) zum lokalen bzw. lokoregionaeren Rezidiv. Neben den oft limitierten operativen Behandlungsmoeglichkeiten ist die Strahlentherapie mit Oberflaechenhyperthermie die

Effectiveness of tipranavir versus darunavir as a salvage therapy in HIV-1 treatment-experienced patients.

Science.gov (United States)

Domínguez-Hermosillo, Juan Carlos; Mata-Marin, José Antonio; Herrera-González, Norma Estela; Chávez-García, Marcelino; Huerta-García, Gloria; Nuñez-Rodríguez, Nohemí; García-Gámez, José Gerardo; Jiménez-Romero, Anai; Gaytán-Martínez, Jesús Enrique

2016-09-30

Although both tipranavir (TPV) and darunavir (DRV) represent important options for the management of patients with multi-protease inhibitor (PI)-resistant human immunodeficiency virus (HIV), currently there are no studies comparing the effectiveness and safety of these two drugs in the Mexican population. The aim of this study was to compare the effectiveness of TPV versus DRV as a salvage therapy in HIV-1 treatment-experienced patients. This was a comparative, prospective, cohort study. Patients with HIV and triple-class drug resistance evaluated at the Hospital de Infectología "La Raza", National Medical Center, were included. All patients had the protease and retrotranscriptase genotype; resistance mutation interpretation was done using the Stanford database. A total of 35 HIV-1 triple-class drug-resistant patients were analyzed. All of them received tenofovir and raltegravir, 22 received darunavir/ritonavir (DRV/r), and 13 received tipranavir/ritonavir (TPV/r) therapies. The median baseline RNA HIV-1 viral load and CD4+ cell count were 4.34 log (interquartile range [IQR], 4.15-4.72) and 267 cells/mm3 (IQR, 177-320) for the DRV/r group, and 4.14 log (IQR, 3.51-4.85) and 445 cells/mm3 (IQR, 252-558) for the TPV/r group. At week 24 of treatment, 91% of patients receiving DRV/r and 100% of patients receiving TPV/r had an RNA HIV-1 viral load HIV-1 patients who were highly experienced in antiretroviral therapy.

Trial Watch: Proteasomal inhibitors for anticancer therapy.

Science.gov (United States)

Obrist, Florine; Manic, Gwenola; Kroemer, Guido; Vitale, Ilio; Galluzzi, Lorenzo

2015-01-01

The so-called "ubiquitin-proteasome system" (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is crucial for the maintenance of intracellular protein homeostasis (both in physiological conditions and in the course of adaptive stress responses), and regulates a wide array of signaling pathways. In line with this notion, defects in the UPS have been associated with aging as well as with several pathological conditions including cardiac, neurodegenerative, and neoplastic disorders. As transformed cells often experience a constant state of stress (as a result of the hyperactivation of oncogenic signaling pathways and/or adverse microenvironmental conditions), their survival and proliferation are highly dependent on the integrity of the UPS. This rationale has driven an intense wave of preclinical and clinical investigation culminating in 2003 with the approval of the proteasomal inhibitor bortezomib by the US Food and Drug Administration for use in multiple myeloma patients. Another proteasomal inhibitor, carfilzomib, is now licensed by international regulatory agencies for use in multiple myeloma patients, and the approved indications for bortezomib have been extended to mantle cell lymphoma. This said, the clinical activity of bortezomib and carfilzomib is often limited by off-target effects, innate/acquired resistance, and the absence of validated predictive biomarkers. Moreover, the antineoplastic activity of proteasome inhibitors against solid tumors is poor. In this Trial Watch we discuss the contribution of the UPS to oncogenesis and tumor progression and summarize the design and/or results of recent clinical studies evaluating the therapeutic profile of proteasome inhibitors in cancer patients.

Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells.

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Yamanegi, Koji; Kawabe, Mutsuki; Futani, Hiroyuki; Nishiura, Hiroshi; Yamada, Naoko; Kato-Kogoe, Nahoko; Kishimoto, Hiromitsu; Yoshiya, Shinichi; Nakasho, Keiji

2015-05-01

The level of vascular endothelial growth inhibitor (VEGI) has been reported to be negatively associated with neovascularization in malignant tumors. The soluble form of VEGI is a potent anti-angiogenic factor due to its effects in inhibiting endothelial cell proliferation. This inhibition is mediated by death receptor 3 (DR3), which contains a death domain in its cytoplasmic tail capable of inducing apoptosis that can be subsequently blocked by decoy receptor 3 (DcR3). We investigated the effects of sodium valproate (VPA) and trichostatin A (TSA), histone deacetylase inhibitors, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Consequently, treatment with VPA and TSA increased the VEGI and DR3 expression levels without inducing DcR3 production in the OS cell lines. In contrast, the effect on the HMVE cells was limited, with no evidence of growth inhibition or an increase in the DR3 and DcR3 expression. However, VPA-induced soluble VEGI in the OS cell culture medium markedly inhibited the vascular tube formation of HMVE cells, while VEGI overexpression resulted in enhanced OS cell death. Taken together, the HDAC inhibitor has anti-angiogenesis and antitumor activities that mediate soluble VEGI/DR3-induced apoptosis via both autocrine and paracrine pathways. This study indicates that the HDAC inhibitor may be exploited as a therapeutic strategy modulating the soluble VEGI/DR3 pathway in osteosarcoma patients.

Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway.

Science.gov (United States)

Dounay, Amy B; Tuttle, Jamison B; Verhoest, Patrick R

2015-11-25

The kynurenine pathway is responsible for the metabolism of more than 95% of dietary tryptophan (TRP) and produces numerous bioactive metabolites. Recent studies have focused on three enzymes in this pathway: indoleamine dioxygenase (IDO1), kynurenine monooxygenase (KMO), and kynurenine aminotransferase II (KAT II). IDO1 inhibitors are currently in clinical trials for the treatment of cancer, and these agents may also have therapeutic utility in neurological disorders, including multiple sclerosis. KMO inhibitors are being investigated as potential treatments for neurodegenerative diseases, such as Huntington's and Alzheimer's diseases. KAT II inhibitors have been proposed in new therapeutic approaches toward psychiatric and cognitive disorders, including cognitive impairment associated with schizophrenia. Numerous medicinal chemistry studies are currently aimed at the design of novel, potent, and selective inhibitors for each of these enzymes. The emerging opportunities and significant challenges associated with pharmacological modulation of these enzymes will be explored in this review.

Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays

DEFF Research Database (Denmark)

Henriksen, Signe Teuber; Liu, J.; Estiu, G.

2010-01-01

histidine biosynthesis pathway, which is predicted to be essential for bacterial biomass productions. Virtual screening of a library of similar to 10(6) compounds identified 49 potential inhibitors of three enzymes of this pathway. Eighteen representative compounds were directly tested on three S. aureus......-and two Escherichia coli strains in standard disk inhibition assays. Thirteen compounds are inhibitors of some or all of the S. aureus strains, while 14 compounds weakly inhibit growth in one or both E. coli strains. The high hit rate obtained from a fast virtual screen demonstrates the applicability...

Post-fire salvage logging reduces carbon sequestration in Mediterranean coniferous forest

OpenAIRE

Serrano-Ortiz, P.; Marañón-Jiménez, S.; Reverter, B.R.; Sánchez-Cañete, E.P.; Castro, J.; Zamora, R.; Kowalski, A.S.

2011-01-01

Post-fire salvage logging is a common silvicultural practice around the world, with the potential to alter the regenerative capacity of an ecosystem and thus its role as a source or a sink of carbon. However, there is no information on the effect of burnt wood management on the net ecosystem carbon balance. Here, we examine for the first time the effect of post-fire burnt wood management on the net ecosystem carbon balance by comparing the carbon exchange of two treatments in a burnt Mediterr...

Effectiveness and Morbidity Associated With Reirradiation in Conservative Salvage Management of Recurrent Soft-Tissue Sarcoma

International Nuclear Information System (INIS)

Indelicato, Daniel J.; Meadows, Kenyon; Gibbs, Charles P.; Morris, Christopher G.; Scarborough, Mark T.; Zlotecki, Robert A.

2009-01-01

Purpose: The management of isolated local recurrence of soft-tissue sarcoma is therapeutically complex, and functional conservative management is preferable to radical or amputative salvage surgery. This study reviews University of Florida experience using conservative resection and reirradiation to manage isolated local recurrences of soft-tissue sarcoma. Methods and Materials: Between 1976 and 2005, a total of 14 patients who underwent primary conservative resection and irradiation developed isolated local recurrence and were managed with salvage conservative resection and reirradiation. Of the patients treated, 3 had tumors of the distal extremity, 8 had tumors of the proximal extremity, and 3 had tumors of the trunk. At the time of recurrence, 64% of tumors were greater than 5 cm and 79% were high grade. In combination with gross total resection, 13 of 14 patients received external beam radiotherapy with or without brachytherapy, and 1 patient was treated with brachytherapy alone. Two patients received chemotherapy. Results: The median follow-up was 30 months, and no living patients were lost during follow-up. From retreatment, the 5-year actuarial overall survival, cause-specific survival, and local control rates were 40%, 40%, and 18% respectively. There was a 50% incidence of serious complication requiring either reoperation or leading to permanent functional impairment. Of the 14 patients, only 1 has remained disease free and without significant complications. No treatment factors, including achieving wide surgical margins or delivering higher radiation dosages, seemed to confer an advantage in local control. Conclusions: Salvage therapy for management of locally recurrent soft-tissue sarcoma is challenging, and the effects of reoperation and reirradiation can be severe

Long-term tolerance and outcomes for dose escalation in early salvage post-prostatectomy radiation therapy

International Nuclear Information System (INIS)

Safdieh, Joseph; Schwartz, David; Weiner, Joseph; Weiss, Jeffrey P.; Madeb, Isaac; Rotman, Marvin; Schreiber, David; Rineer, Justin

2014-01-01

To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting. The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003-2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes. The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%). In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy.

Two thymidine kinases and one multisubstrate deoxyribonucleoside kinase salvage DNA precursors in Arabidopsis thaliana

DEFF Research Database (Denmark)

Clausen, Anders R.; Girandon, Lenart; Ali, Ashfaq

2012-01-01

and AtTK1b catalyze redundant reactions. The results obtained in the present study suggest a crucial role for the salvage of thymidine during early plant development. Sequence data from the present study have been deposited in the EMBL database/GenBank under accession numbers: AT3G07800.1 (AtTK1a), At5G...

Curative salvage liver transplantation in patients with cirrhosis and hepatocellular carcinoma : An intention-to-treat analysis

NARCIS (Netherlands)

de Haas, Robbert J.; Lim, Chetana; Bhangui, Prashant; Salloum, Chady; Compagnon, Philippe; Feray, Cyrille; Calderaro, Julien; Luciani, Alain; Azoulay, Daniel

The salvage liver transplantation (SLT) strategy was conceived for initially resectable and transplantable (R&T) hepatocellular carcinoma (HCC) patients, to try to obviate upfront liver transplantation, with the safety net of SLT in case of postresection recurrence. The SLT strategy is successful or

Calcium Signaling Pathway Is Associated with the Long-Term Clinical Response to Selective Serotonin Reuptake Inhibitors (SSRI and SSRI with Antipsychotics in Patients with Obsessive-Compulsive Disorder.

Directory of Open Access Journals (Sweden)

Hidehiro Umehara

Full Text Available Selective serotonin reuptake inhibitors (SSRI are established first-line pharmacological treatments for obsessive-compulsive disorder (OCD, while antipsychotics are used as an augmentation strategy for SSRI in OCD patients who have either no response or a partial response to SSRI treatment. The goal of the present study was to identify genetic variants and pathways that are associated with the long-term clinical response of OCD patients to SSRI or SSRI with antipsychotics.We first performed a genome-wide association study of 96 OCD patients to examine genetic variants contributing to the response to SSRI or SSRI with antipsychotics. Subsequently, we conducted pathway-based analyses by using Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS to examine the combined effects of genetic variants on the clinical response in OCD.While we failed to detect specific genetic variants associated with clinical responses to SSRI or to SSRI with an atypical antipsychotic at genome-wide levels of significance, we identified 8 enriched pathways for the SSRI treatment response and 5 enriched pathways for the treatment response to SSRI with an antipsychotic medication. Notably, the calcium signaling pathway was identified in both treatment responses.Our results provide novel insight into the molecular mechanisms underlying the variability in clinical response to SSRI and SSRI with antipsychotics in OCD patients.

Residual blood processing by centrifugation, cell salvage or ultrafiltration in cardiac surgery: effects on clinical hemostatic and ex-vivo rheological parameters.

Science.gov (United States)

Vonk, Alexander B; Muntajit, Warayouth; Bhagirath, Pranav; van Barneveld, Laurentius J; Romijn, Johannes W; de Vroege, Roel; Boer, Christa

2012-10-01

The study compared the effects of three blood concentration techniques after cardiopulmonary bypass on clinical hemostatic and ex-vivo rheological parameters. Residual blood of patients undergoing elective cardiac surgery was processed by centrifugation, cell salvage or ultrafiltration, and retransfused (n = 17 per group). Study parameters included blood loss, (free) hemoglobin, hematocrit, fibrinogen and erythrocyte aggregation, deformability and 2,3-diphosphoglycerate content. Patient characteristics were similar between groups. Ultrafiltration was associated with the highest weight of the transfusion bag [649 ± 261 vs. 320 ± 134 g (centrifugation) and 391 ± 158 g (cell salvage); P levels in the transfusion bag. Retransfusion of cell saver blood induced the largest gain in postoperative patient hemoglobin levels when compared to centrifugation and ultrafiltration, and was associated with the largest increase in 2,3-diphosphoglycerate when compared to ultrafiltration (Δ2,3-diphosphoglycerate 1.34 ± 1.92 vs. -0.77 ± 1.56 mmol/l; P = 0.03). Cell salvage is superior with respect to postoperative hemoglobin gain and washout of free hemoglobin when compared to centrifugation or ultrafiltration.

The Leishmania nicotinamidase is essential for NAD+ production and parasite proliferation.

Science.gov (United States)

Gazanion, E; Garcia, D; Silvestre, R; Gérard, C; Guichou, J F; Labesse, G; Seveno, M; Cordeiro-Da-Silva, A; Ouaissi, A; Sereno, D; Vergnes, B

2011-10-01

NAD+ is a central cofactor that plays important roles in cellular metabolism and energy production in all living cells. Genomics-based reconstruction of NAD+ metabolism revealed that Leishmania protozoan parasites are NAD+ auxotrophs. Consequently, these parasites require assimilating NAD+ precursors (nicotinamide, nicotinic acid, nicotinamide riboside) from their host environment to synthesize NAD+ by a salvage pathway. Nicotinamidase is a key enzyme of this salvage pathway that catalyses conversion of nicotinamide (NAm) to nicotinic acid (Na), and that is absent in higher eukaryotes. We present here the biochemical and functional characterizations of the Leishmania infantum nicotinamidase (LiPNC1). Generation of Lipnc1 null mutants leads to a decrease in NAD+ content, associated with a metabolic shutdown-like phenotype with an extensive lag phase of growth. Both phenotypes could be rescued by an add-back construct or by addition of exogenous Na. In addition, Lipnc1 null mutants were unable to establish a sustained infection in a murine experimental model. Altogether, these results illustrate that NAD+ homeostasis is a fundamental component of Leishmania biology and virulence, and that NAm constitutes its main NAD+ source in the mammalian host. The crystal structure of LiPNC1 we solved allows now the design of rational inhibitors against this new promising therapeutic target. © 2011 Blackwell Publishing Ltd.

DMPD: Endogenous anti-inflammatory substances, inter-alpha-inhibitor and bikunin. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 17132099 Endogenous anti-inflammatory substances, inter-alpha-inhibitor and bikunin.... Kobayashi H. Biol Chem. 2006 Dec;387(12):1545-9. (.png) (.svg) (.html) (.csml) Show Endogenous anti-inflam...matory substances, inter-alpha-inhibitor and bikunin. PubmedID 17132099 Title Endogenous anti-inflammatory s

Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors

Energy Technology Data Exchange (ETDEWEB)

Medina, Jesus R.; Becker, Christopher J.; Blackledge, Charles W.; Duquenne, Celine; Feng, Yanhong; Grant, Seth W.; Heerding, Dirk; Li, William H.; Miller, William H.; Romeril, Stuart P.; Scherzer, Daryl; Shu, Arthur; Bobko, Mark A.; Chadderton, Antony R.; Dumble, Melissa; Gardiner, Christine M.; Gilbert, Seth; Liu, Qi; Rabindran, Sridhar K.; Sudakin, Valery; Xiang, Hong; Brady, Pat G.; Campobasso, Nino; Ward, Paris; Axten, Jeffrey M. (GSKPA)

2014-10-02

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

International Nuclear Information System (INIS)

Rancourt, Raymond C.; Veress, Livia A.; Ahmad, Aftab; Hendry-Hofer, Tara B.; Rioux, Jacqueline S.; Garlick, Rhonda B.; White, Carl W.

2013-01-01

Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Methods: Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O 2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin–antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Results: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Conclusions: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. - Highlights: • TFPI administration to rats after mustard inhalation reduces airway cast formation. • Inhibition of thrombin activation is the likely mechanism for limiting casts. • Rats given TFPI had

Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

Energy Technology Data Exchange (ETDEWEB)

Rancourt, Raymond C., E-mail: raymond.rancourt@ucdenver.edu; Veress, Livia A., E-mail: livia.veress@ucdenver.edu; Ahmad, Aftab, E-mail: aftab.ahmad@ucdenver.edu; Hendry-Hofer, Tara B., E-mail: tara.hendry-hofer@ucdenver.edu; Rioux, Jacqueline S., E-mail: jacqueline.rioux@ucdenver.edu; Garlick, Rhonda B., E-mail: rhonda.garlick@ucdenver.edu; White, Carl W., E-mail: carl.w.white@ucdenver.edu

2013-10-01

Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Methods: Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O{sub 2} saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin–antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Results: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Conclusions: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. - Highlights: • TFPI administration to rats after mustard inhalation reduces airway cast formation. • Inhibition of thrombin activation is the likely mechanism for limiting casts. • Rats given TFPI

Robot-assisted Salvage Lymph Node Dissection for Clinically Recurrent Prostate Cancer.

Science.gov (United States)

Montorsi, Francesco; Gandaglia, Giorgio; Fossati, Nicola; Suardi, Nazareno; Pultrone, Cristian; De Groote, Ruben; Dovey, Zach; Umari, Paolo; Gallina, Andrea; Briganti, Alberto; Mottrie, Alexandre

2017-09-01

Salvage lymph node dissection has been described as a feasible treatment for the management of prostate cancer patients with nodal recurrence after primary treatment. To report perioperative, pathologic, and oncologic outcomes of robot-assisted salvage nodal dissection (RASND) in patients with nodal recurrence after radical prostatectomy (RP). We retrospectively evaluated 16 patients affected by nodal recurrence following RP documented by positive positron emission tomography/computed tomography scan. Surgery was performed using DaVinci Si and Xi systems. A pelvic nodal dissection that included lymphatic stations overlying the external, internal, and common iliac vessels, the obturator fossa, and the presacral nodes was performed. In 13 (81.3%) patients a retroperitoneal lymph node dissection that included all nodal tissue located between the aortic bifurcation and the renal vessels was performed. Perioperative outcomes consisted of operative time, blood loss, length of hospital stay, and complications occurred within 30 d after surgery. Biochemical response (BR) was defined as a prostate-specific antigen level <0.2 ng/ml at 40 d after RASND. Median operative time, blood loss, and length of hospital stay were 210min, 250ml, and 3.5 d. The median number of nodes removed was 16.5. Positive lymph nodes were detected in 11 (68.8%) patients. Overall, four (25.0%) and five (31.2%) patients experienced intraoperative and postoperative complications, respectively. Overall, one (6.3%) and four (25.0%) patients had Clavien I and II complications within 30 d after RASND, respectively. Overall, five (33.3%) patients experienced BR after surgery. Our study is limited by the small cohort of patients evaluated and by the follow-up duration. RASND represents a feasible procedure in patients with nodal recurrence after RP and provides acceptable short-term oncologic outcomes, where one out of three patients experience BR immediately after surgery. Long-term data are needed to

Impact of salvage therapy for biochemical recurrence on health-related quality of life following radical prostatectomy

International Nuclear Information System (INIS)

Namiki, Shunichi; Saito, Seiichi; Arai, Yoichi; Tochigi, Tatsuo; Ioritani, Naomasa; Terai, Akito

2007-01-01

The objective of this study was to determine the impact of salvage therapy for prostate-specific antigen (PSA) recurrence on the health-related quality of life (HRQOL) of patients after radical retropubic prostatectomy (RP). Between January 2000 and December 2003, a total of 249 patients who underwent RP were available for 2-year follow up. Of the respondents, 203 men did not show evidence of recurrence (group A), and 46 men received salvage hormonal therapy and/or radiotherapy after RP because of a rise in PSA (group B). The general and prostate-target HRQOL was assessed with the Medical Outcomes Study 36-Item Short Form and University of California, Los Angeles Prostate Cancer Index, respectively. Patients completed the HRQOL instruments by mail at baseline and at 24 months after RP. All of the patients completed both questionnaires. At baseline no significant differences were found between the two groups in any of the HRQOL domains. There were significant improvements in mental health and social function for the patients without biochemical recurrence postoperatively. Repeated measure analysis of variance (ANOVA) revealed significantly different patterns of alteration in several general HRQOL domains among the treatment groups. The urinary and bowel domains were equivalent between the two treatment groups at baseline and 24 months after RP. The patients treated with salvage hormonal therapy tended to show delayed recovery of sexual function. Using a self-administered questionnaire, biochemical recurrence following RP was found to impose a substantial burden in patients with localized prostate cancer. (author)

Adjuvant and Salvage Radiation Therapy After Prostatectomy: American Society for Radiation Oncology/American Urological Association Guidelines

Energy Technology Data Exchange (ETDEWEB)

Valicenti, Richard K., E-mail: Richard.valicenti@ucdmc.ucdavis.edu [Department of Radiation Oncology, University of California, Davis School of Medicine, Davis, California (United States); Thompson, Ian [Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (United States); Albertsen, Peter [Division of Urology, University of Connecticut Health Center, Farmington, Connecticut (United States); Davis, Brian J. [Department of Radiation Oncology, Mayo Medical School, Rochester, Minnesota (United States); Goldenberg, S. Larry [Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia (Canada); Wolf, J. Stuart [Department of Urology, University of Michigan, Ann Arbor, Michigan (United States); Sartor, Oliver [Department of Medicine and Urology, Tulane Medical School, New Orleans, Louisiana (United States); Klein, Eric [Glickman Urological Kidney Institute, Cleveland Clinic, Cleveland, Ohio (United States); Hahn, Carol [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Michalski, Jeff [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Roach, Mack [Department of Radiation Oncology, University of California, San Francisco, San Francisco, California (United States); Faraday, Martha M. [Four Oaks, Inc (United States)

2013-08-01

Purpose: The purpose of this guideline was to provide a clinical framework for the use of radiation therapy after radical prostatectomy as adjuvant or salvage therapy. Methods and Materials: A systematic literature review using PubMed, Embase, and Cochrane database was conducted to identify peer-reviewed publications relevant to the use of radiation therapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed. Results: Guideline statements are provided for patient counseling, use of radiation therapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a restaging evaluation. Conclusions: Physicians should offer adjuvant radiation therapy to patients with adverse pathologic findings at prostatectomy (ie, seminal vesicle invastion, positive surgical margins, extraprostatic extension) and salvage radiation therapy to patients with prostate-specific antigen (PSA) or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiation therapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiation therapy as well as the potential benefits of preventing recurrence. The decision to administer radiation therapy should be made by the patient and the multidisciplinary treatment team with full consideration of the patient's history, values, preferences, quality of life, and functional status. The American Society for Radiation Oncology and American Urological Association websites show this guideline in its entirety, including the full literature review.

Adjuvant and Salvage Radiation Therapy After Prostatectomy: American Society for Radiation Oncology/American Urological Association Guidelines

International Nuclear Information System (INIS)

Valicenti, Richard K.; Thompson, Ian; Albertsen, Peter; Davis, Brian J.; Goldenberg, S. Larry; Wolf, J. Stuart; Sartor, Oliver; Klein, Eric; Hahn, Carol; Michalski, Jeff; Roach, Mack; Faraday, Martha M.

2013-01-01

Purpose: The purpose of this guideline was to provide a clinical framework for the use of radiation therapy after radical prostatectomy as adjuvant or salvage therapy. Methods and Materials: A systematic literature review using PubMed, Embase, and Cochrane database was conducted to identify peer-reviewed publications relevant to the use of radiation therapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed. Results: Guideline statements are provided for patient counseling, use of radiation therapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a restaging evaluation. Conclusions: Physicians should offer adjuvant radiation therapy to patients with adverse pathologic findings at prostatectomy (ie, seminal vesicle invastion, positive surgical margins, extraprostatic extension) and salvage radiation therapy to patients with prostate-specific antigen (PSA) or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiation therapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiation therapy as well as the potential benefits of preventing recurrence. The decision to administer radiation therapy should be made by the patient and the multidisciplinary treatment team with full consideration of the patient's history, values, preferences, quality of life, and functional status. The American Society for Radiation Oncology and American Urological Association websites show this guideline in its entirety, including the full literature review

The outcome of rectal cancer after early salvage TME following TEM compared with primary TME

DEFF Research Database (Denmark)

Levic, K; Bulut, O; Hesselfeldt, P

2012-01-01

difference between two groups of patients in the median number of harvested lymph nodes (P = 0.34), median circumferential resection margin (CRM) (P = 0.99) or the completeness of the mesorectal fascia plane. No local recurrences occurred among the patients with salvage TME, and there were 2 patients (8...

The outcome of rectal cancer after early salvage TME following TEM compared with primary TME

DEFF Research Database (Denmark)

Bulut, O; Levic, K; Hesselfeldt, P

2014-01-01

difference between two groups of patients in the median number of harvested lymph nodes (P = 0.34), median circumferential resection margin (CRM) (P = 0.99) or the completeness of the mesorectal fascia plane. No local recurrences occurred among the patients with salvage TME, and there were 2 patients (8...

Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor.

Science.gov (United States)

Ma, Haikuo; Chen, Qin; Zhu, Fang; Zheng, Jiyue; Li, Jiajun; Zhang, Hongjian; Chen, Shuaishuai; Xing, Haimei; Luo, Lusong; Zheng, Long Tai; He, Sudan; Zhang, Xiaohu

2018-04-10

Embryonic stem cell pathways such as hedgehog and Wnt pathways are central to the tumorigenic properties of cancer stem cells (CSC). Since CSCs are characterized by their ability to self-renew, form differentiated progeny, and develop resistance to anticancer therapies, targeting the Wnt and hedgehog signaling pathways has been an important strategy for cancer treatment. Although molecules targeting either Wnt or hedgehog are common, to the best of our knowledge, those targeting both pathways have not been documented. Here we report a small molecule (compound 1) that inhibits both Wnt (IC 50  = 0.5 nM) and hedgehog (IC 50  = 71 nM) pathways based on reporter gene assays. We further identified that the molecular target of 1 for Wnt pathway inhibition was porcupine (a member of the membrane-bound O-acyltransferase family of proteins), a post-translational modification node in Wnt signaling; while the target of 1 mitigating hedgehog pathway was Smoothened, a key G protein coupled receptor (GPCR) mediating hedgehog signal transduction. Preliminary analysis of structure-activity-relationship identified key functional elements for hedgehog/Wnt inhibition. In in vivo studies, compound 1 demonstrated good oral exposure and bioavailability while eliciting no overt toxicity in mice. An important consideration in cancer treatment is the potential therapeutic escape through compensatory activation of an interconnected pathway when only one signaling pathway is inhibited. Toward this end, compound 1 may not only lead to the development of new therapeutics for Wnt and hedgehog related cancers, but may also help to develop potential cancer treatment which needs to target Wnt and hedgehog signaling simultaneously. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Late urinary morbidity and quality of life after radical prostatectomy and salvage radiotherapy for prostate cancer

DEFF Research Database (Denmark)

Ervandian, Maria; Hoyer, Morten; Petersen, Stine Elleberg

2017-01-01

OBJECTIVE: There is a paucity of knowledge of long-term urinary morbidity in patients treated for prostate cancer (PCa) with radical prostatectomy (RP) and salvage radiotherapy (SRT). Improved long-term survival calls for heightened awareness of late effects from radiotherapy after RP. The purpos...

Aromatic inhibitors derived from ammonia-pretreated lignocellulose hinder bacterial ethanologenesis by activating regulatory circuits controlling inhibitor efflux and detoxification

Directory of Open Access Journals (Sweden)

David H. Keating

2014-08-01

Full Text Available Efficient microbial conversion of lignocellulosic hydrolysates to biofuels is a key barrier to the economically viable deployment of lignocellulosic biofuels. A chief contributor to this barrier is the impact on microbial processes and energy metabolism of lignocellulose-derived inhibitors, including phenolic carboxylates, phenolic amides (for ammonia-pretreated biomass, phenolic aldehydes, and furfurals. To understand the bacterial pathways induced by inhibitors present in ammonia-pretreated biomass hydrolysates, which are less well studied than acid-pretreated biomass hydrolysates, we developed and exploited synthetic mimics of ammonia-pretreated corn stover hydrolysate (ACSH. To determine regulatory responses to the inhibitors normally present in ACSH, we measured transcript and protein levels in an Escherichia coli ethanologen using RNA-seq and quantitative proteomics during fermentation to ethanol of synthetic hydrolysates containing or lacking the inhibitors. Our study identified four major regulators mediating these responses, the MarA/SoxS/Rob network, AaeR, FrmR, and YqhC. Induction of these regulons was correlated with a reduced rate of ethanol production, buildup of pyruvate, depletion of ATP and NAD(PH, and an inhibition of xylose conversion. The aromatic aldehyde inhibitor 5-hydroxymethylfurfural appeared to be reduced to its alcohol form by the ethanologen during fermentation, whereas phenolic acid and amide inhibitors were not metabolized. Together, our findings establish that the major regulatory responses to lignocellulose-derived inhibitors are mediated by transcriptional rather than translational regulators, suggest that energy consumed for inhibitor efflux and detoxification may limit biofuel production, and identify a network of regulators for future synthetic biology efforts.

Identification and characterization of the furfural and 5-(hydroxymethyl)furfural degradation pathways of Cupriavidus basilensis HMF14

OpenAIRE

Koopman, F.; Wierckx, N.; Winde, de, J.H.; Ruijssenaars, H.J.

2010-01-01

The toxic fermentation inhibitors in lignocellulosic hydrolysates pose significant problems for the production of second-generation biofuels and biochemicals. Among these inhibitors, 5-(hydroxymethyl)furfural (HMF) and furfural are specifically notorious. In this study, we describe the complete molecular identification and characterization of the pathway by which Cupriavidus basilensis HMF14 metabolizes HMF and furfural. The identification of this pathway enabled the construction of an HMF an...

Clinical development of galunisertib (LY2157299 monohydrate, a small molecule inhibitor of transforming growth factor-beta signaling pathway

Directory of Open Access Journals (Sweden)

Herbertz S

2015-08-01

Full Text Available Stephan Herbertz,1 J Scott Sawyer,2 Anja J Stauber,2 Ivelina Gueorguieva,3 Kyla E Driscoll,4 Shawn T Estrem,2 Ann L Cleverly,3 Durisala Desaiah,2 Susan C Guba,2 Karim A Benhadji,2 Christopher A Slapak,2 Michael M Lahn21Lilly Deutschland GmbH, Bad Homburg, Germany; 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 3Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK; 4Lilly Research Laboratories, Eli Lilly and Company, New York, NY, USA Abstract: Transforming growth factor-beta (TGF-β signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab

Assessing Subunit Dependency of the Plasmodium Proteasome Using Small Molecule Inhibitors and Active Site Probes

NARCIS (Netherlands)

Li, H.; Linden, W.A. van der; Verdoes, M.; Florea, B.I.; McAllister, F.E.; Govindaswamy, K.; Elias, J.E.; Bhanot, P.; Overkleeft, H.S.; Bogyo, M.

2014-01-01

The ubiquitin-proteasome system (UPS) is a potential pathway for therapeutic intervention for pathogens such as Plasmodium, the causative agent of malaria. However, due to the essential nature of this proteolytic pathway, proteasome inhibitors must avoid inhibition of the host enzyme complex to

Design and synthesis of imidazopyridine analogues as inhibitors of phosphoinositide 3-kinase signaling and angiogenesis.

Science.gov (United States)

Kim, Okseon; Jeong, Yujeong; Lee, Hyunseung; Hong, Sun-Sun; Hong, Sungwoo

2011-04-14

Phosphatidylinositol 3-kinase α (PI3Kα) is an important regulator of intracellular signaling pathways, controlling remarkably diverse arrays of physiological processes. Because the PI3K pathway is frequently up-regulated in human cancers, the inhibition of PI3Kα can be a promising approach to cancer therapy. In this study, we have designed and synthesized a new series of imidazo[1,2-a]pyridine derivatives as PI3Kα inhibitors through the fragment-growing strategy. By varying groups at the 3- and 6-positions of imidazo[1,2-a]pyridines, we studied the structure-activity relationships (SAR) profiles and identified a series of potent PI3Kα inhibitors. Representative derivatives showed good activity in cellular proliferation and apoptosis assays. Moreover, these inhibitors exhibited noteworthy antiangiogenic activity.

Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms

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Temkin, Elizabeth; Torre-Cisneros, Julian; Beovic, Bojana; Benito, Natividad; Giannella, Maddalena; Gilarranz, Raúl; Jeremiah, Cameron; Loeches, Belén; Machuca, Isabel; Jiménez-Martín, María José; Martínez, José Antonio; Mora-Rillo, Marta; Navas, Enrique; Osthoff, Michael; Pozo, Juan Carlos; Ramos Ramos, Juan Carlos; Rodriguez, Marina; Sánchez-García, Miguel; Viale, Pierluigi; Wolff, Michel

2016-01-01

ABSTRACT Ceftazidime-avibactam (CAZ-AVI) is a recently approved β-lactam–β-lactamase inhibitor combination with the potential to treat serious infections caused by carbapenem-resistant organisms. Few patients with such infections were included in the CAZ-AVI clinical trials, and clinical experience is lacking. We present a case series of patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (CRPa) who were treated with CAZ-AVI salvage therapy on a compassionate-use basis. Physicians who had prescribed CAZ-AVI completed a case report form. We used descriptive statistics to summarize patient characteristics and treatment outcomes. We used the Wilcoxon rank sum test and Fisher's exact test to compare patients by treatment outcome. The sample included 36 patients infected with CRE and two with CRPa. The most common infections were intra-abdominal. Physicians categorized 60.5% of patients as having life-threatening infections. All but two patients received other antibiotics before CAZ-AVI, for a median of 13 days. The median duration of CAZ-AVI treatment was 16 days. Twenty-five patients (65.8%) concurrently received other antibiotics to which their pathogen was nonresistant in vitro. Twenty-eight patients (73.7%, 95% confidence interval [CI], 56.9 to 86.6%) experienced clinical and/or microbiological cure. Five patients (20.8%) with documented microbiological cure died, whereas 10 patients (71.4%) with no documented microbiological cure died (P = 0.01). In three-quarters of cases, CAZ-AVI (alone or combined with other antibiotics) cured infections caused by carbapenem-resistant organisms, 95% of which had failed previous therapy. Microbiological cure was associated with improved survival. CAZ-AVI shows promising clinical results for infections for which treatment options are limited. PMID:27895014

Methods Of Using Chemical Libraries To Search For New Kinase Inhibitors

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Gray, Nathanael S. , Schultz, Peter , Wodicka, Lisa , Meijer, Laurent , Lockhart, David J.

2003-06-03

The generation of selective inhibitors for specific protein kinases would provide new tools for analyzing signal transduction pathways and possibly new therapeutic agents. We have invented an approach to the development of selective protein kinase inhibitors based on the unexpected binding mode of 2,6,9-trisubstituted purines to the ATP binding site of human CDK2. The most potent inhibitor, purvalanol B (IC.sub.50 =6 nM), binds with a 30-fold greater affinity than the known CDK2 inhibitor, flavopiridol. The cellular effects of this class of compounds were examined and compared to those of flavopiridol by monitoring changes in mRNA expression levels for all genes in treated cells of Saccharomyces cerevisiae using high-density oligonucleotide probe arrays.

Systemic Chemotherapy as Salvage Treatment for Locally Advanced Rectal Cancer Patients Who Fail to Respond to Standard Neoadjuvant Chemoradiotherapy.

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Sclafani, Francesco; Brown, Gina; Cunningham, David; Rao, Sheela; Tekkis, Paris; Tait, Diana; Morano, Federica; Baratelli, Chiara; Kalaitzaki, Eleftheria; Rasheed, Shahnawaz; Watkins, David; Starling, Naureen; Wotherspoon, Andrew; Chau, Ian

2017-06-01

The potential of chemotherapy as salvage treatment after failure of neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC) has never been explored. We conducted a single-center, retrospective analysis to address this question. Patients with newly diagnosed LARC who were inoperable or candidates for extensive (i.e., beyond total mesorectal excision [TME]) surgery after long-course chemoradiotherapy and who received salvage chemotherapy were included. The primary objective was to estimate the proportion of patients who became suitable for TME after chemotherapy. Forty-five patients were eligible (39 candidates for extensive surgery and 6 unresectable). Previous radiotherapy was given concurrently with chemotherapy in 43 cases (median dose: 54.0 Gy). Oxaliplatin- and irinotecan-based salvage chemotherapy was administered in 40 (88.9%) and 5 (11.1%) cases, respectively. Eight patients (17.8%) became suitable for TME after chemotherapy, 10 (22.2%) ultimately underwent TME with clear margins, and 2 (4.4%) were managed with a watch and wait approach. Additionally, 13 patients had extensive surgery with curative intent. Three-year progression-free survival and 5-year overall survival in the entire population were 30.0% (95% confidence interval [CI]: 15.0-46.0) and 44.0% (95% CI: 26.0-61.0), respectively. For the curatively resected and "watch and wait" patients, these figures were 52.0% (95% CI: 27.0-73.0) and 67.0% (95% CI: 40.0-84.0), respectively. Systemic chemotherapy may be an effective salvage strategy for LARC patients who fail to respond to chemoradiotherapy and are inoperable or candidates for beyond TME surgery. According to our study, one out of five patients may become resectable or be spared from an extensive surgery after systemic chemotherapy. High-quality evidence to inform the optimal management of rectal cancer patients who are inoperable or candidates for beyond total mesorectal excision surgery following standard chemoradiotherapy is

Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals.

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Olajuyigbe, Folasade M; Demitri, Nicola; De Zorzi, Rita; Geremia, Silvano

2016-10-31

Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal. Increased pH in the crystal allows a stereospecific nucleophile attack of an ammonia molecule onto an epoxide carbon, with formation of a new inhibitor containing amino-alcohol functions. The described experiments open a pathway for the development of new stereospecific protease inhibitors from a reactive lead compound.

Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals

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Folasade M. Olajuyigbe

2016-10-01

Full Text Available Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal. Increased pH in the crystal allows a stereospecific nucleophile attack of an ammonia molecule onto an epoxide carbon, with formation of a new inhibitor containing amino-alcohol functions. The described experiments open a pathway for the development of new stereospecific protease inhibitors from a reactive lead compound.

Tissue Factor and Tissue Factor Pathway Inhibitor in the Wound-Healing Process After Neurosurgery.

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Ślusarz, Robert; Głowacka, Mariola; Biercewicz, Monika; Barczykowska, Ewa; Haor, Beata; Rość, Danuta; Gadomska, Grażyna

2016-03-01

The aim of the study was to assess the concentrations of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in the blood of patients with a postoperative wound after neurosurgery. Participants included 20 adult patients who underwent neurosurgery because of degenerative spine changes. The concentration of TF and TFPI in the patients' blood serum was measured 3 times: before surgery, during the first 24 hr after surgery, and between the 5th and 7th days after surgery. The control group comprised 20 healthy volunteers similar to the patient group with respect to gender and age. A statistically significant difference was observed between TF concentration at all three measurement time points in the research group and TF concentration in the control group (p = .018, p = .010, p = .001). A statistically significant difference was found between TFPI concentration at the second time point in the research group and TFPI concentration in the control group (p = .041). No statistically significant within-subject difference was found between TF concentrations before and after surgery. A statistically significant within-subject difference was found between TFPI concentrations within 24 hr after surgery and 5-7 days after surgery (p = .004). High perioperative concentrations of TF indicate not only the presence of thrombophilia but also the importance of TF in the wound-healing process. Perioperative changes in TFPI concentrations are related to its compensatory influence on hemostasis in thrombophilic conditions. © The Author(s) 2015.

Development of antibody-based c-Met inhibitors for targeted cancer therapy

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Lee D

2015-02-01

Full Text Available Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract: Signaling pathways mediated by receptor tyrosine kinases (RTKs and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. Keywords: hepatocyte growth factor, ligands, receptor tyrosine kinase, signaling pathway, therapeutic agent

Clinically Applicable Inhibitors Impacting Genome Stability.

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Prakash, Anu; Garcia-Moreno, Juan F; Brown, James A L; Bourke, Emer

2018-05-13

Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases.

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22.

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Cheng, Fan; Ramos da Silva, Suzane; Huang, I-Chueh; Jung, Jae U; Gao, Shou-Jiang

2018-02-15

The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application. IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV

Glioma-Associated Oncogene Homolog Inhibitors Have the Potential of Suppressing Cancer Stem Cells of Breast Cancer.

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Jeng, Kuo-Shyang; Jeng, Chi-Juei; Sheen, I-Shyan; Wu, Szu-Hua; Lu, Ssu-Jung; Wang, Chih-Hsuan; Chang, Chiung-Fang

2018-05-05

Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells. The therapeutic effects of Gli inhibitors were examined in terms of the cell proliferation, apoptosis, cancer stem cells, cell migration and gene expression. Blockade of the Shh signaling pathway could reduce cell proliferation and migration only in MDA-MB-231 cells. Hh pathway inhibitor-1 (HPI-1) increased the percentages of late apoptotic cells in MDA-MB-231 cells and early apoptotic cells in T2 cells. It reduced Bcl2 expression for cell proliferation and increased Bim expression for apoptosis. In addition, Gli inhibitor HPI-1 decreased significantly the percentages of cancer stem cells in T2 cells. HPI-1 worked more effectively than GANT-58 against breast carcinoma cells. In conclusion, HPI-1 could inhibit cell proliferation, reduce cell invasion and decrease cancer stem cell population in breast cancer cells. To target Gli-1 could be a potential strategy to suppress breast cancer stem cells.

Amputations for extremity soft tissue sarcoma in an era of limb salvage treatment : Local control and survival

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Stevenson, Marc G; Musters, Annelie H; Geertzen, Jan H B; van Leeuwen, Barbara L; Hoekstra, Harald J; Been, Lukas B

2018-01-01

BACKGROUND: Despite multimodality limb salvage treatment (LST) for locally advanced extremity soft tissue sarcoma (ESTS), some patients still need an amputation. Indications for amputation and oncological outcome for these patients are described. METHODS: Between 1996 and 2016, all patients who

Salvage cryotherapy for local recurrence after radiotherapy for prostate cancer.

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Kvorning Ternov, Klara; Krag Jakobsen, Ane; Bratt, Ola; Ahlgren, Göran

2015-04-01

The aim of this study was to present the outcome of patients treated with salvage cryotherapy after radiotherapy for prostate cancer at one institution. Consecutive patients treated between 2007 and 2013 with transperineal cryotherapy for biopsy-verified local recurrence after radiotherapy were investigated. An external reviewer retrieved outcome data retrospectively from medical records. Complications were graded according to the Clavien classification. One patient with less than 1 year of follow-up was excluded from the analysis of side-effects. Thirty patients were included, 29 of whom had a follow-up of at least 1 year. The median follow-up was 2.7 years (range 1-6.5 years). Eleven of the 23 patients without hormonal treatment at the time of cryotherapy reached a prostate-specific antigen (PSA) nadir of less than 0.5 ng/ml. At the end of follow-up five of these 23 patients still had a PSA below 0.5 ng/ml and 10 were free from recurrence according to the Phoenix definition. Clinical recurrence (verified with imaging or biopsies) was detected in 13 patients, six of which were local. One patient died from prostate cancer. Eleven patients had urinary incontinence grade 1-2 and three had grade 3-4, seven had pelvic pain, three had severe but transitory tissue sloughing, three developed a urethral stricture or had prolonged urinary retention, and one developed a urinary fistula 4.5 years after cryotherapy. Salvage cryotherapy should be considered as an alternative to hormonal treatment and surgery for local recurrence after radiotherapy for prostate cancer. The results compare well to those reported from centres with longer experience.

The use of a prosthetic inlay resurfacing as a salvage procedure for a failed cartilage repair.

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Dhollander, Aad Alfons Maria; Almqvist, Karl Fredrik; Moens, Kris; Vandekerckhove, Pieter-Jan; Verdonk, René; Verdonk, Peter; Victor, Jan

2015-08-01

This study was designed to describe the clinical and radiographical outcome of the HemiCAP(®) resurfacing system as a salvage treatment for a failed index cartilage procedure. Fourteen patients were treated consecutively and clinically prospectively followed for a mean period of 26.1 ± 12.8 months. All patients were previously treated for their cartilage lesion. Radiographical data were analysed based on the Kellgren and Lawrence system. The patients involved in this study demonstrated a gradual clinical improvement in time. However, radiographically significant osteoarthritic changes were observed during the follow-up period. The position of the HemiCAP(®) resurfacing system was adequate in all cases, and no signs of loosening were observed during the follow-up period. The HemiCAP(®) resurfacing system is feasible as a salvage treatment for a failed index cartilage procedure and resulted in a gradual clinical improvement. However, the favourable clinical outcome was not confirmed by the radiographical findings. IV.

Sonidegib, a novel smoothened inhibitor for the treatment of advanced basal cell carcinoma

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Doan HQ

2016-09-01

Full Text Available Hung Q Doan,1 Sirunya Silapunt,1 Michael R Migden2,3 1Department of Dermatology, University of Texas, McGovern Medical School, 2Mohs Surgery Unit, Department of Dermatology, 3Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Basal cell carcinoma (BCC is the most common nonmelanoma skin cancer. If left untreated, BCCs can become locally aggressive or even metastasize. Currently available treatments include local destruction, surgery, and radiation. Systemic options for advanced disease are limited. The Hedgehog (Hh pathway is aberrantly activated in a majority of BCCs and in other cancers. Hh pathway inhibitors are targeted agents that inhibit the aberrant activation of the Hh pathway, with smoothened being a targeted component. Sonidegib is a novel smoothened inhibitor that was recently approved by the US Food and Drug Administration. This review focuses on BCC pathogenesis and the clinical efficacy of sonidegib for the treatment of advanced BCC. Keywords: nonmelanoma skin cancer, Hedgehog pathway, clinical trials

Identification and detoxification of glycolaldehyde, an unattended bioethanol fermentation inhibitor.

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Jayakody, Lahiru N; Ferdouse, Jannatul; Hayashi, Nobuyuki; Kitagaki, Hiroshi

2017-03-01

Although there have been approximately 60 chemical compounds identified as potent fermentation inhibitors in lignocellulose hydrolysate, our research group recently discovered glycolaldehyde as a key fermentation inhibitor during second generation biofuel production. Accordingly, we have developed a yeast S. cerevisiae strain exhibiting tolerance to glycolaldehyde. During this glycolaldehyde study, we established novel approaches for rational engineering of inhibitor-tolerant S. cerevisiae strains, including engineering redox cofactors and engineering the SUMOylation pathway. These new technical dimensions provide a novel platform for engineering S. cerevisiae strains to overcome one of the key barriers for industrialization of lignocellulosic ethanol production. As such, this review discusses novel biochemical insight of glycolaldehyde in the context of the biofuel industry.

Molecular Pathways

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Lok, Benjamin H.; Powell, Simon N.

2012-01-01

The Rad52 protein was largely ignored in humans and other mammals when the mouse knockout revealed a largely “no-effect” phenotype. However, using synthetic lethal approaches to investigate context dependent function, new studies have shown that Rad52 plays a key survival role in cells lacking the function of the BRCA1-BRCA2 pathway of homologous recombination. Biochemical studies also showed significant differences between yeast and human Rad52, in which yeast Rad52 can promote strand invasion of RPA-coated single-stranded DNA in the presence of Rad51, but human Rad52 cannot. This results in the paradox of how is human Rad52 providing Rad51 function: presumably there is something missing in the biochemical assays that exists in-vivo, but the nature of this missing factor is currently unknown. Recent studies have suggested that Rad52 provides back-up Rad51 function for all members of the BRCA1-BRCA2 pathway, suggesting that Rad52 may be a target for therapy in BRCA pathway deficient cancers. Screening for ways to inhibit Rad52 would potentially provide a complementary strategy for targeting BRCA-deficient cancers in addition to PARP inhibitors. PMID:23071261

TIMP-1 stimulates proliferation of human aortic smooth muscle cells and Ras effector pathways

International Nuclear Information System (INIS)

Akahane, Takemi; Akahane, Manabu; Shah, Amy; Thorgeirsson, Unnur P.

2004-01-01

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional protein, which is found in most tissues and body fluids. Here, we demonstrated that recombinant TIMP-1 but not the synthetic matrix metalloproteinase inhibitor, GM6001, stimulated proliferation of human aortic smooth muscle cells (AoSMC) in a dose-dependent manner. The mitogenic effect was associated with activation of Ras, increased phosphorylation of ERK, and stimulation of cyclin D1 expression. The phosphatidylinositol 3-kinase (PI3K) signaling pathway was also involved since the PI3K inhibitor, LY294002, abolished the TIMP-1-mediated growth stimulation. These data suggest that TIMP-1 activates Ras, which then turns on the ERK and PI3K signaling pathways to promote cell cycle progression of the AoSMC

The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas

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Pinelopi Argyriou

2012-01-01

Full Text Available Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.

Use of proteasome inhibitors in anticancer therapy

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Sara M. Schmitt

2011-10-01

Full Text Available The importance of the ubiquitin-proteasome pathway to cellular function has brought it to the forefront in the search for new anticancer therapies. The ubiquitin-proteasome pathway has proven promising in targeting various human cancers. The approval of the proteasome inhibitor bortezomib for clinical treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma has validated the ubiquitin-proteasome as a rational target. Bortezomib has shown positive results in clinical use but some toxicity and side effects, as well as resistance, have been observed, indicating that further development of novel, less toxic drugs is necessary. Because less toxic drugs are necessary and drug development can be expensive and time-consuming, using existing drugs that can target the ubiquitin-proteasome pathway in new applications, such as cancer therapy, may be effective in expediting the regulatory process and bringing new drugs to the clinic. Toward this goal, previously approved drugs, such as disulfiram, as well as natural compounds found in common foods, such as green tea polyphenol (--EGCG and the flavonoid apigenin, have been investigated for their possible proteasome inhibitory and cell death inducing abilities. These compounds proved quite promising in preclinical studies and have now moved into clinical trials, with preliminary results that are encouraging. In addition to targeting the catalytic activity of the proteasome pathway, upstream regulators, such as the 19S regulatory cap, as well as E1, E2, and E3, are now being investigated as potential drug targets. This review outlines the development of novel proteasome inhibitors from preclinical to clinical studies, highlighting their abilities to inhibit the tumor proteasome and induce apoptosis in several human cancers.

Accelerated Total Lymphoid Irradiation-containing Salvage Regimen for Patients With Refractory and Relapsed Hodgkin Lymphoma: 20 Years of Experience

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Rimner, Andreas; Lovie, Shona [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Hsu, Meier [Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Chelius, Monica [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Zhang, Zhigang [Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Chau, Karen [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Moskowitz, Alison J.; Matasar, Matthew; Moskowitz, Craig H. [Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Yahalom, Joachim, E-mail: yahalomj@mskcc.org [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States)

2017-04-01

Purpose: We report the long-term results of integrated accelerated involved field radiation therapy (IFRT) followed by total lymphoid irradiation (TLI) as part of the high-dose salvage regimen followed by autologous bone marrow transplantation or autologous stem cell transplantation in patients with relapsed or refractory Hodgkin lymphoma (HL). Methods and Materials: From November 1985 to July 2008, 186 previously unirradiated patients with relapsed or refractory HL underwent salvage therapy on 4 consecutive institutional review board–approved protocols. All patients had biopsy-proven primary refractory or relapsed HL. After standard-dose salvage chemotherapy (SC), accelerated IFRT (18-20 Gy) was given to relapsed or refractory sites, followed by TLI (15-18 Gy) and high-dose chemotherapy. Overall survival (OS) and event-free survival (EFS) were analyzed by Cox analysis and disease-specific survival (DSS) by competing-risk regression. Results: With a median follow-up period of 57 months among survivors, 5- and 10-year OS rates were 68% and 56%, respectively; 5- and 10-year EFS rates were 62% and 56%, respectively; and 5- and 10-year cumulative incidences of HL-related deaths were 21% and 29%, respectively. On multivariate analysis, complete response to SC was independently associated with improved OS and EFS. Primary refractory disease and extranodal disease were independently associated with poor DSS. Eight patients had grade 3 or higher cardiac toxicity, with 3 deaths. Second malignancies developed in 10 patients, 5 of whom died. Conclusions: Accelerated IFRT followed by TLI and high-dose chemotherapy is an effective, feasible, and safe salvage strategy for patients with relapsed or refractory HL with excellent long-term OS, EFS, and DSS. Complete response to SC is the most important prognostic factor.

Vinorelbine-based salvage therapy in HER2-positive metastatic breast cancer patients progressing during trastuzumab-containing regimens: a retrospective study

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Viale Giuseppe

2008-07-01

Full Text Available Abstract Background The vinka-alkaloyd vinorelbine is a potentially valuable treatment in patients with HER2-positive, trastuzumab-resistant advanced breast cancer. We sought to document the clinical activity of vinorelbine-based salvage treatments in this clinical setting. Methods We analyzed a cohort of 424 consecutive women receiving trastuzumab-based therapy for HER2-positive advanced breast cancer. Of these, 299 were identified as progressing during the initial trastuzumab-based treatment, and 77 received vinorelbine-based therapy as first salvage treatment. Central review of pathological specimens revealed that 70 patients had HER2-amplification detected by FISH. For these patients we determined overall response rate (ORR = complete-CR + partial-PR and clinical benefit (CB = CR+PR+ Stable disease lasting at least 6 months, time to progression (TTP and overall survival (OS from the initiation of vinorelbine-based salvage therapy. Results In 60 patients who were evaluable for tumor response, ORR and CB rates were 28% (95% C.I. 18%-41% and 50% (95% C.I. 38%-62%, respectively. Median follow-up from the initiation of salvage therapy was 15 months (range 1–63 months. Median TTP and OS were 7.1 months (95% C.I. 6.6–7.7 months and 21 months (95% C.I. 14.3–27.7 months, respectively. No differences in clinical outcomes were observed according to whether vinorelbine was administered as a single agent or in combination with other cytostatics, or whether trastuzumab was stopped or continued beyond disease progression. Conclusion our findings suggests that vinorelbine-based combinations are active and should be further evaluated in studies conducted in trastuzumab-resistant patients, including those evaluating newer HER2-targeting agents.

Accelerated Total Lymphoid Irradiation-containing Salvage Regimen for Patients With Refractory and Relapsed Hodgkin Lymphoma: 20 Years of Experience

International Nuclear Information System (INIS)

Rimner, Andreas; Lovie, Shona; Hsu, Meier; Chelius, Monica; Zhang, Zhigang; Chau, Karen; Moskowitz, Alison J.; Matasar, Matthew; Moskowitz, Craig H.; Yahalom, Joachim

2017-01-01

Purpose: We report the long-term results of integrated accelerated involved field radiation therapy (IFRT) followed by total lymphoid irradiation (TLI) as part of the high-dose salvage regimen followed by autologous bone marrow transplantation or autologous stem cell transplantation in patients with relapsed or refractory Hodgkin lymphoma (HL). Methods and Materials: From November 1985 to July 2008, 186 previously unirradiated patients with relapsed or refractory HL underwent salvage therapy on 4 consecutive institutional review board–approved protocols. All patients had biopsy-proven primary refractory or relapsed HL. After standard-dose salvage chemotherapy (SC), accelerated IFRT (18-20 Gy) was given to relapsed or refractory sites, followed by TLI (15-18 Gy) and high-dose chemotherapy. Overall survival (OS) and event-free survival (EFS) were analyzed by Cox analysis and disease-specific survival (DSS) by competing-risk regression. Results: With a median follow-up period of 57 months among survivors, 5- and 10-year OS rates were 68% and 56%, respectively; 5- and 10-year EFS rates were 62% and 56%, respectively; and 5- and 10-year cumulative incidences of HL-related deaths were 21% and 29%, respectively. On multivariate analysis, complete response to SC was independently associated with improved OS and EFS. Primary refractory disease and extranodal disease were independently associated with poor DSS. Eight patients had grade 3 or higher cardiac toxicity, with 3 deaths. Second malignancies developed in 10 patients, 5 of whom died. Conclusions: Accelerated IFRT followed by TLI and high-dose chemotherapy is an effective, feasible, and safe salvage strategy for patients with relapsed or refractory HL with excellent long-term OS, EFS, and DSS. Complete response to SC is the most important prognostic factor.

The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Is a Potent Inhibitor of ATM- and DNA-PKCs-Mediated DNA Damage Responses

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Bipasha Mukherjee

2012-01-01

Full Text Available Inhibitors of PI3K/Akt signaling are being actively developed for tumor therapy owing to the frequent mutational activation of the PI3K-Akt-mTORC1 pathway in many cancers, including glioblastomas (GBMs. NVP-BEZ235 is a novel and potent dual PI3K/mTOR inhibitor that is currently in phase 1/2 clinical trials for advanced solid tumors. Here, we show that NVP-BEZ235 also potently inhibits ATM and DNA-PKcs, the two major kinases responding to ionizing radiation (IR-induced DNA double-strand breaks (DSBs. Consequently, NVP-BEZ235 blocks both nonhomologous end joining and homologous recombination DNA repair pathways resulting in significant attenuation of DSB repair. In addition, phosphorylation of ATMtargets and implementation of the G2/M cell cycle checkpoint are also attenuated by this drug. As a result, NVP-BEZ235 confers an extreme degree of radiosensitization and impairs DSB repair in a panel of GBM cell lines irrespective of their Akt activation status. NVP-BEZ235 also significantly impairs DSB repair in a mouse tumor model thereby validating the efficacy of this drug as a DNA repair inhibitor in vivo. Our results, showing that NVP-BEZ235 is a potent and novel inhibitor of ATM and DNA-PKcs, have important implications for the informed and rational design of clinical trials involving this drug and also reveal the potential utility of NVP-BEZ235 as an effective radiosensitizer for GBMs in the clinic.

How do they get here: Does the method of transportation impact salvage for patients with testicular torsion?

Science.gov (United States)

Weiss, D A; Tsarouhas, N; Carr, M C; Kalmus, A; Zderic, S A

2017-06-01

A growing number of patients are arriving at our tertiary care center for evaluation of possible testicular torsion using ambulance or helicopter transport. In many cases the parents arrive by car before the patient arrives. Are these advanced methods of medical transport worth the expense and risk in the case of suspected testicular torsion? We evaluated the total number of patients presenting to our emergency room for suspected testicular torsion to see if the means of transport affected testicular survival. Retrospective. As shown below in the table, the means of transport did not impact on testicular salvage. It is understandable that many patients with scrotal pain seek treatment closer to home because of their pediatrician's recommendation and/or family preference. However once evaluated many patients are transferred because of a lack of urologists willing to evaluate and treat the pediatric patients in community settings or because of a lack of anesthesia support. These patients are often transported by ambulance or helicopter. Our data would suggest that there is no improvement in the testicular salvage rate seen with these more advanced means of medical transportation compared with transfer by private car even when we restrict the analysis to patients traveling from over 40 miles away. We suspect that important time is lost while waiting to make such transfer arrangements. Furthermore transfer by ambulance or helicopter is more expensive and these costs are often passed on to families. Transfer by helicopter is also riskier. While an argument can be made in favor of medical transport over long distances or long driving times, this data suggests that many of these transfers could be accomplished by car with no effect on testicular salvage rates. The rate of testicular salvage was not affected by the means of transport to our tertiary facility. Only 4 patients would have required advanced of medical transport if this were limited to those facilities over 100

Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12.

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Akcora, Büsra Öztürk; Storm, Gert; Bansal, Ruchi

2018-03-01

Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl 4 -induced acute liver injury mouse model. Fibroblasts-conditioned medium studies were performed to assess the Wnt-regulated paracrine factors involved in crosstalk between HSCs-macrophages and HSCs-endothelial cells. Canonical Wnt signaling pathway components were significantly up-regulated in-vitro and in-vivo. In-vitro, ICG-001 significantly inhibited fibrotic parameters, 3D-collagen contractility and wound healing. Conditioned medium induced fibroblasts-mediated macrophage and endothelial cells activation was significantly inhibited by ICG-001. In-vivo, ICG-001 significantly attenuated collagen accumulation and HSC activation. Interestingly, ICG-001 drastically inhibited macrophage infiltration, intrahepatic inflammation and angiogenesis. We further analyzed the paracrine factors involved in Wnt-mediated effects and found CXCL12 was significantly suppressed both in-vitro and in-vivo following Wnt inhibition. Wnt-regulated CXCL12 secretion from activated HSCs potentiated macrophage infiltration and activation, and angiogenesis. Pharmacological inhibition of canonical Wnt signaling pathway via suppression of stromal CXCL12 suggests a potential therapeutic approach targeting activated HSCs in liver fibrosis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Experience of an orthoplastic limb salvage team after the Haiti earthquake: analysis of caseload and early outcomes.

LENUS (Irish Health Repository)

Clover, A James P

2011-06-01

After the devastating earthquake in Haiti on January 12, 2010, a British orthoplastic limb salvage team was mobilized. The team operated in a suburb of Port-au-Prince from January 20, 2010. This analysis gives an overview of the caseload and early outcomes.