Identification of acquired antimicrobial resistance genes

DEFF Research Database (Denmark)

Zankari, Ea; Hasman, Henrik; Cosentino, Salvatore

2012-01-01

ObjectivesIdentification of antimicrobial resistance genes is important for understanding the underlying mechanisms and the epidemiology of antimicrobial resistance. As the costs of whole-genome sequencing (WGS) continue to decline, it becomes increasingly available in routine diagnostic laborato......ObjectivesIdentification of antimicrobial resistance genes is important for understanding the underlying mechanisms and the epidemiology of antimicrobial resistance. As the costs of whole-genome sequencing (WGS) continue to decline, it becomes increasingly available in routine diagnostic...... laboratories and is anticipated to substitute traditional methods for resistance gene identification. Thus, the current challenge is to extract the relevant information from the large amount of generated data.MethodsWe developed a web-based method, ResFinder that uses BLAST for identification of acquired...... antimicrobial resistance genes in whole-genome data. As input, the method can use both pre-assembled, complete or partial genomes, and short sequence reads from four different sequencing platforms. The method was evaluated on 1862 GenBank files containing 1411 different resistance genes, as well as on 23 de...

The role of miRNA regulation in cancer progression and drug resistance

DEFF Research Database (Denmark)

Joshi, Tejal

RNAs in the context of cancer biology, drug resistance and disease progression. The first project described in Chapter 6 addresses the problem of tamoxifen resistance, an anti-estrogen drug that is generally highly effective in the treatment of ER-positive breast cancers. The underlying molecular mechanisms...... to the disease transformation. In summary, this thesis focuses on regulatory role of miRNAs in drug resistance and disease progression. The findings provide hints toward various biologically and perhaps therapeutically relevant gene regulatory events. This thesis demonstrates the right choice of data analysis...... for the acquired resistance to tamoxifen are not very well understood. Therefore, with the aid of miRNA and gene expression profiles for MCF7/S0.5 (tamoxifen sensitive) and three MCF7/S0.5 derived tamoxifen resistant cell lines, we obtained several miRNA-mediated regulatory events in the tamoxifen resistant cell...

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

DEFF Research Database (Denmark)

Jacobsen, Kirstine; Bertran-Alamillo, Jordi; Molina, Miguel Angel

2017-01-01

Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms....... The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance......, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover...

Surveillance for Travel and Domestically Acquired Multidrug-Resistant Human Shigella Infections-Pennsylvania, 2006-2014.

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Li, Yu Lung; Tewari, Deepanker; Yealy, Courtney C; Fardig, David; M'ikanatha, Nkuchia M

2016-01-01

Shigellosis is a leading cause of enteric infections in the United States. We compared antimicrobial resistance in Shigella infections related to overseas travel (travel-associated) and in those acquired domestically by analyzing antimicrobial resistance patterns, geographic distributions, and pulsed-field gel electrophoresis (PFGE) patterns. We tested samples (n = 204) from a collection of isolates recovered from patients in Pennsylvania between 2006 and 2014. Isolates were grouped into travel- and non-travel-associated categories. Eighty-one (79.4%) of the Shigella isolates acquired during international travel were resistant to multiple antibiotics compared to 53 (52.1%) of the infections transmitted in domestic settings. A majority (79.4%) of isolates associated with international travel demonstrated resistance to aminoglycosides and tetracyclines, whereas 47 (46.1%) of the infections acquired domestically were resistant to tetracycline. Almost all isolates (92.2%) transmitted in domestic settings were resistant to aminoglycosides, and 5 isolates from adult male patients were resistant to azithromycin, a drug often used for empiric treatment of severe shigellosis. Twenty (19.6%) isolates associated with illnesses acquired during overseas travel in 4 countries were resistant to quinolones. One S. sonnei PFGE pattern was traced to a multidrug-resistant isolate acquired overseas that had caused a multistate outbreak of shigellosis, suggesting global dissemination of a drug-resistant species. Resistance to certain drugs-for example, tetracycline-increased in both overseas- and domestic-acquired infections during the study period. The prevalence of resistance to macrolides (azithromycin) and third-generation cephalosporins (ceftriaxone) was less than 1%; however, efforts to better monitor changes in drug resistance over time combined with increased antimicrobial stewardship are essential at the local, national, and global levels.

Tracking acquired antibiotic resistance in commensal bacteria of Galápagos land iguanas: no man, no resistance.

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Maria Cristina Thaller

Full Text Available BACKGROUND: Antibiotic resistance, evolving and spreading among bacterial pathogens, poses a serious threat to human health. Antibiotic use for clinical, veterinary and agricultural practices provides the major selective pressure for emergence and persistence of acquired resistance determinants. However, resistance has also been found in the absence of antibiotic exposure, such as in bacteria from wildlife, raising a question about the mechanisms of emergence and persistence of resistant strains under similar conditions, and the implications for resistance control strategies. Since previous studies yielded some contrasting results, possibly due to differences in the ecological landscapes of the studied wildlife, we further investigated this issue in wildlife from a remote setting of the Galapagos archipelago. METHODOLOGY/PRINCIPAL FINDINGS: Screening for acquired antibiotic resistance was carried out in commensal enterobacteria from Conolophus pallidus, the terrestrial iguana of Isla Santa Fe, where: i the abiotic conditions ensure to microbes good survival possibilities in the environment; ii the animal density and their habits favour microbial circulation between individuals; and iii there is no history of antibiotic exposure and the impact of humans and introduced animal species is minimal except for restricted areas. Results revealed that acquired antibiotic resistance traits were exceedingly rare among bacteria, occurring only as non-dominant strains from an area of minor human impact. CONCLUSIONS/SIGNIFICANCE: Where both the exposure to antibiotics and the anthropic pressure are minimal, acquired antibiotic resistance traits are not normally found in bacteria from wildlife, even if the ecological landscape is highly favourable to bacterial circulation among animals. Monitoring antibiotic resistance in wildlife from remote areas could also be a useful tool to evaluate the impact of anthropic pressure.

Tracking acquired antibiotic resistance in commensal bacteria of Galápagos land iguanas: no man, no resistance.

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Thaller, Maria Cristina; Migliore, Luciana; Marquez, Cruz; Tapia, Washington; Cedeño, Virna; Rossolini, Gian Maria; Gentile, Gabriele

2010-02-01

Antibiotic resistance, evolving and spreading among bacterial pathogens, poses a serious threat to human health. Antibiotic use for clinical, veterinary and agricultural practices provides the major selective pressure for emergence and persistence of acquired resistance determinants. However, resistance has also been found in the absence of antibiotic exposure, such as in bacteria from wildlife, raising a question about the mechanisms of emergence and persistence of resistant strains under similar conditions, and the implications for resistance control strategies. Since previous studies yielded some contrasting results, possibly due to differences in the ecological landscapes of the studied wildlife, we further investigated this issue in wildlife from a remote setting of the Galapagos archipelago. Screening for acquired antibiotic resistance was carried out in commensal enterobacteria from Conolophus pallidus, the terrestrial iguana of Isla Santa Fe, where: i) the abiotic conditions ensure to microbes good survival possibilities in the environment; ii) the animal density and their habits favour microbial circulation between individuals; and iii) there is no history of antibiotic exposure and the impact of humans and introduced animal species is minimal except for restricted areas. Results revealed that acquired antibiotic resistance traits were exceedingly rare among bacteria, occurring only as non-dominant strains from an area of minor human impact. Where both the exposure to antibiotics and the anthropic pressure are minimal, acquired antibiotic resistance traits are not normally found in bacteria from wildlife, even if the ecological landscape is highly favourable to bacterial circulation among animals. Monitoring antibiotic resistance in wildlife from remote areas could also be a useful tool to evaluate the impact of anthropic pressure.

Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab

Science.gov (United States)

Brand, Toni M; Dunn, Emily F; Iida, Mari; Myers, Rebecca A; Kostopoulos, Kellie T; Li, Chunrong; Peet, Chimera R

2011-01-01

The epidermal growth factor receptor (EGFR) is an ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical success; however, many tumors remain non-responsive or acquire resistance during therapy. To explore potential molecular mechanisms of acquired resistance to cetuximab we previously established a series of cetuximab-resistant clones by chronically exposing the NCI-H226 NSCLC cell line to escalating doses of cetuximab. Cetuximab-resistant clones exhibited a dramatic increase in the activation of EGFR, HER2 and HER3 receptors as well as increased signaling through the MAP K and AKT pathways. RNAi studies demonstrated dependence of cetuximab-resistant clones on the EGFR signaling network. These findings prompted investigation on whether or not cells with acquired resistance to cetuximab would be sensitive to the EGFR targeted TKI erlotinib. In vitro, erlotinib was able to decrease signaling through the EGFR axis, decrease cellular proliferation and induce apoptosis. To determine if erlotinib could have therapeutic benefit in vivo, we established cetuximab-resistant NCI-H226 mouse xenografts, and subsequently treated them with erlotinib. Mice harboring cetuximab-resistant tumors treated with erlotinib exhibited either a tumor regression or growth delay as compared with vehicle controls. Analysis of the erlotinib treated tumors demonstrated a decrease in cell proliferation and increased rates of apoptosis. The work presented herein suggests that (1) cells with acquired resistance to cetuximab maintain their dependence on EGFR and (2) tumors developing resistance to cetuximab can benefit from subsequent treatment with erlotinib, providing rationale

Yeasts acquire resistance secondary to antifungal drug treatment by adaptive mutagenesis.

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David Quinto-Alemany

Full Text Available Acquisition of resistance secondary to treatment both by microorganisms and by tumor cells is a major public health concern. Several species of bacteria acquire resistance to various antibiotics through stress-induced responses that have an adaptive mutagenesis effect. So far, adaptive mutagenesis in yeast has only been described when the stress is nutrient deprivation. Here, we hypothesized that adaptive mutagenesis in yeast (Saccharomyces cerevisiae and Candida albicans as model organisms would also take place in response to antifungal agents (5-fluorocytosine or flucytosine, 5-FC, and caspofungin, CSP, giving rise to resistance secondary to treatment with these agents. We have developed a clinically relevant model where both yeasts acquire resistance when exposed to these agents. Stressful lifestyle associated mutation (SLAM experiments show that the adaptive mutation frequencies are 20 (S. cerevisiae -5-FC, 600 (C. albicans -5-FC or 1000 (S. cerevisiae--CSP fold higher than the spontaneous mutation frequency, the experimental data for C. albicans -5-FC being in agreement with the clinical data of acquisition of resistance secondary to treatment. The spectrum of mutations in the S. cerevisiae -5-FC model differs between spontaneous and acquired, indicating that the molecular mechanisms that generate them are different. Remarkably, in the acquired mutations, an ectopic intrachromosomal recombination with an 87% homologous gene takes place with a high frequency. In conclusion, we present here a clinically relevant adaptive mutation model that fulfils the conditions reported previously.

Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.

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Thewes, Verena; Simon, Ronald; Schroeter, Petra; Schlotter, Magdalena; Anzeneder, Tobias; Büttner, Reinhard; Benes, Vladimir; Sauter, Guido; Burwinkel, Barbara; Nicholson, Robert I; Sinn, Hans-Peter; Schneeweiss, Andreas; Deuschle, Ulrich; Zapatka, Marc; Heck, Stefanie; Lichter, Peter

2015-02-15

Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer. ©2015 American Association for Cancer Research.

Absence of death receptor translocation into lipid rafts in acquired TRAIL-resistant NSCLC cells.

Science.gov (United States)

Ouyang, Wen; Yang, Chunxu; Zhang, Simin; Liu, Yu; Yang, Bo; Zhang, Junhong; Zhou, Fuxiang; Zhou, Yunfeng; Xie, Conghua

2013-02-01

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a major limitation for its clinical use. The mechanisms of TRAIL resistance have been mostly studied in the context of cell lines that are intrinsically resistant to TRAIL. However, little is known about the molecular alterations that contribute to the development of acquired resistance during treatment with TRAIL. In this study, we established H460R, an isogenic cell line with acquired TRAIL resistance, from the TRAIL‑sensitive human lung cancer cell line H460 to investigate the mechanisms of acquired resistance. The acquired TRAIL‑resistant H460R cells remained sensitive to cisplatin. The mRNA and protein expression levels of death receptor 4 (DR4) and death receptor 5 (DR5) were not altered in either of the TRAIL-treated cell lines. Nevertheless, tests in which the DR4 or DR5 gene was overexpressed or silenced suggest that death receptor expression is necessary but not sufficient for TRAIL‑induced apoptosis. Compared with parental TRAIL-sensitive H460 cells, H460R cells showed a decreased TRAIL-induced translocation of DR4/DR5 into lipid rafts. Further studies showed that nystatin partially prevented lipid raft aggregation and DR4 and DR5 clustering and reduced apoptosis in H460 cells again. Analysis of apoptotic molecules showed that more pro-caspase-8, FADD, caspase-3 and Bid, but less cFLIP in H460 cells than in H460R cells. Our findings suggest that the lack of death receptor redistribution negatively impacts DISC assembly in lipid rafts, which at least partially leads to the development of acquired resistance to TRAIL in H460R cells.

Arabidopsis MAP kinase 4 negatively regulates systemic acquired resistance

DEFF Research Database (Denmark)

Petersen, M.; Brodersen, P.; Naested, H.

2000-01-01

Transposon inactivation of Arabidopsis MAP kinase 4 produced the mpk4 mutant exhibiting constitutive systemic acquired resistance (SAR) including elevated salicylic acid (SA) revels, increased resistance to virulent pathogens, and constitutive pathogenesis-related gene expression shown by Northern...... of NPR1. PDF1.2 and THI2.1 gene induction by jasmonate was blocked in mpk4 expressing NahG, suggesting that MPK4 is required for jasmonic acid-responsive gene expression....

Prevalence of Methicillin Resistant Staphylococcus aureus in pyogenic community and hospital acquired skin and soft tissues infections

International Nuclear Information System (INIS)

Ahmad, M. K.; Asrar, A.

2014-01-01

Objective: To determine the percentage and frequency of Methicillin Resistant Staphylococcus aureus in community and hospital-acquired pyogenic skin and soft tissue infections. Methods: The descriptive cross-sectional study was conducted at the Dermatology Department of Combined Military Hospital, Abbottabad, from June 2009 to March 2010, and comprised 144 community-acquired and 54 hospital-acquired skin and soft tissue infections. Pus swabs from the infected lesions one from each individual were sent to laboratory for culture and sensitivity tests. Methicillin resistance was detected by 1 (mu) g oxacillin disk. Organisms were labelled methicillin-resistant once the inhibition zone for oxocillin was less than 10 mm. Data analysis was done by using SPSS 20. Results: Of the 198 patients in the study, 98(49.5%) were males and 100(50.5%) were females, with an overall mean age of 33.7+-14.8144 years. There were 144(72.72%) community-acquired infections and 54(27.27%) had hospital-acquired infections. Community-acquired Methicillin Resistant Staphylococcus aureus numbered 40(27.8%) and hospital-acquired ones numbered 26(48.1%). Conclusion: Prevalence of Methicillin Resistant Staphylococcus aureus in community and hospital-acquired pyogenic skin and soft tissue infections was high. (author)

Presence and mechanisms of acquired antimicrobial resistance in Belgian Brachyspira hyodysenteriae isolates belonging to different clonal complexes.

Science.gov (United States)

Mahu, M; Pasmans, F; Vranckx, K; De Pauw, N; Vande Maele, L; Vyt, Philip; Vandersmissen, Tamara; Martel, A; Haesebrouck, F; Boyen, F

2017-08-01

Swine dysentery (SD) is an economically important disease for which antimicrobial treatment still occupies an important place to control outbreaks. However, acquired antimicrobial resistance is increasingly observed in Brachyspira hyodysenteriae. In this study, the Minimal Inhibitory Concentrations (MIC) of six antimicrobial compounds for 30 recent Belgian B. hyodysenteriae isolates were determined using a broth microdilution method. In addition, relevant regions of the 16S rRNA, 23S rRNA and the L3 protein encoding genes were sequenced to reveal mutations associated with acquired resistance. Finally, a phylogeny was reconstructed using minimal spanning tree analysis of multi locus sequence typing of the isolates. For lincomycin, doxycycline, tylosin and tylvalosin, at least 70% of the isolates did not belong to the wild-type population and were considered to have acquired resistance. For valnemulin and tiamulin, this was over 50%. In all isolates with acquired resistance to doxycycline, the G1058C mutation was present in their 16S rRNA gene. All isolates showing acquired resistance to lincomycin and both macrolides displayed the A2058T mutation in their 23S rRNA gene. Other mutations in this gene and the N148S mutation in the L3 protein were present in both wild-type isolates and isolates considered to have acquired resistance. Multi locus sequence analysis revealed a previously undescribed clonal complex, with 4 novel sequence types in which the majority of isolates showed acquired resistance to all tested antimicrobial products. In conclusion, acquired antimicrobial resistance is widespread among Belgian B. hyodysenteriae isolates. The emergence of multi-resistant clonal complexes can pose a threat to swine industry. Copyright © 2017 Elsevier B.V. All rights reserved.

Intrinsic, adaptive and acquired antimicrobial resistance in Gram-negative bacteria.

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Arzanlou, Mohsen; Chai, Wern Chern; Venter, Henrietta

2017-02-28

Gram-negative bacteria are responsible for a large proportion of antimicrobial-resistant infections in humans and animals. Among this class of bacteria are also some of the most successful environmental organisms. Part of this success is their adaptability to a variety of different niches, their intrinsic resistance to antimicrobial drugs and their ability to rapidly acquire resistance mechanisms. These mechanisms of resistance are not exclusive and the interplay of several mechanisms causes high levels of resistance. In this review, we explore the molecular mechanisms underlying resistance in Gram-negative organisms and how these different mechanisms enable them to survive many different stress conditions. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

The Genomic Basis of Intrinsic and Acquired Antibiotic Resistance in the Genus Serratia

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Luisa Sandner-Miranda

2018-05-01

Full Text Available Serratia marcescens, a member of the Enterobacteriaceae family, was long thought to be a non-pathogenic bacterium prevalent in environmental habitats. Together with other members of this genus, it has emerged in recent years as an opportunistic nosocomial pathogen causing various types of infections. One important feature of pathogens belonging to this genus is their intrinsic and acquired resistance to a variety of antibiotic families, including β-lactam, aminoglycosides, quinolones and polypeptide antibiotics. The aim of this study was to elucidate which genes participate in the intrinsic and acquired antibiotic resistance of this genus in order to determine the Serratia genus resistome. We performed phylogenomic and comparative genomic analyses using 32 Serratia spp. genomes deposited in the NCBI GenBank from strains isolated from different ecological niches and different lifestyles. S. marcescens strain SmUNAM836, which was previously isolated from a Mexican adult with obstructive pulmonary disease, was included in this study. The results show that most of the antibiotic resistance genes (ARGs were found on the chromosome, and to a lesser degree, on plasmids and transposons acquired through horizontal gene transfer. Four strains contained the gyrA point mutation in codon Ser83 that confers quinolone resistance. Pathogenic and environmental isolates presented a high number of ARGs, especially genes associated with efflux systems. Pathogenic strains, specifically nosocomial strains, presented more acquired resistance genes than environmental isolates. We may conclude that the environment provides a natural reservoir for antibiotic resistance, which has been underestimated in the medical field.

The Genomic Basis of Intrinsic and Acquired Antibiotic Resistance in the Genus Serratia

Science.gov (United States)

Sandner-Miranda, Luisa; Vinuesa, Pablo; Cravioto, Alejandro; Morales-Espinosa, Rosario

2018-01-01

Serratia marcescens, a member of the Enterobacteriaceae family, was long thought to be a non-pathogenic bacterium prevalent in environmental habitats. Together with other members of this genus, it has emerged in recent years as an opportunistic nosocomial pathogen causing various types of infections. One important feature of pathogens belonging to this genus is their intrinsic and acquired resistance to a variety of antibiotic families, including β-lactam, aminoglycosides, quinolones and polypeptide antibiotics. The aim of this study was to elucidate which genes participate in the intrinsic and acquired antibiotic resistance of this genus in order to determine the Serratia genus resistome. We performed phylogenomic and comparative genomic analyses using 32 Serratia spp. genomes deposited in the NCBI GenBank from strains isolated from different ecological niches and different lifestyles. S. marcescens strain SmUNAM836, which was previously isolated from a Mexican adult with obstructive pulmonary disease, was included in this study. The results show that most of the antibiotic resistance genes (ARGs) were found on the chromosome, and to a lesser degree, on plasmids and transposons acquired through horizontal gene transfer. Four strains contained the gyrA point mutation in codon Ser83 that confers quinolone resistance. Pathogenic and environmental isolates presented a high number of ARGs, especially genes associated with efflux systems. Pathogenic strains, specifically nosocomial strains, presented more acquired resistance genes than environmental isolates. We may conclude that the environment provides a natural reservoir for antibiotic resistance, which has been underestimated in the medical field.

Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells.

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Gaspar, Nathalie; Sharp, Swee Y; Pacey, Simon; Jones, Chris; Walton, Michael; Vassal, Gilles; Eccles, Suzanne; Pearson, Andrew; Workman, Paul

2009-03-01

Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), which is currently in phase II/phase III clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma (GB), a primary brain tumor with poor prognosis. GB cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG-resistant GB cell lines were generated. High-resistance levels with resistance indices (RI = resistant line IC(50)/parental line IC(50)) of 20 to 137 were obtained rapidly (2-8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilized. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021, and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NAD(P)H/quinone oxidoreductase 1 (NQO1) expression/activity and 17-AAG IC(50) was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in GB, melanoma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors.

Foliar application of systemic acquired resistance (SAR) inducers for ...

African Journals Online (AJOL)

nbuensanteai

2013-08-14

Aug 14, 2013 ... induced by chitosan and BTH were involved in defense mechanism, reflecting the strong direct positive effect that chitosan ... to control plant diseases based on the systemic acquired resistance ... salicylic acid (SA) as a signal molecule and is associated ... treated plants for SAR relating chemical analyses.

Synthesis of a radioiodinated antiestrogen glucuronide compound (TAM-G)

International Nuclear Information System (INIS)

Fazilet Zumrut Biber Muftuler; Perihan Unak; Cigdem Ichedef; Ilknur Demir

2011-01-01

Tamoxifen [TAM; ([Z]-2-[4-(1,2-diphenyl-1-di-butenyl)-phenoxy]-N,N-dimethylethanamine) has been used as an antiestrogen drug for treatment and prevention of human breast cancer. The aim of this study is conjugation of hydrophilic glucuronic acid to the starting substance TAM and labeling with 131 I using iodogen as oxidizing agent. The reactions are completed in three steps, including enzymatic reaction, with the following sub-steps; preparation of microsomal fraction from rat liver and subsequent purification of UDP-glucuronyl transferase (UDPGT), estimation of protein amount in microsomal samples and glucuronidation reaction. Synthesized glucuronide derivative (TAM-G) was purified using high performance liquid chromatography (HPLC). Mass spectroscopy of cold standard showed that the labeling most probably occurs in ortho position to the aromatic ring containing the ether group of TAM-G as expected. Radiochemical yield of the 131 I labeled TAM-G ([ 131 I]TAM-G) is determined by using Thin Layer Radio Chromatography (TLRC). The radiopharmaceutical potential of [ 131 I]TAM-G is examined by biodistribution studies that is run on normal female Albino Wistar rats. According to biodistribution results 131 I labeled TAM-G may be proposed as a new antiestrogen glucuronide imaging agent for breast and uterus. Electronic supplementary material. The online version of this article (doi:10.1007/s10967-010-0932-7) contains supplementary material, which is available to authorized users. (author)

The changing face of community-acquired methicillin-resistant Staphylococcus aureus

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P Kale

2016-01-01

Full Text Available Methicillin-resistant Staphylococcus aureus (MRSA is an important cause of infection, both in hospitalised patients with significant healthcare exposure and in patients without healthcare risk factors. Community-acquired methicillin-resistant S. aureus (CA-MRSA are known for their rapid community transmission and propensity to cause aggressive skin and soft tissue infections and community-acquired pneumonia. The distinction between the healthcare-associated (HA-MRSA and CA-MRSA is gradually fading owing to the acquisition of multiple virulence factors and genetic elements. The movement of CA-MRSA strains into the nosocomial setting limits the utility of using clinical risk factors alone to designate community or HA status. Identification of unique genetic characteristics and genotyping are valuable tools for MRSA epidemiological studies. Although the optimum pharmacotherapy for CA-MRSA infections has not been determined, many CA-MRSA strains remain broadly susceptible to several non-β-lactam antibacterial agents. This review aimed at illuminating the characteristic features of CA-MRSA, virulence factors, changing clinical settings and molecular epidemiology, insurgence into the hospital settings and therapy with drug resistance.

Acquired resistance to EGFR inhibitors: mechanisms and prevention strategies

International Nuclear Information System (INIS)

Viloria-Petit, Alicia M.; Kerbel, Robert S.

2004-01-01

Potent and specific, or relatively specific, inhibitors of epidermal growth factor receptor (EGFR) signaling, including monoclonal antibodies and small molecular weight compounds, have been successfully developed. Both types of agent have been found to have significant antitumor activity, especially when used in combination with radio- hormone- and chemotherapy in preclinical studies. Because of the potentiation of the conventional drug activity in these combination settings, inhibitors of EGFR signaling have often been referred to as sensitizers for chemotherapy or radiation, as well as drug resistance reversal agents. Phase II clinical trials in head-and-neck as well as lung cancer suggested this concept of chemosensitization might translate into the clinic, but this remains to be definitively proven in randomized, double-blind Phase III trials. Given the extensive preclinical literature on EGFR blocking drugs and the advanced clinical development of such agents, it is surprising that the possibility of development of acquired resistance to the EGFR inhibitors themselves, a common clinical problem with virtually all other currently used anticancer drugs, remains a largely unexplored subject of investigation. Here we summarize some of the possible mechanisms that can result in acquired resistance to EGFR-targeting drugs. Alternative combination therapies to circumvent and delay this problem are suggested

Antibiotic resistance patterns of pediatric community-acquired urinary infections

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Eliana Biondi Medeiros Guidoni

Full Text Available Knowledge about antimicrobial resistance patterns of the etiological agents of urinary tract infections (UTIs is essential for appropriate therapy. Urinary isolates from symptomatic UTI cases attended at Santa Casa University Hospital of São Paulo from August 1986 to December 1989 and August 2004 to December 2005 were identified by conventional methods. Antimicrobial resistance testing was performed by Kirby Bauer's disc diffusion method. Among the 257 children, E. coli was found in 77%. A high prevalence of resistance was observed against ampicillin and TMP/SMX (55% and 51%. The antibiotic resistance rates for E. coli were: nitrofurantoin (6%, nalidixic acid (14%, 1st generation cephalosporin (13%, 3rd generation cephalosporins (5%, aminoglycosides (2%, norfloxacin (9% and ciprofloxacin (4%. We found that E. coli was the predominant bacterial pathogen of community-acquired UTIs. We also detected increasing resistance to TMP/SMX among UTI pathogens in this population.

Pattern of secondary acquired drug resistance to antituberculosis drug in Mumbai, India--1991-1995.

Science.gov (United States)

Chowgule, R V; Deodhar, L

1998-01-01

A retrospective observational study was conducted to find out whether secondary acquired drug resistance to isoniazid and ethambutol is high and to rifamycin and pyrazinamide is low, as is commonly believed in India. There were 2033 patients, whose sputum samples (6099) were reviewed from a specimen registry of the microbiology laboratory for the years 1991 to 1995. Of these, 521 (25.6%) patients [335 males and 186 females; age ranged from 11 to 75 years] had sputum positive culture and sensitivity for acid-fast bacilli (AFB). The drug resistance patterns in our study were: isoniazid (H) 15%, rifamycin (R) 66.8%, pyrazinamide (Z) 72.2%, ethambutol (E) 8.4%, streptomycin (S) 53.6%, cycloserine (C) 39.2% kanamycin (K) 25.1% and ethionamide (Eth) 65.3%. The resistance to streptomycin showed a significant fall over a year while there was a rise in resistance to cycloserine and kanamycin which is significant. The rate of secondary acquired resistance of isoniazid and ethambutol was low, and the rate of secondary acquired resistance to rifamycin and pyrazinamide was high, which is contarary to the common belief regarding these drugs in India. This implies that isoniazid is still a valuable drug in the treatment of multidrug resistance in India.

Functional screen for genes responsible for tamoxifen resistance in human breast cancer cells

NARCIS (Netherlands)

Meijer, Danielle; van Agthoven, Ton; Bosma, Peter T.; Nooter, Kees; Dorssers, Lambert C. J.

2006-01-01

Antiestrogens, such as tamoxifen, are widely used for endocrine treatment of estrogen receptor-positive breast cancer. However, as breast cancer progresses, development of tamoxifen resistance is inevitable. The mechanisms underlying this resistance are not well understood. To identify genes

Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells.

Science.gov (United States)

Li, Guangmin; Guo, Jun; Shen, Ben-Quan; Bumbaca Yadav, Daniela; Sliwkowski, Mark X; Crocker, Lisa M; Lacap, Jennifer A; Lewis Phillips, Gail D

2018-04-25

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and up-regulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1 resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1 resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Copyright ©2018, American Association for Cancer Research.

A mechanism of acquired resistance to complement-mediated lysis by Entamoeba histolytica.

Science.gov (United States)

Gutiérrez-Kobeh, L; Cabrera, N; Pérez-Montfort, R

1997-04-01

Some Entamoeba histolytica strains resist complement-mediated lysis by serum. Susceptible and resistant strains activate the complement system equivalently, but resistant amebas evade killing by membrane attack complexes. Our objective was to determine the mechanism by which trophozoites of E. histolytica resist lysis by human serum. Amebas were made resistant to lysis by incubation with increasing concentrations of normal human serum. The possibility that resistant cells ingest membrane attack complexes was explored by subcellular fractionation of susceptible and resistant trophozoites treated with sublytic concentrations of human serum containing radiolabeled C9. In both cases, most of the label was in the fractions containing plasma membrane. The susceptible strain consistently showed more label associated with these fractions than the resistant strain. Thus, the possibility that the membrane attack complexes were released to the medium was explored. Both resistant and susceptible trophozoites release to the medium similar amounts of material excluded by Sepharose CL-2B in the presence or absence of normal human serum. Labeled C9 elutes together with the main bulk of proteins from the medium: this indicates that it is not in vesicles or high molecular weight aggregates. Coincubation of susceptible amebas with lysates of resistant trophozoites confers resistance to susceptible cells within 30 min. Resistance to lysis by serum can also be acquired by susceptible amebas after coincubation with lysates from human erythrocytes or after feeding them with whole human red blood cells. Resistant but not susceptible trophozoites show intense immunofluorescent staining on their surface with anti-human erythrocytic membrane antibody. These results suggest that amebas acquire resistance to lysis by serum by incorporating into their membranes complement regulatory proteins.

Bacterial viruses enable their host to acquire antibiotic resistance genes from neighbouring cells

DEFF Research Database (Denmark)

Haaber, Jakob Krause; Leisner, Jørgen; Cohn, Marianne Thorup

2016-01-01

Prophages are quiescent viruses located in the chromosomes of bacteria. In the human pathogen, Staphylococcus aureus, prophages are omnipresent and are believed to be responsible for the spread of some antibiotic resistance genes. Here we demonstrate that release of phages from a subpopulation of S....... aureus cells enables the intact, prophage-containing population to acquire beneficial genes from competing, phage-susceptible strains present in the same environment. Phage infection kills competitor cells and bits of their DNA are occasionally captured in viral transducing particles. Return...... of such particles to the prophage-containing population can drive the transfer of genes encoding potentially useful traits such as antibiotic resistance. This process, which can be viewed as ‘auto-transduction’, allows S. aureus to efficiently acquire antibiotic resistance both in vitro and in an in vivo virulence...

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

DEFF Research Database (Denmark)

Jacobsen, Kirstine; Bertran-Alamillo, Jordi; Molina, Miguel Angel

2017-01-01

Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms....

Antiestrogenic constituents of the Thai medicinal plants Capparis flavicans and Vitex glabrata.

Science.gov (United States)

Luecha, Prathan; Umehara, Kaoru; Miyase, Toshio; Noguchi, Hiroshi

2009-11-01

Antiestrogenic compounds were investigated from Thai indigenous plants for galactogogues since estrogen is reported to suppress lactation in breastfeeding women. The aerial parts of the Thai medicinal plant Capparis flavicans, which has traditionally been used to promote lactation, gave the new compound capparoside A (1), along with 28 known compounds. The leaves of Vitex glabrata belong to the same genus as the chaste tree (Vitex agnus-castus), which is used traditionally to support lactation, and afforded the new compounds khainaoside A (14), khainaoside B (15), and khainaoside C (16), together with six known compounds. The isolates were tested for their biological activity using the estrogen-responsive human breast cancer cell lines MCF-7 and T47D. Syringaresinol (3) and principin (6), from C. flavicans, and khainaoside A (14) showed the most potent inhibitory effects on estrogen-enhanced cell proliferation among all compounds isolated. These results suggest that the lactation-promoting properties of C. flavicans might be related to the inhibitory effect on excess estrogen of women who experience insufficient breastfeeding and highlight the possibility of using V. glabrata leaves for their antiestrogenic properties.

Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas.

Science.gov (United States)

Yin, Jinlong; Jung, Ji-Eun; Choi, Sun Il; Kim, Sung Soo; Oh, Young Taek; Kim, Tae-Hoon; Choi, Eunji; Lee, Sun Joo; Kim, Hana; Kim, Eun Ok; Lee, Yu Sun; Chang, Hee Jin; Park, Joo Yong; Kim, Yeejeong; Yun, Tak; Heo, Kyun; Kim, Youn-Jae; Kim, Hyunggee; Kim, Yun-Hee; Park, Jong Bae; Choi, Sung Weon

2018-02-01

Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth in vivo. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC. Copyright © 2017 Elsevier B.V. All rights reserved.

P-glycoprotein confers acquired resistance to 17-DMAG in lung cancers with an ALK rearrangement

International Nuclear Information System (INIS)

Kim, Hee Joung; Lee, Kye Young; Kim, Young Whan; Choi, Yun Jung; Lee, Jung-Eun; Choi, Chang Min; Baek, In-Jeoung; Rho, Jin Kyung; Lee, Jae Cheol

2015-01-01

Because anaplastic lymphoma kinase (ALK) is dependent on Hsp90 for protein stability, Hsp90 inhibitors are effective in controlling growth of lung cancer cells with ALK rearrangement. We investigated the mechanism of acquired resistance to 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin analogue Hsp90 inhibitor, in H3122 and H2228 non-small cell lung cancer cell lines with ALK rearrangement. Resistant cell lines (H3122/DR-1, H3122/DR-2 and H2228/DR) were established by repeated exposure to increasing concentrations of 17-DMAG. Mechanisms for resistance by either NAD(P)H/quinone oxidoreductase 1 (NQO1), previously known as a factor related to 17-DMAG resistance, or P-glycoprotein (P-gp; ABCB1/MDR1) were queried using RT-PCR, western blot analysis, chemical inhibitors, the MTT cell proliferation/survival assay, and cellular efflux of rhodamine 123. The resistant cells showed no cross-resistance to AUY922 or ALK inhibitors, suggesting that ALK dependency persists in cells with acquired resistance to 17-DMAG. Although expression of NQO1 was decreased in H3122/DR-1 and H3122/DR-2, NQO1 inhibition by dicumarol did not affect the response of parental cells (H2228 and H3122) to 17-DMAG. Interestingly, all resistant cells showed the induction of P-gp at the protein and RNA levels, which was associated with an increased efflux of the P-gp substrate rhodamine 123 (Rho123). Transfection with siRNA directed against P-gp or treatment with verapamil, an inhibitor of P-gp, restored the sensitivity to the drug in all cells with acquired resistance to 17-DMAG. Furthermore, we also observed that the growth-inhibitory effect of 17-DMAG was decreased in A549/PR and H460/PR cells generated to over-express P-gp by long-term exposure to paclitaxel, and these cells recovered their sensitivity to 17-DMAG through the inhibition of P-gp. P-gp over-expression is a possible mechanism of acquired resistance to 17-DMAG in cells with ALK rearrangement. The online

Effect of the antiestrogen ethamoxytriphetol (MER-25) on placental low density lipoprotein uptake and degradation in baboons

International Nuclear Information System (INIS)

Henson, M.C.; Babischkin, J.S.; Pepe, G.J.; Albrecht, E.D.

1988-01-01

The present study determined if the decline in placental progesterone (P4) production that results from administration of the antiestrogen ethamoxytriphetol (MER-25) to pregnant baboons results from a change in placental low density lipoprotein (LDL) uptake and/or degradation. Pregnant baboons (Papio anubis) were untreated (n = 10) or received MER-25 (25 mg/kg BW, orally; n = 10) daily on days 140-170 of gestation (term, 184 days). Placentas were removed by cesarean section on day 170 of gestation, and villous tissue was dispersed with 0.1% collagenase at 37 C for 40 min. Placental cells (10(6)) were incubated in medium 199 (pH 7.2) for 12 h at 37 C with increasing amounts (5-100 micrograms) of [125I]LDL, with or without a 100-fold excess of unlabeled baboon LDL. Mean (+/- SE) peripheral serum P4 concentrations on days 140-170 of gestation were 51% lower (P less than 0.01) in MER-25-treated (5.7 +/- 0.3 ng/ml) than in untreated (11.6 +/- 0.5 ng/ml) baboons. The uptake of LDL was 56% lower (P less than 0.01) in placental cells from antiestrogen-treated (6.3 +/- 1.6 ng/micrograms cell protein) than in those from untreated (14.4 +/- 1.9 ng/micrograms cell protein) baboons. The dissociation constants for placental LDL uptake, as assessed by Scatchard analysis, however, were similar in untreated (0.80 microgram/ml) and MER-25-treated (0.76 microgram/ml) animals. The amount of [125I]LDL concomitantly degraded by cells from baboons that received MER-25 was 54% of that degraded by cells from untreated controls. The relative decline in LDL degradation by cells of antiestrogen-treated baboons was proportionate to the decline in overall LDL uptake. The results indicate, therefore, that antiestrogen treatment decreased the amount of placental LDL uptake, but did not change the affinity for the lipoprotein

Effect of the antiestrogen ethamoxytriphetol (MER-25) on placental low density lipoprotein uptake and degradation in baboons

Energy Technology Data Exchange (ETDEWEB)

Henson, M.C.; Babischkin, J.S.; Pepe, G.J.; Albrecht, E.D.

1988-05-01

The present study determined if the decline in placental progesterone (P4) production that results from administration of the antiestrogen ethamoxytriphetol (MER-25) to pregnant baboons results from a change in placental low density lipoprotein (LDL) uptake and/or degradation. Pregnant baboons (Papio anubis) were untreated (n = 10) or received MER-25 (25 mg/kg BW, orally; n = 10) daily on days 140-170 of gestation (term, 184 days). Placentas were removed by cesarean section on day 170 of gestation, and villous tissue was dispersed with 0.1% collagenase at 37 C for 40 min. Placental cells (10(6)) were incubated in medium 199 (pH 7.2) for 12 h at 37 C with increasing amounts (5-100 micrograms) of (125I)LDL, with or without a 100-fold excess of unlabeled baboon LDL. Mean (+/- SE) peripheral serum P4 concentrations on days 140-170 of gestation were 51% lower (P less than 0.01) in MER-25-treated (5.7 +/- 0.3 ng/ml) than in untreated (11.6 +/- 0.5 ng/ml) baboons. The uptake of LDL was 56% lower (P less than 0.01) in placental cells from antiestrogen-treated (6.3 +/- 1.6 ng/micrograms cell protein) than in those from untreated (14.4 +/- 1.9 ng/micrograms cell protein) baboons. The dissociation constants for placental LDL uptake, as assessed by Scatchard analysis, however, were similar in untreated (0.80 microgram/ml) and MER-25-treated (0.76 microgram/ml) animals. The amount of (125I)LDL concomitantly degraded by cells from baboons that received MER-25 was 54% of that degraded by cells from untreated controls. The relative decline in LDL degradation by cells of antiestrogen-treated baboons was proportionate to the decline in overall LDL uptake. The results indicate, therefore, that antiestrogen treatment decreased the amount of placental LDL uptake, but did not change the affinity for the lipoprotein.

Radiation-resistant acquired immunity of vaccinated mice to Schistosoma mansoni

International Nuclear Information System (INIS)

Aitken, R.; Coulson, P.S.; Dixon, B.; Wilson, R.A.

1987-01-01

Vaccination of mice with attenuated cercariae of Schistosoma mansoni induces specific acquired resistance to challenge infection. This resistance is immunologically-mediated, possibly via a delayed-type hypersensitivity. Studies of parasite migration have shown that the protective mechanism operates most effectively in the lungs of vaccinated mice. We have probed the mechanism by exposing mice to 500 rads of gamma radiation before challenge infection. Our results show that the effector mechanism operative against challenge larvae is resistant to radiation. In contrast, classical immune responses are markedly suppressed by the same treatment. While leukocyte populations in the blood fall dramatically after irradiation, numbers of cells recoverable by bronchoalveolar lavage are unaffected. We suggest that vaccination with attenuated cercariae establishes populations of sensitized cells in the lungs which trigger the mechanism of resistance when challenge schistosomula migrate through pulmonary capillary beds. Although the cells may be partially disabled by irradiation, they remain responsive to worm antigens and thereby capable of initiating the elimination mechanism. This hypothesis would explain the radiation resistance of vaccine-induced immunity to S. mansoni

Long-term persistence of acquired resistance to 5-fluorouracil in the colon cancer cell line SW620

Energy Technology Data Exchange (ETDEWEB)

Tentes, I.K., E-mail: itentes@med.duth.gr [Department of Biochemistry, Medical School, Democritus University of Thrace, 6th km Alexandroupolis-Komotini (Dragana), 68100 Alexandroupolis (Greece); Schmidt, W.M. [Center for Anatomy and Cell Biology, Waehringer Strasse 13, 1090 Vienna (Austria); Krupitza, G. [Institute of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria); Steger, G.G.; Mikulits, W. [Department of Medicine I, Medical University of Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria); Kortsaris, A. [Department of Biochemistry, Medical School, Democritus University of Thrace, 6th km Alexandroupolis-Komotini (Dragana), 68100 Alexandroupolis (Greece); Mader, R.M. [Department of Medicine I, Medical University of Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria)

2010-11-15

Treatment resistance to antineoplastic drugs represents a major clinical problem. Here, we investigated the long-term stability of acquired resistance to 5-fluorouracil (FU) in an in vitro colon cancer model, using four sub-clones characterised by increasing FU-resistance derived from the cell line SW620. The resistance phenotype was preserved after FU withdrawal for 15 weeks ({approx} 100 cell divisions) independent of the established level of drug resistance and of epigenetic silencing. Remarkably, resistant clones tolerated serum deprivation, adopted a CD133{sup +} CD44{sup -} phenotype, and further exhibited loss of membrane-bound E-cadherin together with predominant nuclear {beta}-catenin localisation. Thus, we provide evidence for a long-term memory of acquired drug resistance, driven by multiple cellular strategies (epithelial-mesenchymal transition and selective propagation of CD133{sup +} cells). These resistance phenomena, in turn, accentuate the malignant phenotype.

Toxic shock syndrome due to community-acquired methicillin-resistant Staphylococcus aureus infection: Two case reports and a literature review in Japan.

Science.gov (United States)

Sada, Ryuichi; Fukuda, Saori; Ishimaru, Hiroyasu

2017-01-01

Community-acquired methicillin-resistant Staphylococcus aureus has been spreading worldwide, including in Japan. However, few cases of toxic shock syndrome caused by Community-acquired methicillin-resistant Staphylococcus aureus have been reported in Japan. We report 2 cases, in middle-aged women, of toxic shock syndrome due to Community-acquired methicillin-resistant Staphylococcus aureus via a vaginal portal of entry. The first patient had used a tampon and the second patient had vaginitis due to a cleft narrowing associated with vulvar lichen sclerosus. Both patients were admitted to our hospital with septic shock and severe acute kidney injury and subsequently recovered with appropriate antibiotic treatment. In our review of the literature, 8 cases of toxic shock syndrome caused by Community-acquired methicillin-resistant Staphylococcus aureus were reported in Japan. In these 8 cases, the main portals of entry were the skin and respiratory tract; however, the portal of entry of Community-acquired methicillin-resistant Staphylococcus aureus from a vaginal lesion has not been reported in Japan previously.

Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

Science.gov (United States)

Suda, Kenichi; Mizuuchi, Hiroshi; Maehara, Yoshihiko; Mitsudomi, Tetsuya

2012-12-01

Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.

Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer

International Nuclear Information System (INIS)

Ji, Wonjun; Lee, Dae Ho; Lee, Jae Cheol; Choi, Chang-Min; Rho, Jin Kyung; Jang, Se Jin; Park, Young Soo; Chun, Sung-Min; Kim, Woo Sung; Lee, Jung-Shin; Kim, Sang-We

2013-01-01

Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations. Among patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry. Twenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis. The mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary

Community-acquired methicillin-resistant Staphylococcus aureus: community transmission, pathogenesis, and drug resistance.

Science.gov (United States)

Yamamoto, Tatsuo; Nishiyama, Akihito; Takano, Tomomi; Yabe, Shizuka; Higuchi, Wataru; Razvina, Olga; Shi, Da

2010-08-01

Methicillin-resistant Staphylococcus aureus (MRSA) is able to persist not only in hospitals (with a high level of antimicrobial agent use) but also in the community (with a low level of antimicrobial agent use). The former is called hospital-acquired MRSA (HA-MRSA) and the latter community-acquired MRSA (CA-MRSA). It is believed MRSA clones are generated from S. aureus through insertion of the staphylococcal cassette chromosome mec (SCCmec), and outbreaks occur as they spread. Several worldwide and regional clones have been identified, and their epidemiological, clinical, and genetic characteristics have been described. CA-MRSA is likely able to survive in the community because of suitable SCCmec types (type IV or V), a clone-specific colonization/infection nature, toxin profiles (including Pantone-Valentine leucocidin, PVL), and narrow drug resistance patterns. CA-MRSA infections are generally seen in healthy children or young athletes, with unexpected cases of diseases, and also in elderly inpatients, occasionally surprising clinicians used to HA-MRSA infections. CA-MRSA spreads within families and close-contact groups or even through public transport, demonstrating transmission cores. Re-infection (including multifocal infection) frequently occurs, if the cores are not sought out and properly eradicated. Recently, attention has been given to CA-MRSA (USA300), which originated in the US, and is growing as HA-MRSA and also as a worldwide clone. CA-MRSA infection in influenza season has increasingly been noted as well. MRSA is also found in farm and companion animals, and has occasionally transferred to humans. As such, the epidemiological, clinical, and genetic behavior of CA-MRSA, a growing threat, is focused on in this study.

Toxic shock syndrome due to community-acquired methicillin-resistant Staphylococcus aureus infection: Two case reports and a literature review in Japan

OpenAIRE

Sada, Ryuichi; Fukuda, Saori; Ishimaru, Hiroyasu

2017-01-01

Community-acquired methicillin-resistant Staphylococcus aureus has been spreading worldwide, including in Japan. However, few cases of toxic shock syndrome caused by Community-acquired methicillin-resistant Staphylococcus aureus have been reported in Japan. We report 2 cases, in middle-aged women, of toxic shock syndrome due to Community-acquired methicillin-resistant Staphylococcus aureus via a vaginal portal of entry. The first patient had used a tampon and the second patient had vaginitis ...

Prevalence of methicillin-resistant Staphylococcus aureus (MRSA in community-acquired primary pyoderma

Directory of Open Access Journals (Sweden)

Patil Rahul

2006-01-01

Full Text Available Background: Although prevalence of MRSA strains is reported to be increasing, there are no studies of their prevalence in community-acquired primary pyodermas in western India. Aims: This study aimed at determining the prevalence of MRSA infection in community-acquired primary pyodermas. Methods: Open, prospective survey carried out in a tertiary care hospital in Mumbai. Materials and Methods: Eighty-six patients with primary pyoderma, visiting the dermatology outpatient, were studied clinically and microbiologically. Sensitivity testing was done for vancomycin, sisomycin, gentamicin, framycetin, erythromycin, methicillin, cefazolin, cefuroxime, penicillin G and ciprofloxacin. Phage typing was done for MRSA positive strains. Results : The culture positivity rate was 83.7%. Staphylococcus aureus was isolated in all cases except two. Barring one, all strains of Staphylococcus were sensitive to methicillin. Conclusions: Methicillin resistance is uncommon in community-acquired primary pyodermas in Mumbai. Treatment with antibacterials active against MRSA is probably unwarranted for community-acquired primary pyodermas.

Next-generation systemic acquired resistance.

Science.gov (United States)

Luna, Estrella; Bruce, Toby J A; Roberts, Michael R; Flors, Victor; Ton, Jurriaan

2012-02-01

Systemic acquired resistance (SAR) is a plant immune response to pathogen attack. Recent evidence suggests that plant immunity involves regulation by chromatin remodeling and DNA methylation. We investigated whether SAR can be inherited epigenetically following disease pressure by Pseudomonas syringae pv tomato DC3000 (PstDC3000). Compared to progeny from control-treated Arabidopsis (Arabidopsis thaliana; C(1)), progeny from PstDC3000-inoculated Arabidopsis (P(1)) were primed to activate salicylic acid (SA)-inducible defense genes and were more resistant to the (hemi)biotrophic pathogens Hyaloperonospora arabidopsidis and PstDC3000. This transgenerational SAR was sustained over one stress-free generation, indicating an epigenetic basis of the phenomenon. Furthermore, P(1) progeny displayed reduced responsiveness of jasmonic acid (JA)-inducible genes and enhanced susceptibility to the necrotrophic fungus Alternaria brassicicola. This shift in SA- and JA-dependent gene responsiveness was not associated with changes in corresponding hormone levels. Instead, chromatin immunoprecipitation analyses revealed that SA-inducible promoters of PATHOGENESIS-RELATED GENE1, WRKY6, and WRKY53 in P(1) plants are enriched with acetylated histone H3 at lysine 9, a chromatin mark associated with a permissive state of transcription. Conversely, the JA-inducible promoter of PLANT DEFENSIN1.2 showed increased H3 triple methylation at lysine 27, a mark related to repressed gene transcription. P(1) progeny from the defense regulatory mutant non expressor of PR1 (npr1)-1 failed to develop transgenerational defense phenotypes, demonstrating a critical role for NPR1 in expression of transgenerational SAR. Furthermore, the drm1drm2cmt3 mutant that is affected in non-CpG DNA methylation mimicked the transgenerational SAR phenotype. Since PstDC3000 induces DNA hypomethylation in Arabidopsis, our results suggest that transgenerational SAR is transmitted by hypomethylated genes that direct priming

Prevalence and resistance pattern of Moraxella catarrhalis in community-acquired lower respiratory tract infections

Directory of Open Access Journals (Sweden)

Shaikh SBU

2015-07-01

Full Text Available Safia Bader Uddin Shaikh, Zafar Ahmed, Syed Ali Arsalan, Sana Shafiq Department of Pulmonology, Liaquat National Hospital, Karachi, Pakistan Introduction: Moraxella catarrhalis previously considered as commensal of upper respiratory tract has gained importance as a pathogen responsible for respiratory tract infections. Its beta-lactamase-producing ability draws even more attention toward its varying patterns of resistance. Methods: This was an observational study conducted to evaluate the prevalence and resistance pattern of M. catarrhalis. Patients aged 20–80 years admitted in the Department of Chest Medicine of Liaquat National Hospital from March 2012 to December 2012 were included in the study. Respiratory samples of sputum, tracheal secretions, and bronchoalveolar lavage were included, and their cultures were followed. Results: Out of 110 respiratory samples, 22 showed positive cultures for M. catarrhalis in which 14 were males and eight were females. Ten samples out of 22 showed resistance to clarithromycin, and 13 samples out of 22 displayed resistance to erythromycin, whereas 13 showed resistance to levofloxacin. Hence, 45% of the cultures showed resistance to macrolides so far and 59% showed resistance to quinolones. Conclusion: Our study shows that in our environment, M. catarrhalis may be resistant to macrolides and quinolones; hence, these should not be recommended as an alternative treatment in community-acquired lower respiratory tract infections caused by M. catarrhalis. However, a study of larger sample size should be conducted to determine if the recommendations are required to be changed. Keywords: community-acquired lower respiratory tract infections or pneumonia, M. catarrhalis, antibiotic resistance, gram-negative diplococcic, Pakistan

Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell–matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis

Energy Technology Data Exchange (ETDEWEB)

Chen, Yan; Li, Zheng; He, Yan; Shang, Dandan; Pan, Jigang; Wang, Hongmei; Chen, Huamei; Zhu, Zhuxia [Department of Physiology/Cancer Research Group, Guiyang Medical University School of Basic Medicine, 9 Beijing Road, Guiyang 550004, Guizhou (China); Wan, Lei [Department of Pharmacology, Guiyang Medical University School of Basic Medicine, 9 Beijing Road, Guiyang 550004, Guizhou (China); Wang, Xudong, E-mail: xdwang@gmc.edu.cn [Department of Physiology/Cancer Research Group, Guiyang Medical University School of Basic Medicine, 9 Beijing Road, Guiyang 550004, Guizhou (China)

2014-03-01

Fulvestrant (ICI 182 780, ICI) has been used in treating patients with hormone-sensitive breast cancer, yet initial or acquired resistance to endocrine therapies frequently arises and, in particular, cancer recurs as metastasis. We demonstrate here that both 17-beta-estradiol (E2) and ICI enhance cell adhesion to matrigel in MCF-7 breast cancer cells, with increased autolysis of calpain 1 (large subunit) and proteolysis of focal adhesion kinase (FAK), indicating calpain activation. Additionally, either E2 or ICI induced down-regulation of estrogen receptor α without affecting G protein coupled estrogen receptor 30 (GPR30) expression. Interestingly, GPR30 agonist G1 triggered calpain 1 autolysis but not calpain 2, whereas ER agonist diethylstilbestrol caused no apparent calpain autolysis. Furthermore, the actions of E2 and ICI on calpain and cell adhesion were tremendously suppressed by G15, or knockdown of GPR30. E2 and ICI also induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 phosphorylation by U0126 profoundly impeded calpain activation triggered by estrogenic and antiestrogenic stimulations indicating implication of ERK1/2 in the GPR30-mediated action. Lastly, the E2- or ICI-induced cell adhesion was dramatically impaired by calpain-specific inhibitors, ALLN or calpeptin, suggesting requirement of calpain in the GPR30-associated action. These data show that enhanced cell adhesion by E2 and ICI occurs via a novel GPR30-ERK1/2-calpain pathway. Our results indicate that targeting the GPR30 signaling may be a potential strategy to reduce metastasis and improve the efficacy of antiestrogens in treatment of advanced breast cancer. - Highlights: • Estrogen and ICI augment adhesion to matrigel with calpain activation in MCF-7 cells. • GPR30 mediates cell–matrigel adhesion and calpain activation via ERK1/2. • Calpain is required in the cell–matrigel adhesion induced by E2 and ICI.

Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell–matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis

International Nuclear Information System (INIS)

Chen, Yan; Li, Zheng; He, Yan; Shang, Dandan; Pan, Jigang; Wang, Hongmei; Chen, Huamei; Zhu, Zhuxia; Wan, Lei; Wang, Xudong

2014-01-01

Fulvestrant (ICI 182 780, ICI) has been used in treating patients with hormone-sensitive breast cancer, yet initial or acquired resistance to endocrine therapies frequently arises and, in particular, cancer recurs as metastasis. We demonstrate here that both 17-beta-estradiol (E2) and ICI enhance cell adhesion to matrigel in MCF-7 breast cancer cells, with increased autolysis of calpain 1 (large subunit) and proteolysis of focal adhesion kinase (FAK), indicating calpain activation. Additionally, either E2 or ICI induced down-regulation of estrogen receptor α without affecting G protein coupled estrogen receptor 30 (GPR30) expression. Interestingly, GPR30 agonist G1 triggered calpain 1 autolysis but not calpain 2, whereas ER agonist diethylstilbestrol caused no apparent calpain autolysis. Furthermore, the actions of E2 and ICI on calpain and cell adhesion were tremendously suppressed by G15, or knockdown of GPR30. E2 and ICI also induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 phosphorylation by U0126 profoundly impeded calpain activation triggered by estrogenic and antiestrogenic stimulations indicating implication of ERK1/2 in the GPR30-mediated action. Lastly, the E2- or ICI-induced cell adhesion was dramatically impaired by calpain-specific inhibitors, ALLN or calpeptin, suggesting requirement of calpain in the GPR30-associated action. These data show that enhanced cell adhesion by E2 and ICI occurs via a novel GPR30-ERK1/2-calpain pathway. Our results indicate that targeting the GPR30 signaling may be a potential strategy to reduce metastasis and improve the efficacy of antiestrogens in treatment of advanced breast cancer. - Highlights: • Estrogen and ICI augment adhesion to matrigel with calpain activation in MCF-7 cells. • GPR30 mediates cell–matrigel adhesion and calpain activation via ERK1/2. • Calpain is required in the cell–matrigel adhesion induced by E2 and ICI

Antibacterial resistance patterns of pediatric community-acquired urinary infection: Overview.

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Konca, Capan; Tekin, Mehmet; Uckardes, Fatih; Akgun, Sadik; Almis, Habip; Bucak, Ibrahim Hakan; Genc, Yeliz; Turgut, Mehmet

2017-03-01

Urinary tract infection (UTI) is common in children. The aim of this study was therefor to construct a guide for the empirical antibiotic treatment of community-acquired UTI by investigating the etiology and antimicrobial resistance patterns of uropathogens and analyzing the epidemiological and clinical patient characteristics. A total of 158 children with positive urine culture were included in the study. Antibiotic susceptibility testing was performed with Vitek 2 Compact for 28 commonly used antimicrobials. Mean age was 3.36 ± 3.38 years (range, 45 days-15 years). Escherichia coli (60.1%), and Klebsiella spp. (16.5%) were the most common uropathogens. For all Gram-negative isolates, a high level of resistance was found against ampicillin/sulbactam (60.1%), trimethoprim/sulfamethoxazole (44.2%), cefazolin (36.2%), cefuroxime sodium (33.5%), and amoxicillin/clavulanate (31.5%). A low level of resistance was noted against cefepime (8.7%), ertapenem (4.6%), norfloxacin (1.3%), and meropenem (0.7%). There was no resistance against amikacin. There is high antibiotic resistance in children with UTI. The patterns of uropathogen antimicrobial resistance vary in susceptibility to antimicrobials depending on region and time. Thus, the trends of antibiotic susceptibility patterns should be analyzed periodically to select the appropriate regimen for UTI treatment. © 2016 Japan Pediatric Society.

Vorinostat-induced autophagy switches from a death-promoting to a cytoprotective signal to drive acquired resistance.

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Dupéré-Richer, D; Kinal, M; Ménasché, V; Nielsen, T H; Del Rincon, S; Pettersson, F; Miller, W H

2013-02-07

Histone deacetylase inhibitors (HDACi) have shown promising activity against hematological malignancies in clinical trials and have led to the approval of vorinostat for the treatment of cutaneous T-cell lymphoma. However, de novo or acquired resistance to HDACi therapy is inevitable, and their molecular mechanisms are still unclear. To gain insight into HDACi resistance, we developed vorinostat-resistant clones from the hematological cell lines U937 and SUDHL6. Although cross-resistant to some but not all HDACi, the resistant cell lines exhibit dramatically increased sensitivity toward chloroquine, an inhibitor of autophagy. Consistent with this, resistant cells growing in vorinostat show increased autophagy. Inhibition of autophagy in vorinostat-resistant U937 cells by knockdown of Beclin-1 or Lamp-2 (lysosome-associated membrane protein 2) restores sensitivity to vorinostat. Interestingly, autophagy is also activated in parental U937 cells by de novo treatment with vorinostat. However, in contrast to the resistant cells, inhibition of autophagy decreases sensitivity to vorinostat. These results indicate that autophagy can switch from a proapoptotic signal to a prosurvival function driving acquired resistance. Moreover, inducers of autophagy (such as mammalian target of rapamycin inhibitors) synergize with vorinostat to induce cell death in parental cells, whereas the resistant cells remain insensitive. These data highlight the complexity of the design of combination strategies using modulators of autophagy and HDACi for the treatment of hematological malignancies.

Investigating the effects of ABC transporter-based acquired drug resistance mechanisms at the cellular and tissue scale.

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Liu, Cong; Krishnan, J; Xu, Xiao Yun

2013-03-01

In this paper we systematically investigate the effects of acquired drug resistance at the cellular and tissue scale, with a specific focus on ATP-binding cassette (ABC) transporter-based mechanisms and contrast this with other representative intracellular resistance mechanisms. This is done by developing in silico models wherein the drug resistance mechanism is overlaid on a coarse-grained description of apoptosis; these cellular models are coupled with interstitial drug transport, allowing for a transparent examination of the effect of acquired drug resistances at the tissue level. While ABC transporter-mediated resistance mechanisms counteract drug effect at the cellular level, its tissue-level effect is more complicated, revealing unexpected trends in tissue response as drug stimuli are systematically varied. Qualitatively different behaviour is observed in other drug resistance mechanisms. Overall the paper (i) provides insight into the tissue level functioning of a particular resistance mechanism, (ii) shows that this is very different from other resistance mechanisms of an apparently similar type, and (iii) demonstrates a concrete instance of how the functioning of a negative feedback based cellular adaptive mechanism can have unexpected higher scale effects.

Primary and acquired resistance to biologic therapies in gastrointestinal cancers.

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Lubner, Sam J; Uboha, Nataliya V; Deming, Dustin A

2017-06-01

Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds. Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways.

Rapid determination of anti-estrogens by gas chromatography/mass spectrometry in urine: Method validation and application to real samples

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E. Gerace

2012-02-01

Full Text Available A fast screening protocol was developed for the simultaneous determination of nine anti-estrogenic agents (aminoglutethimide, anastrozole, clomiphene, drostanolone, formestane, letrozole, mesterolone, tamoxifen, testolactone plus five of their metabolites in human urine. After an enzymatic hydrolysis, these compounds can be extracted simultaneously from urine with a simple liquid–liquid extraction at alkaline conditions. The analytes were subsequently analyzed by fast-gas chromatography/mass spectrometry (fast-GC/MS after derivatization. The use of a short column, high-flow carrier gas velocity and fast temperature ramping produced an efficient separation of all analytes in about 4 min, allowing a processing rate of 10 samples/h. The present analytical method was validated according to UNI EN ISO/IEC 17025 guidelines for qualitative methods. The range of investigated parameters included the limit of detection, selectivity, linearity, repeatability, robustness and extraction efficiency. High MS-sampling rate, using a benchtop quadrupole mass analyzer, resulted in accurate peak shape definition under both scan and selected ion monitoring modes, and high sensitivity in the latter mode. Therefore, the performances of the method are comparable to the ones obtainable from traditional GC/MS analysis. The method was successfully tested on real samples arising from clinical treatments of hospitalized patients and could profitably be used for clinical studies on anti-estrogenic drug administration. Keywords: Anti-estrogens, Fast-GC/MS, Urine screening, Validation, Breast cancer

A Case of Acquired Rifampin Resistance in Mycobacterium bovis Bacillus Calmette-Guérin-Induced Cystitis: Necessity for Treatment Guidelines

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Joyce N Wolfe

2006-01-01

Full Text Available A case of presumed bacillus Calmette-Guérin (BCG cystitis in an elderly female patient following direct intravesical BCG instillation treatment for papillary transitional cell carcinoma is reported. The organism cultured from urine samples was eventually identified as a rifampin-resistant Mycobacterium bovis BCG isolate. Because the patient had received rifampin monotherapy during the course of treatment for presumed BCG disease, the clinical picture favoured acquired rifampin resistance. Sequencing of the target gene for rifampin (rpoB confirmed a known mutation responsible for conferring high levels of resistance to both rifampin and rifabutin (Ser531Tyr. To the authors' knowledge, this is the first reported case of M bovis BCG disease in a non-HIV patient where the organism had acquired drug resistance to rifampin, and the second reported case of M bovis BCG that had acquired drug resistance. The present case demonstrates the necessity to re-evaluate appropriate guidelines for the effective treatment of BCG disease.

A critical role for Arabidopsis MILDEW RESISTANCE LOCUS O2 in systemic acquired resistance.

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Gruner, Katrin; Zeier, Tatyana; Aretz, Christina; Zeier, Jürgen

2018-04-16

Members of the MILDEW RESISTANCE LOCUS O (MLO) gene family confer susceptibility to powdery mildews in different plant species, and their existence therefore seems to be disadvantageous for the plant. We recognized that expression of the Arabidopsis MLO2 gene is induced after inoculation with the bacterial pathogen Pseudomonas syringae, promoted by salicylic acid (SA) signaling, and systemically enhanced in the foliage of plants exhibiting systemic acquired resistance (SAR). Importantly, distinct mlo2 mutant lines were unable to systemically increase resistance to bacterial infection after inoculation with P. syringae, indicating that the function of MLO2 is necessary for biologically-induced SAR in Arabidopsis. Our data also suggest that the close homolog MLO6 has a supportive but less critical role in SAR. In contrast to SAR, basal resistance to bacterial infection was not affected in mlo2. Remarkably, SAR-defective mlo2 mutants were still competent in systemically increasing the levels of the SAR-activating metabolites pipecolic acid (Pip) and SA after inoculation, and to enhance SAR-related gene expression in distal plant parts. Furthermore, although MLO2 was not required for SA- or Pip-inducible defense gene expression, it was essential for the proper induction of disease resistance by both SAR signals. We conclude that MLO2 acts as a critical downstream component in the execution of SAR to bacterial infection, being required for the translation of elevated defense responses into disease resistance. Moreover, our data suggest a function for MLO2 in the activation of plant defense priming during a P. syringae challenge. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Radiation response of human lung cancer cells with inherent and acquired resistance to cisplatin

International Nuclear Information System (INIS)

Twentyman, P.R.; Wright, K.A.; Rhodes, T.

1991-01-01

We have derived sublines of three human lung cancer cell lines with acquired resistance to cisplatin. The cisplatin resistant sublines of NCI-H69 (small cell), COR-L23 (large cell), and MOR (adenocarcinoma) show 5.3 fold, 3.1 fold, and 3.8 fold resistance, respectively, determined in a 6-day MTT assay. Although the parent lines show a wide range of glutathione content per cell, the sublines each show similar values to their corresponding parent line. Radiation response curves have been obtained using a soft agar clonogenic assay. Values obtained for the parent lines (95% CL in parentheses) were: NCI-H69: Do = 0.99 Gy (0.87-1.16), n = 2.9 (1.6-5.2), GSH = 14 ng/10(4) cells; COR-L23: Do = 1.23 Gy (1.05-1.49), n = 1.3 (0.7-2.2), GSH = 47 ng/10(4) cells; MOR: Do = 1.66 Gy (1.48-1.88), n = 3.0 (1.9-4.8), GSH = 86 ng/10(4) cells. The cisplatin resistant variants of NCI-H69 and COR-L23 showed 31% and 63% increases, respectively, in Do compared to their parent lines, whereas no change in radiation response was seen in MOR. In this panel of lines, therefore, although there is a correlation between glutathione content and radiosensitivity of the parent cell lines, acquired resistance to cisplatin is not accompanied by increased glutathione content. However, two of the three cisplatin resistant lines do show a significantly reduced radiosensitivity

Sym004, a Novel EGFR Antibody Mixture, Can Overcome Acquired Resistance to Cetuximab1

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Iida, Mari; Brand, Toni M; Starr, Megan M; Li, Chunrong; Huppert, Evan J; Luthar, Neha; Pedersen, Mikkel W; Horak, Ivan D; Kragh, Michael; Wheeler, Deric L

2013-01-01

The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (CtxR) cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for CtxR tumor cells. Sym004 treatment of CtxR clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo CtxR NCI-H226 mouse xenografts and subsequently treated CtxR tumors with Sym004. Sym004 treatment of mice harboring CtxR tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in CtxR tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for CtxR tumors. PMID:24204198

Multidrug-Resistant CTX-M-(15, 9, 2)- and KPC-2-Producing Enterobacter hormaechei and Enterobacter asburiae Isolates Possessed a Set of Acquired Heavy Metal Tolerance Genes Including a Chromosomal sil Operon (for Acquired Silver Resistance).

Science.gov (United States)

Andrade, Leonardo N; Siqueira, Thiago E S; Martinez, Roberto; Darini, Ana Lucia C

2018-01-01

Bacterial resistance to antibiotics is concern in healthcare-associated infections. On the other hand, bacterial tolerance to other antimicrobials, like heavy metals, has been neglected and underestimated in hospital pathogens. Silver has long been used as an antimicrobial agent and it seems to be an important indicator of heavy metal tolerance. To explore this perspective, we searched for the presence of acquired silver resistance genes ( sil operon: silE, silS, silR, silC, silF, silB, silA , and silP ) and acquired extended-spectrum cephalosporin and carbapenem resistance genes ( bla CTX-M and bla KPC ) in Enterobacter cloacae Complex (EcC) ( n = 27) and Enterobacter aerogenes ( n = 8) isolated from inpatients at a general hospital. Moreover, the genetic background of the silA (silver-efflux pump) and the presence of other acquired heavy metal tolerance genes, pcoD (copper-efflux pump), arsB (arsenite-efflux pump), terF (tellurite resistance protein), and merA (mercuric reductase) were also investigated. Outstandingly, 21/27 (78%) EcC isolates harbored silA gene located in the chromosome. Complete sil operon was found in 19/21 silA -positive EcC isolates. Interestingly, 8/20 (40%) E. hormaechei and 5/6 (83%) E. asburiae co-harbored silA/pcoD genes and bla CTX-M-(15,2,or9) and/or bla KPC-2 genes. Frequent occurrences of arsB, terF , and merA genes were detected, especially in silA/pcoD -positive, multidrug-resistant (MDR) and/or CTX-M-producing isolates. Our study showed co-presence of antibiotic and heavy metal tolerance genes in MDR EcC isolates. In our viewpoint, there are few studies regarding to bacterial heavy metal tolerance and we call attention for more investigations and discussion about this issue in different hospital pathogens.

Multidrug-Resistant CTX-M-(15, 9, 2- and KPC-2-Producing Enterobacter hormaechei and Enterobacter asburiae Isolates Possessed a Set of Acquired Heavy Metal Tolerance Genes Including a Chromosomal sil Operon (for Acquired Silver Resistance

Directory of Open Access Journals (Sweden)

Leonardo N. Andrade

2018-03-01

Full Text Available Bacterial resistance to antibiotics is concern in healthcare-associated infections. On the other hand, bacterial tolerance to other antimicrobials, like heavy metals, has been neglected and underestimated in hospital pathogens. Silver has long been used as an antimicrobial agent and it seems to be an important indicator of heavy metal tolerance. To explore this perspective, we searched for the presence of acquired silver resistance genes (sil operon: silE, silS, silR, silC, silF, silB, silA, and silP and acquired extended-spectrum cephalosporin and carbapenem resistance genes (blaCTX−M and blaKPC in Enterobacter cloacae Complex (EcC (n = 27 and Enterobacter aerogenes (n = 8 isolated from inpatients at a general hospital. Moreover, the genetic background of the silA (silver-efflux pump and the presence of other acquired heavy metal tolerance genes, pcoD (copper-efflux pump, arsB (arsenite-efflux pump, terF (tellurite resistance protein, and merA (mercuric reductase were also investigated. Outstandingly, 21/27 (78% EcC isolates harbored silA gene located in the chromosome. Complete sil operon was found in 19/21 silA-positive EcC isolates. Interestingly, 8/20 (40% E. hormaechei and 5/6 (83% E. asburiae co-harbored silA/pcoD genes and blaCTX−M−(15,2,or9 and/or blaKPC−2 genes. Frequent occurrences of arsB, terF, and merA genes were detected, especially in silA/pcoD-positive, multidrug-resistant (MDR and/or CTX-M-producing isolates. Our study showed co-presence of antibiotic and heavy metal tolerance genes in MDR EcC isolates. In our viewpoint, there are few studies regarding to bacterial heavy metal tolerance and we call attention for more investigations and discussion about this issue in different hospital pathogens.

Antibodies and antiestrogens combined with boron for use in the neutron capture therapy

International Nuclear Information System (INIS)

Abraham, R.

1987-01-01

The ZR-75-1 cell line developed from a mammary carcinoma was chosen to characterise the binding of antiestrogen U23.469-M to the cell, which was subsequently compared to that of a derivative combined with boron. It was found that the original U23.469-M showed antiestrogenic activity, while this effect was largely abolished after the substance had been modified using b-decachloro-o-carborane. In this study, boron-conjugated antibodies were produced in order to find out whether those modified immunoglobulins would be suitable to bind sufficient quantities of boron to the tumour cells. It was calculated by experts on radiation biology that a minimum of 1000 boron atoms is required for a tumour-specific antibody to be therapeutically effective. When oxidated dextran of a molecular weight of 33 kD was used as a linking molecule, a reproducible method could be developed that permitted more than 1000 boron atoms to be bound per antibody. In one of the monoclonal antibodies tested here a combination with boron could, however, only be achieved at the expense of complete inactivation. A model was developed allowing to significantly increase the number modified antibodies attached to any one tumour cell. The cell binding experiments and radioimmunoassays then carried out were able to show that the number of antibodies bound to tumour cells can be increased to different degrees, depending on the monoclonal antibody used in each case. (orig./MG) [de

Monoterpenes Support Systemic Acquired Resistance within and between Plants.

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Riedlmeier, Marlies; Ghirardo, Andrea; Wenig, Marion; Knappe, Claudia; Koch, Kerstin; Georgii, Elisabeth; Dey, Sanjukta; Parker, Jane E; Schnitzler, Jörg-Peter; Vlot, A Corina

2017-06-01

This study investigates the role of volatile organic compounds in systemic acquired resistance (SAR), a salicylic acid (SA)-associated, broad-spectrum immune response in systemic, healthy tissues of locally infected plants. Gas chromatography coupled to mass spectrometry analyses of SAR-related emissions of wild-type and non-SAR-signal-producing mutant plants associated SAR with monoterpene emissions. Headspace exposure of Arabidopsis thaliana to a mixture of the bicyclic monoterpenes α-pinene and β-pinene induced defense, accumulation of reactive oxygen species, and expression of SA- and SAR-related genes, including the SAR regulatory AZELAIC ACID INDUCED1 ( AZI1 ) gene and three of its paralogs. Pinene-induced resistance was dependent on SA biosynthesis and signaling and on AZI1 Arabidopsis geranylgeranyl reductase1 mutants with reduced monoterpene biosynthesis were SAR-defective but mounted normal local resistance and methyl salicylate-induced defense responses, suggesting that monoterpenes act in parallel with SA The volatile emissions from SAR signal-emitting plants induced defense in neighboring plants, and this was associated with the presence of α-pinene, β-pinene, and camphene in the emissions of the "sender" plants. Our data suggest that monoterpenes, particularly pinenes, promote SAR, acting through ROS and AZI1 , and likely function as infochemicals in plant-to-plant signaling, thus allowing defense signal propagation between neighboring plants. © 2017 American Society of Plant Biologists. All rights reserved.

New Real-Time PCR Assays for Detection of Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Group.

Science.gov (United States)

Shallom, Shamira J; Moura, Natalia S; Olivier, Kenneth N; Sampaio, Elizabeth P; Holland, Steven M; Zelazny, Adrian M

2015-11-01

Members of the Mycobacterium abscessus group (MAG) cause lung, soft tissue, and disseminated infections. The oral macrolides clarithromycin and azithromycin are commonly used for treatment. MAG can display clarithromycin resistance through the inducible erm(41) gene or via acquired mutations in the rrl (23S rRNA) gene. Strains harboring a truncation or a T28C substitution in erm(41) lose the inducible resistance trait. Phenotypic detection of clarithromycin resistance requires extended incubation (14 days), highlighting the need for faster methods to detect resistance. Two real-time PCR-based assays were developed to assess inducible and acquired clarithromycin resistance and tested on a total of 90 clinical and reference strains. A SYBR green assay was designed to distinguish between a full-length and truncated erm(41) gene by temperature shift in melting curve analysis. Single nucleotide polymorphism (SNP) allele discrimination assays were developed to distinguish T or C at position 28 of erm(41) and 23S rRNA rrl gene mutations at position 2058 and/or 2059. Truncated and full-size erm(41) genes were detected in 21/90 and 69/90 strains, respectively, with 64/69 displaying T at nucleotide position 28 and 5/69 containing C at that position. Fifteen isolates showed rrl mutations conferring clarithromycin resistance, including A2058G (11 isolates), A2058C (3 isolates), and A2059G (1 isolate). Targeted sequencing and phenotypic assessment of resistance concurred with molecular assay results. Interestingly, we also noted cooccurring strains harboring an active erm(41), inactive erm(41), and/or acquired mutational resistance, as well as slowly growing MAG strains and also strains displaying an inducible resistance phenotype within 5 days, long before the recommended 14-day extended incubation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Trend and seasonality of community-acquired Escherichia coli antimicrobial resistance and its dynamic relationship with antimicrobial use assessed by ARIMA models.

Science.gov (United States)

Asencio Egea, María Ángeles; Huertas Vaquero, María; Carranza González, Rafael; Herráez Carrera, Óscar; Redondo González, Olga; Arias Arias, Ángel

2017-12-04

We studied the trend and seasonality of community-acquired Escherichia coli resistance and quantified its correlation with the previous use of certain antibiotics. A time series study of resistant community-acquired E. coli isolates and their association with antibiotic use was conducted in a Primary Health Care Area from 2008 to 2012. A Poisson regression model was constructed to estimate the trend and seasonality of E. coli resistance. A significant increasing trend in mean E. coli resistance to cephalosporins, aminoglycosides and nitrofurantoin was observed. Seasonal resistance to ciprofloxacin and amoxicillin-clavulanic acid was significantly higher in autumn-winter. There was a delay of 7, 10 and 12 months between the use of cotrimoxazole (P<0.038), fosfomycin (P<0.024) and amoxicillin-clavulanic acid (P<0.015), respectively, and the occurrence of E. coli resistance. An average delay of 10 months between the previous use of amoxicillin-clavulanic acid, cotrimoxazole and fosfomycin and the appearance of resistant community-acquired E. coli strains was detected. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Design of two molecular methodologies for the rapid identification of Colombian community-acquired methicillin-resistant Staphylococcus aureus isolates

OpenAIRE

Escobar, Javier Antonio; Gómez, Ingrid Tatiana; Murillo, Martha Johanna; Castro, Betsy Esperanza; Chavarro, Bibiana; Márquez, Ricaurte Alejandro; Vanegas, Natasha

2012-01-01

Introduction. Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are found with increasing the frequency, both in healthy individuals in the community and in hospitalized patients. In Colombia and the Andean region, CA-MRSA isolates have a genetic background that is related to the pandemic USA300 clone. Objective. Two molecular methods are designed and standardized for the rapid differentiation of Colombian community-acquired and hospital-acquired methicillin-...

Combinatorial Synthesis for the Expedited Discovery of Novel Selective Antiestrogens for Breast Cancer Prevention and Therapy

Science.gov (United States)

2001-09-01

From the Original Proposal Estrogens: H H OH COH CH0 HQ ~ HHo QH HHO ’ OH3 HAOH 3 H Estradiol Hexestrol Benzestrol Cyclofenil Y~e Pure Antiestrogens...overlapping s, fl-CH 2), 4.95 (2H, PS-ArCH 20), 5.16 emission wavelength of 364 nm were used, based on the (1H, cx/cx’-CH), 7.98 (4H, ArCH

The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

International Nuclear Information System (INIS)

Loh, Yan Ni; Hedditch, Ellen L; Baker, Laura A; Jary, Eve; Ward, Robyn L; Ford, Caroline E

2013-01-01

Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically. An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays. TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT. These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt

Identification of genes differentially expressed in association with acquired cisplatin resistance

Science.gov (United States)

Johnsson, A; Zeelenberg, I; Min, Y; Hilinski, J; Berry, C; Howell, S B; Los, G

2000-01-01

The goal of this study was to identify genes whose mRNA levels are differentially expressed in human cells with acquired cisplatin (cDDP) resistance. Using the parental UMSCC10b head and neck carcinoma cell line and the 5.9-fold cDDP-resistant subline, UMSCC10b/Pt-S15, two suppressive subtraction hybridization (SSH) cDNA libraries were prepared. One library represented mRNAs whose levels were increased in the cDDP resistant variant (the UP library), the other one represented mRNAs whose levels were decreased in the resistant cells (the DOWN library). Arrays constructed with inserts recovered from these libraries were hybridized with SSH products to identify truly differentially expressed elements. A total of 51 cDNA fragments present in the UP library and 16 in the DOWN library met the criteria established for differential expression. The sequences of 87% of these cDNA fragments were identified in Genbank. Among the mRNAs in the UP library that were frequently isolated and that showed high levels of differential expression were cytochrome oxidase I, ribosomal protein 28S, elongation factor 1α, α-enolase, stathmin, and HSP70. The approach taken in this study permitted identification of many genes never before linked to the cDDP-resistant phenotype. © 2000 Cancer Research Campaign PMID:10993653

Update on HIV-1 acquired and transmitted drug resistance in Africa.

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Ssemwanga, Deogratius; Lihana, Raphael W; Ugoji, Chinenye; Abimiku, Alash'le; Nkengasong, John; Dakum, Patrick; Ndembi, Nicaise

2015-01-01

The last ten years have witnessed a significant scale-up and access to antiretroviral therapy in Africa, which has improved patient quality of life and survival. One major challenge associated with increased access to antiretroviral therapy is the development of antiretroviral resistance due to inconsistent drug supply and/or poor patient adherence. We review the current state of both acquired and transmitted drug resistance in Africa over the past ten years (2001-2011) to identify drug resistance associated with the different drug regimens used on the continent and to help guide affordable strategies for drug resistance surveillance. A total of 161 references (153 articles, six reports and two conference abstracts) were reviewed. Antiretroviral resistance data was available for 40 of 53 African countries. A total of 5,541 adult patients from 99 studies in Africa were included in this analysis. The pooled prevalence of drug resistance mutations in Africa was 10.6%, and Central Africa had the highest prevalence of 54.9%. The highest prevalence of nucleoside reverse transcriptase inhibitor mutations was in the west (55.3%) and central (54.8%) areas; nonnucleoside reverse transcriptase inhibitor mutations were highest in East Africa (57.0%) and protease inhibitors mutations highest in Southern Africa (16.3%). The major nucleoside reverse transcriptase inhibitor mutation in all four African regions was M184V. Major nonnucleoside reverse transcriptase inhibitor as well as protease inhibitor mutations varied by region. The prevalence of drug resistance has remained low in several African countries although the emergence of drug resistance mutations varied across countries. Continued surveillance of antiretroviral therapy resistance remains crucial in gauging the effectiveness of country antiretroviral therapy programs and strategizing on effective and affordable strategies for successful treatment.

Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles

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Chen, Lijue; She, Xiaodong; Wang, Tao; He, Li; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

2015-08-01

Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest.Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The

Risk Factors for Acquired Rifamycin and Isoniazid Resistance: A Systematic Review and Meta-Analysis.

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Neesha Rockwood

Full Text Available Studies looking at acquired drug resistance (ADR are diverse with respect to geographical distribution, HIV co-infection rates, retreatment status and programmatic factors such as regimens administered and directly observed therapy. Our objective was to examine and consolidate evidence from clinical studies of the multifactorial aetiology of acquired rifamycin and/or isoniazid resistance within the scope of a single systematic review. This is important to inform policy and identify key areas for further studies.Case-control and cohort studies and randomised controlled trials that reported ADR as an outcome during antitubercular treatment regimens including a rifamycin and examined the association of at least 1 risk factor were included. Post hoc, we carried out random effects Mantel-Haenszel weighted meta-analyses of the impact of 2 key risk factors 1 HIV and 2 baseline drug resistance on the binary outcome of ADR. Heterogeneity was assessed used I2 statistic. As a secondary outcome, we calculated median cumulative incidence of ADR, weighted by the sample size of the studies.Meta-analysis of 15 studies showed increased risk of ADR with baseline mono- or polyresistance (RR 4.85 95% CI 3.26 to 7.23, heterogeneity I2 58%, 95% CI 26 to 76%. Meta-analysis of 8 studies showed that HIV co-infection was associated with increased risk of ADR (RR 3.02, 95% CI 1.28 to 7.11; there was considerable heterogeneity amongst these studies (I2 81%, 95% CI 64 to 90%. Non-adherence, extrapulmonary/disseminated disease and advanced immunosuppression in HIV co-infection were other risk factors noted. The weighted median cumulative incidence of acquired multi drug resistance calculated in 24 studies (assuming whole cohort as denominator, regardless of follow up DST was 0.1% (5th to 95th percentile 0.07 to 3.2%.Baseline drug resistance and HIV co-infection were significant risk factors for ADR. There was a trend of positive association with non-adherence which is likely

Bacteriology of hospital-acquired infection and antibiotic resistance in a hospital university of Bushehr Port Fatemeh Zahra (s in 2002-2003

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Katayoon Vahdat

2005-02-01

Full Text Available Nosocomial infection is an increasing problem. The global problem of antimicrobial resistance is particularly pressing in developing countries, where the infectious disease burden is high and cost constraints prevent the widespread application of newer, more expensive agents. In a prospective study, 203 consecutive cases with hospital-acquired infection in a university hospital in Bushehr port were evaluated. The most common hospital-acquired infection was urinary (76 cases, conjunctivitis (16 cases, bacteremia (8 cases, meningitis (5 cases, wound (3 cases, empyema (2 cases and peritonitis (1 case. The patients with hospital-acquired infection were from surgical and internal medicine I.C.Us (53.2% & 15.6%, respectively. The most frequent isolated organisms were Pseudomonas aeruginosa (25.6%, Acinetobacter baumannii (19.7%, E. coli (13.3%, Klebsiella pneumoniae (11.3%, Staphylococcus aureus (8.4%, Staphylococcus epidermidis (7.9%, Enterobacter species (7%, Streptococcus species (6.4%, and Proteus mirabilis (0.5%. The most resistant organisms to antimicrobial agents were Acinetobacter baumannii and Pseudomonas aeruginosa 97 & 93.3% of these bacteria were resistant to third generation cephalosporins. The isolated Staphylococcal species were resistant to amikacin (94%. In conclusion, gram negative bacteria were the most common etiologic agent of hospital-acquired infection and had a high level of resistance to amikacin and third generation cephalosporins. Therefore, new therapeutic strategies should be designed to combat these microorganisms.

Prevalence of quinolone resistance mechanisms in Enterobacteriaceae producing acquired AmpC β-lactamases and/or carbapenemases in Spain.

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Machuca, Jesús; Agüero, Jesús; Miró, Elisenda; Conejo, María Del Carmen; Oteo, Jesús; Bou, Germán; González-López, Juan José; Oliver, Antonio; Navarro, Ferran; Pascual, Álvaro; Martínez-Martínez, Luis

2017-10-01

Quinolone resistance in Enterobacteriaceae species has increased over the past few years, and is significantly associated to beta-lactam resistance. The aim of this study was to evaluate the prevalence of chromosomal- and plasmid-mediated quinolone resistance in acquired AmpC β-lactamase and/or carbapenemase-producing Enterobacteriaceae isolates. The presence of chromosomal- and plasmid-mediated quinolone resistance mechanisms [mutations in the quinolone resistance determining region (QRDR) of gyrA and parC and qnr, aac(6')-Ib-cr and qepA genes] was evaluated in 289 isolates of acquired AmpC β-lactamase- and/or carbapenemase-producing Enterobacteriaceae collected between February and July 2009 in 35 Spanish hospitals. Plasmid mediated quinolone resistance (PMQR) genes were detected in 92 isolates (31.8%), qnr genes were detected in 83 isolates (28.7%), and the aac(6')-Ib-cr gene was detected in 20 isolates (7%). qnrB4 gene was the most prevalent qnr gene detected (20%), associated, in most cases, with DHA-1. Only 14.6% of isolates showed no mutations in gyrA or parC with a ciprofloxacin MIC of 0.5mg/L or higher, whereas PMQR genes were detected in 90% of such isolates. qnrB4 gene was the most prevalent PMQR gene detected, and was significantly associated with acquired AmpC β-lactamase DHA-1. PMQR determinants in association with other chromosomal-mediated quinolone resistance mechanisms, different to mutations in gyrA and parC (increased energy-dependent efflux, altered lipopolysaccharide or porin loss), could lead to ciprofloxacin MIC values that exceed breakpoints established by the main international committees to define clinical antimicrobial susceptibility breakpoints. Copyright © 2016 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Increasing trend of community-acquired methicillin-resistant: Staphylococcal carriers: An alarming bell for urgent measures

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Poongodi Lakshmi Santhana Kumarasamy

2015-01-01

Full Text Available Background: An increase in the incidence of infections caused by community-associated-methicillin resistant Staphylococcus aureus (MRSA has been reported. Hence, the knowledge of resistance pattern of these isolates is a precondition for alleviating emerging antibiotic resistance and devising better treatment strategies Aim: To find out the prevalence of community-acquired methicillin-resistant staphylococcal strains from nasal carriers. Materials and Methods: A total of 352 nasal swabs collected during routine health checkup were analyzed. Results: Of the 58 (16% staphylococci isolated, 32 (55% were S. aureus and 26 (45% were coagulase-negative staphylococci (CoNS. Methicillin resistance was observed in 7 (22% of staphylococci aureus and 11 (42% of CoNS. "D test" was positive in 1 (14% MRSA, 2 (8% methicillin-susceptible S. aureus and 2 (8% methicillin resistant-CoNS. Conclusion: Effective implementation of the antibiotic policy along with measures like hand wash, isolation of patients will reduce the incidence of resistance.

Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

International Nuclear Information System (INIS)

Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan; Alizadeh-Rad, Negin; Piell, Kellianne; Van Hoose, Patrick; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Ted S.; Rouchka, Eric C.; Hill, Bradford G.; Klinge, Carolyn M.

2016-01-01

Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.

Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

Energy Technology Data Exchange (ETDEWEB)

Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan; Alizadeh-Rad, Negin; Piell, Kellianne; Van Hoose, Patrick; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Ted S. [Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Rouchka, Eric C. [Bioinformatics and Biomedical Computing Laboratory, Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY 40292 (United States); Hill, Bradford G. [Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Klinge, Carolyn M., E-mail: carolyn.klinge@louisville.edu [Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292 (United States)

2016-09-10

Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.

Drug resistance in community-acquired respiratory tract infections: role for an emerging antibacterial

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Lorenzo Aguilar

2010-06-01

Full Text Available Lorenzo Aguilar1, María-José Giménez1, José Barberán21Microbiology Department, School of Medicine, University Complutense, Madrid; 2Infectious Diseases Department, Hospital Central de la Defensa Gomez Ulla, Madrid, SpainAbstract: The nasopharynx is the ecological niche where evolution towards resistance occurs in respiratory tract isolates. Dynamics of different bacterial populations in antibiotic-free multibacterial niches are the baseline that antibiotic treatments can alter by shifting the competitive balance in favor of resistant populations. For this reason, antibiotic resistance is increasingly being considered to be an ecological problem. Traditionally, resistance has implied the need for development of new antibiotics for which basic efficacy and safety data are required prior to licensing. Antibiotic development is mainly focused on demonstrating clinical efficacy and setting susceptibility breakpoints for efficacy prediction. However, additional information on pharmacodynamic data predicting absence of selection of resistance and of resistant subpopulations, and specific surveillance on resistance to core antibiotics (to detect emerging resistances and its link with antibiotic consumption in the community are valuable data in defining the role of a new antibiotic, not only from the perspective of its therapeutic potential but also from the ecologic perspective (countering resistances to core antibiotics in the community. The documented information on cefditoren gleaned from published studies in recent years is an example of the role for an emerging oral antibacterial facing current antibiotic resistance in community-acquired respiratory tract infections.Keywords: respiratory tract infection, antibiotic resistance, cefditoren, community

Individual’s Resistance to Social Crises is Acquired in Childhood

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Burvytė Sigita

2011-12-01

Full Text Available Objective: the development of person’s resistance to crises. The aim of the study is to revealthe importance of childhood experience to the person, by acquiring resistance to crises; theneed of pedagogical help in overcoming adaptation difficulties of the first-year pupil at school.The analysis of pedagogical, psychological, philosophical literature; the analysis of empiricalresearch and statistic data; as well as the method of observation were used in the current study.Though 60 percent of preparation possibilities for life are realised until the beginning of the firstgrade, the analysis of various authors’ research, quantitative analysis and observation of firstyearpupils in the schools of Vilnius, allow us to conclude that the main reason for a difficultadaptation of first-year pupils is the prevailing belief, that individuals’ preparation for life beginsat school. Educational system is based on rendering of the knowledge rather than the developmentof thinking ability and universal recognition of the environment. Inactivated brain during infancyand early childhood reduces the possibility of mastering information provided at school, andusing it in life. Family is the basis, which provides the feeling of safety, which instils real values,which creates the conditions of developing resistance to social changes, and various adaptationalskills, which are particularly necessary in the contemporary changing society. Extra attentionshould be paid to the education of parents and preparation for responsible parenthood.

In Utero Estrogen Exposure Increases Antiestrogen Resistance by Inducing EMT

Science.gov (United States)

2015-02-01

currently unclear. Our recent preclinical study found that maternal exposure to excess estrogens during pregnancy increases the risk that AE resistance in...References: 1. Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M. A maternal diet high in n-6-polyunsaturated fats alters mammary...the rate of obesity in this country (high fat diets resulting in elevated circulating estrogen levels), the prevelance of bisphenol A in our drinking

Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib.

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Liu, Yutao; Li, Yan; Ou, Qiuxiang; Wu, Xue; Wang, Xiaonan; Shao, Yang W; Ying, Jianming

2018-04-01

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are promising targeted therapies for EGFR-mutated non-small-cell lung cancer (NSCLC) patients. However, acquired resistance inevitably develops. Comprehensive and dynamic companion genomic diagnosis can gain insights into underlying resistance mechanisms, thereby help oncologists and patients to make informed decision on the potential benefit of the treatment. A 67-year-old male who was initially diagnosed of EGFR L858R-mediated NSCLC received multiple lines of chemotherapy and EGFR TKI therapies after surgery. The EGFR mutational status of individual metastatic lesion was determined by genetic testing of the tumor tissue biopsies using next generation sequencing (NGS) throughout the patient's clinical course. An acquired potentially drug-resistant EGFR mutation was functionally validated in vitro and its sensitivity to different EGFR TKIs was assessed simultaneously. We have identified distinct resistance mechanisms to EGFR blockade in different metastatic lung lesions. Acquired EGFR T790M was first detected that leads to the resistance to the gefitinib treatment. Consequently, osimertinib was administrated and the response lasted until disease progressed. We identified a newly acquired EGFR L718V mutation in one lesion in conjunction with L858R, but not T790M, which showed stable disease on the following erlotinib treatment, while EGFR C797S together with L858R/T790M was detected in the other lesion that continuously progressed. In vitro functional studies demonstrated that EGFR-L858R/L718V confers resistance to osimertinib, but retains sensitivity to the second generation TKI afatinib. We reported that distinct resistance mechanisms could arise in different metastases within the same patient in response to EGFR blockade. We also demonstrated in vitro that EGFR L718V mutation mediates resistance to osimertinib, but retains sensitivity to afatinib. We evidenced that dynamic companion genomic

Acquired resistance to chlorhexidine - is it time to establish an 'antiseptic stewardship' initiative?

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Kampf, G

2016-11-01

Chlorhexidine digluconate (CHG) is an antimicrobial agent used for different types of applications in hand hygiene, skin antisepsis, oral care, and patient washing. Increasing use raises concern regarding development of acquired bacterial resistance. Published data from clinical isolates with CHG minimum inhibitory concentrations (MICs) were reviewed and compared to epidemiological cut-off values to determine resistance. CHG resistance is rarely found in Escherichia coli, Salmonella spp., Staphylococcus aureus or coagulase-negative staphylococci. In Enterobacter spp., Pseudomonas spp., Proteus spp., Providencia spp. and Enterococcus spp., however, isolates are more often CHG resistant. CHG resistance may be detected in multi-resistant isolates such as extremely drug-resistant Klebsiella pneumoniae. Isolates with a higher MIC are often less susceptible to CHG for disinfection. Although cross-resistance to antibiotics remains controversial, some studies indicate that the overall exposure to CHG increases the risk for resistance to some antibiotic agents. Resistance to CHG has resulted in numerous outbreaks and healthcare-associated infections. On an average intensive care unit, most of the CHG exposure would be explained by hand hygiene agents when liquid soaps or alcohol-based hand rubs contain CHG. Exposure to sub-lethal CHG concentration may enhance resistance in Acinetobacter spp., K. pneumoniae, and Pseudomonas spp., all species well known for emerging antibiotic resistance. In order to reduce additional selection pressure in nosocomial pathogens it seems to make sense to restrict the valuable agent CHG to those indications with a clear patient benefit and to eliminate it from applications without any benefit or with a doubtful benefit. Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells

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Tyler, Andreas, E-mail: andreas.tyler@medbio.umu.se [Department of Medical Biosciences, Umeå University, S-901 85 Umea (Sweden); Johansson, Anders [Department of Odontology, Umeå University, S-901 85 Umea (Sweden); Karlsson, Terese [Department of Radiation Sciences, Oncology, S-901 85 Umea (Sweden); Gudey, Shyam Kumar; Brännström, Thomas; Grankvist, Kjell; Behnam-Motlagh, Parviz [Department of Medical Biosciences, Umeå University, S-901 85 Umea (Sweden)

2015-08-01

Background: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expression of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance. Methods: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analyzed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72 h on expression and cisplatin cytotoxicity was tested. Results: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells. Conclusions: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin

Risk factors for hospital-acquired bacteremia due to carbapenem-resistant Pseudomonas aeruginosa in a Colombian hospital.

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Valderrama, Sandra Liliana; González, Pedro Felipe; Caro, María Alejandra; Ardila, Natalia; Ariza, Beatriz; Gil, Fabián; Álvarez, Carlos

2016-02-23

Bacteremia due to Pseudomonas aeruginosa resistant to carbapenems is a public health problem due to the limitations it places on therapeutic options, as well as the increased time patients must spend in hospital, costs and the risk of mortality.  To evaluate the risk factors for presentation of bacteremia due to carbapenem-resistant P. aeruginosa acquired in the Hospital Universitario San Ignacio between January 2008 and June 2014.  This was a case control study in which the case patients presented bacteremia due to P. aeruginosa resistant to carbapenems and the control group included patients with P. aeruginosa susceptible to this group of antibiotics. Variables such as the previous use of meropenem and ertapenem, immunosuppression and neoplasia were measured. Mortality and duration of hospital were also described.  In all, 168 patients were evaluated, of which 42 were cases and 126 controls. Using a multivariate model, the risk factors related to bacteremia due to carbapenem-resistant P. aeruginosa acquired in hospital were the following: use of parenteral nutrition (OR=8.28; 95% CI: 2.56-26.79; p=0); use of meropenem (OR=1.15; 95% CI: 1.03-1.28; p=0.01); and use of ciprofloxacin (OR=81.99; 95% CI: 1.14-5884; p=0.043).  In order to prevent the emergence of carbapenem-resistant P. aeruginosa, antimicrobial control programs should be strengthened by promoting the prudent administration of carbapenems and quinolones. The correct use of parenteral nutrition should also be monitored.

Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.

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Hing, Zachary A; Mantel, Rose; Beckwith, Kyle A; Guinn, Daphne; Williams, Erich; Smith, Lisa L; Williams, Katie; Johnson, Amy J; Lehman, Amy M; Byrd, John C; Woyach, Jennifer A; Lapalombella, Rosa

2015-05-14

Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells and increases overall survival compared with ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance. © 2015 by The American Society of Hematology.

Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors.

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Shao, Yi; Zhong, Dian-Sheng

2018-04-01

Non-small-cell lung cancer patients with sensitive epidermal growth factor receptor mutations generally respond well to tyrosine kinase inhibitors (TKIs). However, acquired resistance will eventually develop place after 8-16 months. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification, epithelial mesenchymal transformation and PIK3CA mutation; however, histological transformation is a rare mechanism. The patterns and mechanisms underlying histological transformation need to be explored. We searched PubMed, EMBASE and search engines Google Scholar, Medical Matrix for literature related to histological transformation. Case reports, cases series, and clinical and basic medical research articles were reviewed. Sixty-one articles were included in this review. Cases of transformation to small-cell lung cancer, squamous cell carcinoma, large-cell neuroendocrine carcinoma and sarcoma after TKI resistance have all been reported. As the clinical course differed dramatically between cases, a new treatment scheme needs to be recruited. The mechanisms underlying histological transformation have not been fully elucidated and probably relate to cancer stem cells, driver genetic alterations under selective pressure or the heterogeneity of the tumor. When TKI resistance develops, we recommend that patients undergo a second biopsy to determine the reason, guide the next treatment and predict the prognosis.

The human microbiota: novel targets for hospital-acquired infections and antibiotic resistance.

Science.gov (United States)

Pettigrew, Melinda M; Johnson, J Kristie; Harris, Anthony D

2016-05-01

Hospital-acquired infections are increasing in frequency due to multidrug resistant organisms (MDROs), and the spread of MDROs has eroded our ability to treat infections. Health care professionals cannot rely solely on traditional infection control measures and antimicrobial stewardship to prevent MDRO transmission. We review research on the microbiota as a target for infection control interventions. We performed a literature review of key research findings related to the microbiota as a target for infection control interventions. These data are summarized and used to outline challenges, opportunities, and unanswered questions in the field. The healthy microbiota provides protective functions including colonization resistance, which refers to the microbiota's ability to prevent colonization and/or expansion of pathogens. Antibiotic use and other exposures in hospitalized patients are associated with disruptions of the microbiota that may reduce colonization resistance and select for antibiotic resistance. Novel methods to exploit protective mechanisms provided by an intact microbiota may provide the key to preventing the spread of MDROs in the health care setting. Research on the microbiota as a target for infection control has been limited. Epidemiologic studies will facilitate progress toward the goal of manipulating the microbiota for control of MDROs in the health care setting. Copyright © 2016 Elsevier Inc. All rights reserved.

Combination therapy of apatinib with icotinib for primary acquired icotinib resistance in patients with advanced pulmonary adenocarcinoma with EGFR mutation.

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Xia, Pinghui; Cao, Jinlin; Lv, Xiayi; Wang, Luming; Lv, Wang; Hu, Jian

2018-05-01

Multi-targeted agents represent the next generation of targeted therapies for solid tumors, and patients with acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) may also benefit from their combination with TKI therapy. Third-generation targeted drugs, such as osimertinib, are very expensive, thus a more economical solution is required. The aim of this study was to explore the use of apatinib combined with icotinib therapy for primary acquired resistance to icotinib in three patients with advanced pulmonary adenocarcinoma with EGFR mutations. We achieved favorable oncologic outcomes in all three patients, with progression-free survival of four to six months. Unfortunately, the patients ultimately had to cease combination therapy because of intolerable adverse effects of hand and foot syndrome and oral ulcers. Combination therapy of apatinib with icotinib for primary acquired resistance to icotinib may be an option for patients with advanced pulmonary adenocarcinoma with EGFR mutations, but physicians must also be aware of the side effects caused by such therapy. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Impact of amoxicillin therapy on resistance selection in patients with community-acquired lower respiratory tract infections

DEFF Research Database (Denmark)

Malhotra-Kumar, Surbhi; Van Heirstraeten, Liesbet; Coenen, Samuel

2016-01-01

OBJECTIVES: To determine the effect of amoxicillin treatment on resistance selection in patients with community-acquired lower respiratory tract infections in a randomized, placebo-controlled trial. METHODS: Patients were prescribed amoxicillin 1 g, three times daily (n = 52) or placebo (n = 50) ...

The spatiotemporal system dynamics of acquired resistance in an engineered microecology.

Science.gov (United States)

Datla, Udaya Sree; Mather, William H; Chen, Sheng; Shoultz, Isaac W; Täuber, Uwe C; Jones, Caroline N; Butzin, Nicholas C

2017-11-22

Great strides have been made in the understanding of complex networks; however, our understanding of natural microecologies is limited. Modelling of complex natural ecological systems has allowed for new findings, but these models typically ignore the constant evolution of species. Due to the complexity of natural systems, unanticipated interactions may lead to erroneous conclusions concerning the role of specific molecular components. To address this, we use a synthetic system to understand the spatiotemporal dynamics of growth and to study acquired resistance in vivo. Our system differs from earlier synthetic systems in that it focuses on the evolution of a microecology from a killer-prey relationship to coexistence using two different non-motile Escherichia coli strains. Using empirical data, we developed the first ecological model emphasising the concept of the constant evolution of species, where the survival of the prey species is dependent on location (distance from the killer) or the evolution of resistance. Our simple model, when expanded to complex microecological association studies under varied spatial and nutrient backgrounds may help to understand the complex relationships between multiple species in intricate natural ecological networks. This type of microecological study has become increasingly important, especially with the emergence of antibiotic-resistant pathogens.

Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer

Energy Technology Data Exchange (ETDEWEB)

Isozaki, Hideko [Department of Clinical Pharmaceutics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558 (Japan); Takigawa, Nagio, E-mail: ntakigaw@gmail.com [Department of General Internal Medicine 4, Kawasaki Medical School, Okayama 700-8505 (Japan); Kiura, Katsuyuki [Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama 700-8558 (Japan)

2015-04-30

The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene.

Mono- and Digalactosyldiacylglycerol Lipids Function Nonredundantly to Regulate Systemic Acquired Resistance in Plants

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Qing-ming Gao

2014-12-01

Full Text Available Summary: The plant galactolipids monogalactosyldiacylglycerol (MGDG and digalactosyldiacylglycerol (DGDG have been linked to the anti-inflammatory and cancer benefits of a green leafy vegetable diet in humans due to their ability to regulate the levels of free radicals like nitric oxide (NO. Here, we show that DGDG contributes to plant NO as well as salicylic acid biosynthesis and is required for the induction of systemic acquired resistance (SAR. In contrast, MGDG regulates the biosynthesis of the SAR signals azelaic acid (AzA and glycerol-3-phosphate (G3P that function downstream of NO. Interestingly, DGDG is also required for AzA-induced SAR, but MGDG is not. Notably, transgenic expression of a bacterial glucosyltransferase is unable to restore SAR in dgd1 plants even though it does rescue their morphological and fatty acid phenotypes. These results suggest that MGDG and DGDG are required at distinct steps and function exclusively in their individual roles during the induction of SAR. : The galactolipids monogalactosyldiacylglycerol (MGDG and digalactosyldiacylglycerol (DGDG constitute ∼80% of total membrane lipids in plants. Gao et al. now show that these galactolipids function nonredundantly to regulate systemic acquired resistance (SAR. Furthermore, they show that the terminal galactose on the α-galactose-β-galactose head group of DGDG is critical for SAR.

Expression and Significance of CYR61 Expression in Breast Cancer Tumor Specimens

National Research Council Canada - National Science Library

Lupu, Ruth

2002-01-01

Breast cancer often progresses from an estrogen (ER)-dependent, non-metastatic, antiestrogen-sensitive phenotype to an ER-independent, antiestrogen-resistant, highly invasive, and metastatic phenotype...

Contrasting ability of steroidal (ICI 182 780) and non-steroidal (EM-800) antiestrogens to inhibit reproductive organ growth in male and female mice

Czech Academy of Sciences Publication Activity Database

Kotanová, Jana; Köhlerová, Eva; Škarda, Josef

2005-01-01

Roč. 74, - (2005), s. 533-541 ISSN 0001-7213 R&D Projects: GA AV ČR IBS5045302 Institutional research plan: CEZ:AV0Z50450515 Keywords : antiestrogen * growth * mammary gland Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 0.353, year: 2005

Acquired resistance to HSP90 inhibitor 17-AAG and increased metastatic potential are associated with MUC1 expression in colon carcinoma cells.

Science.gov (United States)

Liu, Xin; Ban, Li-Li; Luo, Gang; Li, Zhi-Yao; Li, Yun-Feng; Zhou, Yong-Chun; Wang, Xi-Cai; Jin, Cong-Guo; Ye, Jia-Gui; Ma, Ding-Ding; Xie, Qing; Huang, You-Guang

2016-06-01

Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability and function of many proteins. The chaperoning of oncoproteins by HSP90 enhances the survival, growth, and invasive potential of cancer cells. HSP90 inhibitors are promising new anticancer agents, in which the benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in clinical evaluation. However, the implications of acquired resistance to this class of drug remain largely unexplored. In the present study, we have generated isogenic human colon cancer cell lines that are resistant to 17-AAG by continued culturing in the compound. Cross-resistance was found with another HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin. The resistant cells showed obvious morphology changes with a metastatic phenotype and significant increases in migration and adhesion to collagens. Western blotting analysis of epithelial-mesenchymal transition molecular markers found that expression of E-cadherin downregulated, whereas expression of N-cadherin and β-catenin upregulated in the resistant cells. Mucin 1 (MUC1) has been reported to mediate metastasis as well as chemical resistance in many cancers. Here, we found that MUC1 expression was significantly elevated in the acquired drug resistance cells. 17-AAG treatment could decrease MUC1 more in parental cells than in acquired 17-AAG-resistant cells. Further study found that knockdown of MUC1 expression by small interfering RNA could obviously re-sensitize the resistant cells to 17-AAG treatment, and decrease the cell migration and adhesion. These were coupled with a downregulation in N-cadherin and β-catenin. The results indicate that HSP90 inhibitor therapies in colon carcinomas could generate resistance and increase metastatic potential that might mediated by upregulation of MUC1 expression. Findings from this study further our understanding of the potential clinical effects of HSP90-directed therapies in

Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells.

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Keisuke Tabara

Full Text Available Non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR mutations attains a meaningful response to EGFR-tyrosine kinase inhibitors (TKIs. However, acquired resistance to EGFR-TKIs could affect long-term outcome in almost all patients. To identify the potential mechanisms of resistance, we established cell lines resistant to EGFR-TKIs from the human lung cancer cell lines PC9 and11-18, which harbored activating EGFR mutations. One erlotinib-resistant cell line from PC9 and two erlotinib-resistant cell lines and two gefitinib-resistant cell lines from 11-18 were independently established. Almost complete loss of mutant delE746-A750 EGFR gene was observed in the erlotinib-resistant cells isolated from PC9, and partial loss of the mutant L858R EGFR gene copy was specifically observed in the erlotinib- and gefitinib-resistant cells from 11-18. However, constitutive activation of EGFR downstream signaling, PI3K/Akt, was observed even after loss of the mutated EGFR gene in all resistant cell lines even in the presence of the drug. In the erlotinib-resistant cells from PC9, constitutive PI3K/Akt activation was effectively inhibited by lapatinib (a dual TKI of EGFR and HER2 or BIBW2992 (pan-TKI of EGFR family proteins. Furthermore, erlotinib with either HER2 or HER3 knockdown by their cognate siRNAs also inhibited PI3K/Akt activation. Transfection of activating mutant EGFR complementary DNA restored drug sensitivity in the erlotinib-resistant cell line. Our study indicates that loss of addiction to mutant EGFR resulted in gain of addiction to both HER2/HER3 and PI3K/Akt signaling to acquire EGFR-TKI resistance.

Naturally occurring dominant drug resistance mutations occur infrequently in the setting of recently acquired hepatitis C.

Science.gov (United States)

Applegate, Tanya L; Gaudieri, Silvana; Plauzolles, Anne; Chopra, Abha; Grebely, Jason; Lucas, Michaela; Hellard, Margaret; Luciani, Fabio; Dore, Gregory J; Matthews, Gail V

2015-01-01

Direct-acting antivirals (DAAs) are predicted to transform hepatitis C therapy, yet little is known about the prevalence of naturally occurring resistance mutations in recently acquired HCV. This study aimed to determine the prevalence and frequency of drug resistance mutations in the viral quasispecies among HIV-positive and -negative individuals with recent HCV. The NS3 protease, NS5A and NS5B polymerase genes were amplified from 50 genotype 1a participants of the Australian Trial in Acute Hepatitis C. Amino acid variations at sites known to be associated with possible drug resistance were analysed by ultra-deep pyrosequencing. A total of 12% of individuals harboured dominant resistance mutations, while 36% demonstrated non-dominant resistant variants below that detectable by bulk sequencing (that is, Resistance variants (resistance from all classes, with the exception of sofosbuvir. Dominant resistant mutations were uncommonly observed in the setting of recent HCV. However, low-level mutations to all DAA classes were observed by deep sequencing at the majority of sites and in most individuals. The significance of these variants and impact on future treatment options remains to be determined. Clinicaltrials.gov NCT00192569.

Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance.

Science.gov (United States)

Bagchi, Atrish; Haidar, Jaafar N; Eastman, Scott W; Vieth, Michal; Topper, Michael; Iacolina, Michelle D; Walker, Jason M; Forest, Amelie; Shen, Yang; Novosiadly, Ruslan D; Ferguson, Kathryn M

2018-02-01

Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2.8 Å resolution of the necitumumab Fab bound to an S468R variant of EGFR domain III. The arginine is accommodated in a large, preexisting cavity in the necitumumab paratope. We predict that this paratope shape will be permissive to other epitope substitutions, and show that necitumumab binds to most cetuximab- and panitumumab-resistant EGFR variants. We find that a simple computational approach can predict with high success which EGFR epitope substitutions abrogate antibody binding. This computational method will be valuable to determine whether necitumumab will bind to EGFR as new epitope resistance variants are identified. This method could also be useful for rapid evaluation of the effect on binding of alterations in other antibody/antigen interfaces. Together, these data suggest that necitumumab may be active in patients who are resistant to cetuximab or panitumumab through EGFR epitope mutation. Furthermore, our analysis leads us to speculate that antibodies with large paratope cavities may be less susceptible to resistance due to mutations mapping to the antigen epitope. Mol Cancer Ther; 17(2); 521-31. ©2017 AACR . ©2017 American Association for Cancer Research.

Rapid determination of anti-estrogens by gas chromatography/mass spectrometry in urine: Method validation and application to real samples.

Science.gov (United States)

Gerace, E; Salomone, A; Abbadessa, G; Racca, S; Vincenti, M

2012-02-01

A fast screening protocol was developed for the simultaneous determination of nine anti-estrogenic agents (aminoglutethimide, anastrozole, clomiphene, drostanolone, formestane, letrozole, mesterolone, tamoxifen, testolactone) plus five of their metabolites in human urine. After an enzymatic hydrolysis, these compounds can be extracted simultaneously from urine with a simple liquid-liquid extraction at alkaline conditions. The analytes were subsequently analyzed by fast-gas chromatography/mass spectrometry (fast-GC/MS) after derivatization. The use of a short column, high-flow carrier gas velocity and fast temperature ramping produced an efficient separation of all analytes in about 4 min, allowing a processing rate of 10 samples/h. The present analytical method was validated according to UNI EN ISO/IEC 17025 guidelines for qualitative methods. The range of investigated parameters included the limit of detection, selectivity, linearity, repeatability, robustness and extraction efficiency. High MS-sampling rate, using a benchtop quadrupole mass analyzer, resulted in accurate peak shape definition under both scan and selected ion monitoring modes, and high sensitivity in the latter mode. Therefore, the performances of the method are comparable to the ones obtainable from traditional GC/MS analysis. The method was successfully tested on real samples arising from clinical treatments of hospitalized patients and could profitably be used for clinical studies on anti-estrogenic drug administration.

Interconnection between flowering time control and activation of systemic acquired resistance

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Zeeshan Zahoor Banday

2015-03-01

Full Text Available The ability to avoid or neutralize pathogens is inherent to all higher organisms including plants. Plants recognize pathogens through receptors, and mount resistance against the intruders, with the help of well-elaborated defense arsenal. In response to some local infections, plants develop systemic acquired resistance (SAR, which provides heightened resistance during subsequent infections. Infected tissues generate mobile signalling molecules that travel to the systemic tissues, where they epigenetically modify expression of a set of genes to initiate the manifestation of SAR in distant tissues. Immune responses are largely regulated at transcriptional level. Flowering is a developmental transition that occurs as a result of the coordinated action of large numbers of transcription factors that respond to intrinsic signals and environmental conditions. The plant hormone salicylic acid (SA which is required for SAR activation positively regulates flowering. Certain components of chromatin remodelling complexes that are recruited for suppression of precocious flowering are also involved in suppression of SAR in healthy plants. FLOWERING LOCUS D (FLD, a putative histone demethylase positively regulates SAR manifestation and flowering transition in Arabidopsis. Similarly, incorporation of histone variant H2A.Z in nucleosomes mediated by PHOTOPERIOD-INDEPENDENT EARLY FLOWERING 1 (PIE1, an orthologue of yeast chromatin remodelling complex SWR1, concomitantly influences SAR and flowering time. SUMO conjugation and deconjugation mechanisms also similarly affect SAR and flowering in an SA-dependent manner. The evidences suggest a common underlying regulatory mechanism for activation of SAR and flowering in plants.

Glycerol-3-phosphate metabolism in wheat contributes to systemic acquired resistance against Puccinia striiformis f. sp. tritici.

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Yuheng Yang

Full Text Available Glycerol-3-phosphate (G3P is a proposed regulator of plant defense signaling in basal resistance and systemic acquired resistance (SAR. The GLY1-encoded glycerol-3-phosphate dehydrogenase (G3PDH and GLI1-encoded glycerol kinase (GK are two key enzymes involved in the G3P biosynthesis in plants. However, their physiological importance in wheat defense against pathogens remains unclear. In this study, quantification analysis revealed that G3P levels were significantly induced in wheat leaves challenged by the avirulent Puccinia striiformis f. sp. tritici (Pst race CYR23. The transcriptional levels of TaGLY1 and TaGLI1 were likewise significantly induced by avirulent Pst infection. Furthermore, knocking down TaGLY1 and TaGLI1 individually or simultaneously with barley stripe mosaic virus-induced gene silencing (BSMV-VIGS inhibited G3P accumulation and compromised the resistance in the wheat cultivar Suwon 11, whereas the accumulation of salicylic acid (SA and the expression of the SA-induced marker gene TaPR1 in plant leaves were altered significantly after gene silencing. These results suggested that G3P contributes to wheat systemic acquired resistance (SAR against stripe rust, and provided evidence that the G3P function as a signaling molecule is conserved in dicots and monocots. Meanwhile, the simultaneous co-silencing of multiple genes by the VIGS system proved to be a powerful tool for multi-gene functional analysis in plants.

Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit

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Heiko Löhr

2018-05-01

Full Text Available Summary: Anorexigenic pro-opiomelanocortin (Pomc/alpha-melanocyte stimulating hormone (αMSH neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis. Excessive feeding of larval zebrafish causes leptin resistance and reduced levels of the hypothalamic satiety mediator pomca. In turn, this leads to reduced activation of hypophysiotropic somatostatin (Sst-neurons that express the melanocortin receptor Mc4r, elevated growth hormone (GH expression in the pituitary, and enhanced somatic growth. Mc4r expression and αMSH responsiveness are conserved in Sst-expressing hypothalamic neurons of mice. Thus, acquired leptin resistance and attenuation of pomca transcription in response to excessive caloric intake may represent an ancient mechanism to promote somatic growth when food resources are plentiful. : The melanocortin system controls energy homeostasis and somatic growth, but the underlying mechanisms are elusive. Löhr et al. identify a functional neural circuit in which Pomc neurons stimulate hypothalamic somatostatin neurons, thereby inhibiting hypophyseal growth hormone production. Excessive feeding and acquired leptin resistance attenuate this pathway, allowing faster somatic growth when food resources are rich. Keywords: Pomc neuron, somatostatin neuron, somatic growth, growth hormone, melanocortin system, high-fat diet, obesity, leptin resistance, zebrafish, mouse

Frequency of escherichia coli in patients with community acquired urinary tract infection and their resistance pattern against some commonly used anti bacterials

International Nuclear Information System (INIS)

Ahmad, W.; Jamshed, F.; Ahmad, W.

2015-01-01

Urinary tract infection (UTI) is a very common health problem and Escherichia coli (E coli) are the most common organisms associated with community acquired UTI. Unfortunately these bacteria have developed extensive resistance against most of the commonly used anti-bacterials. The objective of this study was to determine the frequency and resistance pattern of E coli in patients of community acquired UTI in an area in northern part of Pakistan. Methods: Urine specimens were collected from patients who were clinically diagnosed as community acquired UTI. Urine routine examination (Urine RE) was done and samples positive for UTI (Pus cells >10/High Power Field) were included in the study. These samples were inoculated on Eosin Methylene Blue (EMB) agar plates and incubated at 37 degree C for 36 hours. Suspected colonies were then inoculated further on EMB plates for pure cultures of E coli characterized by certain morphological characteristics. IMViC was applied for the confirmation of E coli. In vitro antibiotic susceptibility tests of E coli were performed with standardized commercial susceptibility discs (OXOID). Results: Out of 50 specimens, positive for UTI by urine RE, 20 showed pure growth of E coli on culture (40%). The majority of the isolates (28%; n=14) were from women while only 12% (n=6) were from men. Escherichia coli showed a high rate of resistance towards Ampicillin (90%), Tetracycline (70%), Erythromycin (70%) and Trimethoprim-Sulfamethoxazole (55%). Sparfloxacin showed better results (45%) than ciprofloxacin (50%). Out of 20 E coli isolates, two (10%) were resistant to all the antibacterials except chloramphenicol, eight isolates (40%) showed resistance to six or more than six while 14 (70%) were resistant to four or more than four drugs. Conclusion: Rate of resistance of E coli against commonly used antibacterials was quite high and majority of the strains showed multidrug resistance. (author)

Local cytokine profile and cytological status in children with community-acquired pneumonia arising on the background of the reduced resistance of the organism

Directory of Open Access Journals (Sweden)

T. G. Malanicheva

2017-01-01

Full Text Available Research objective: to study the features of the cytokine profile and cytological status in children with community-acquired pneumonia, proceeding against a background of reduced resistance of the organism for improving treatment methods. 53 children aged 3 to 7 years were examined. The main group consisted of 30 children with community-acquired pneumonia, which ran against a background of reduced resistance of the body. The comparison group consisted of 23 children with community-acquired pneumonia who had good resistance. Local immunity was studied on the basis of  valuation of cytokine status parameters (tumor necrotic factor-α, interleukin-8, and interferon-γ and cellular composition with an estimate of destructive changes in neutrophils in induced sputum. It was revealed that in the main group of children there is a depression of the neutrophils’ release into the bronchial secretion and a marked increase in the number of neutrophils with maximum signs of destruction of the nucleus and cytoplasm against the background of cytokine status imbalance, manifested in an increase in the content of the tumor necrotic factor-α and a decrease in interleukin-8 and interferon- γ. Inclusion in the traditional therapy of community-acquired pneumonia in children who have a reduced resistance, anti-inflammatory drug fenspiride, eliminates the imbalance of proinflammatory cytokines and increases the release of functionally complete neutrophils in the bronchial secret.

The impact of nosocomially-acquired resistant Pseudomonas aeruginosa infection in a burn unit.

Science.gov (United States)

Armour, Alexis D; Shankowsky, Heather A; Swanson, Todd; Lee, Jonathan; Tredget, Edward E

2007-07-01

Nosocomially-acquired Pseudomonas aeruginosa remains a serious cause of infection and septic mortality in burn patients. This study was conducted to quantify the impact of nosocomially-transmitted resistant P. aeruginosa in a burn population. Using a TRACS burn database, 48 patients with P. aeruginosa resistant to gentamicin were identified (Pseudomonas group). Thirty-nine were case-matched to controls without resistant P. aeruginosa cultures (control group) for age, total body surface area, admission year, and presence of inhalation injury. Mortality and various morbidity endpoints were examined, as well as antibiotic costs. There was a significantly higher mortality rate in the Pseudomonas group (33% vs. 8%, p products used (packed cells 51.1 +/- 8.0 vs. 21.1 +/- 3.4, p < 0.01; platelets 11.9 +/- 3.0 vs. 1.4 +/- 0.7, p < 0.01) were all significantly higher in the Pseudomonas group. Cost of antibiotics was also significantly higher ($2,658.52 +/- $647.93 vs. $829.22 +/- $152.82, p < 0.01). Nosocomial colonization or infection, or both, of burn patients with aminoglycoside-resistant P. aeruginosa is associated with significantly higher morbidity, mortality, and cost of care. Increased resource consumption did not prevent significantly higher mortality rates when compared with that of control patients. Thus, prevention, identification, and eradication of nosocomial Pseudomonas contamination are critical for cost-effective, successful burn care.

Nasopharyngeal bacterial carriage and antimicrobial resistance in underfive children with community acquired pneumonia

Directory of Open Access Journals (Sweden)

Cissy B. Kartasasmita

2001-12-01

Full Text Available Lung puncture is the best way to determine the etiology of pneumonia since it yields the highest rate of positive cultures. However, this procedure is difficult, especially for a study in the community. According to WHO, isolates to be tested for antimicrobial resistance in the community should be obtained from nasopharyngeal (NP swabs. Previous studies support the use of NP isolates to determine antimicrobial resistance patterns of isolates from children with pneumonia. The aim of our study was to know the bacterial patterns of the nasopharynx in underfive children with community acquired pneumonia and their antimicrobial resistance. The study was carried out in 4 Primary Health Clinics in Majalaya sub-district, Bandung, Indonesia. All underfives with cough or difficult breathing and classified as having non-severe pneumonia (WHO guidelines, were included in the study. Nasopharyngeal swabs (CDC/WHO Manual were obtained by the doctor, the swabs were placed in Amies transport medium and stored in a sterile jar before taken to the laboratory in the same day. All children were treated with co-trimoxazole. During the nine month study, 698 children with clinical signs of non-severe pneumonia were enrolled. About 25% of the nasopharyngeal specimens yielded bacterial isolates; the two most frequently found were S. pneumoniae and S. epidermidis. The antimicrobial resistance test to co-trimoxazole showed 48.2% S. pneumoniae strain had full resistance and 32.7% showed intermediate resistance to co-trimoxazole. This result is almost similar to other studies from Asian countries. It seems that H. influenzae is not a problem in the study area; however, further studies are needed.

Nasopharyngeal bacterial carriage and antimicrobial resistance in underfive children with community acquired pneumonia

Directory of Open Access Journals (Sweden)

Cissy B. Kartasasmita

2002-09-01

Full Text Available Pathogens in nasopharynx is a significant risk factor of pneumonia. According to WHO, isolates to be tested for antimicrobial resistance in the community should be obtained from nasopharyngeal (NP swabs. The aim of this study is to know the bacterial patterns of the nasopharynx and cotrimoxazole resistance in under five-year old children with community acquired pneumonia. The study was carried out in 4 primary health clinic (Puskesmas in Majalaya sub-district, Bandung, West Java, Indonesia. All underfive children with cough and/or difficult breathing and classified as having non-severe pneumonia (WHO guidelines were placed in Amies transport medium and stored in a sterile jar, before taken to the laboratory for further examination, in the same day. During this nine month study, 698 children with clinical signs of non-severe pneumonia were enrolled. About 25.4% (177/698 of the nasopharyngeal specimens yielded bacterial isolates; i.e. 120 (67.8% were positive for S pneumoniae, 21 for S epidermidis and alpha streptococcus, 6 for Hafnia alvei, 5 for S aureus, 2 for B catarrhalis, and 1(0.6% for H influenza and Klebsiella, respectively. The antimicrobial resistance test to cotrimoxazole showed that 48.2% of S pneumoniae strain had full resistance and 32.7% showed intermediate resistance to cotrimoxazole. This result is almost similar to the other studies from Asian countries. It seems that H influenza is not a problem in the study area, however, a further study is needed. (Med J Indones 2002; 11: 164-8 Keywords: nasopharyngeal swab, S pneumoniae, cotrimoxazole

Determination and confirmation of selective estrogen receptor modulators (SERMs), anti-estrogens and aromatase inhibitors in bovine and porcine urine using UHPLC-MS/MS.

Science.gov (United States)

Meijer, Thijs; Essers, Martien L; Kaklamanos, George; Sterk, Saskia S; van Ginkel, Leendert A

2017-04-01

Selective estrogen receptor modulators (SERMs), anti-estrogens and aromatase inhibitors are prohibited in human sports doping. However, they also present a risk of being used illegally in animal husbandry for fattening purposes. A method was developed and validated using UHPLC-MS/MS for the determination and confirmation of SERMs, anti-estrogens and aromatase inhibiters in bovine and porcine urine. This method was used in a survey of more than 200 bovine and porcine urine samples from Dutch farms. In 18 out of 103 porcine urine samples (17%) and two out of 114 bovine samples (2%) formestane, an aromatase inhibitor, was detected. None of the other compounds was detected. From human doping control it is known that formestane can, in some cases, be of natural origin. Analyses of reference samples from untreated bovine and porcine animals demonstrated the presence of formestane in bovine animals, but not yet in porcine animals. Future research will focus on whether the detected formestane in porcine and bovine urine is from endogenous or exogenous origin, using GC-c-IRMS.

Travel to Asia and traveller's diarrhoea with antibiotic treatment are independent risk factors for acquiring ciprofloxacin-resistant and extended spectrum β-lactamase-producing Enterobacteriaceae-a prospective cohort study.

Science.gov (United States)

Reuland, E A; Sonder, G J B; Stolte, I; Al Naiemi, N; Koek, A; Linde, G B; van de Laar, T J W; Vandenbroucke-Grauls, C M J E; van Dam, A P

2016-08-01

Travel to (sub)tropical countries is a well-known risk factor for acquiring resistant bacterial strains, which is especially of significance for travellers from countries with low resistance rates. In this study we investigated the rate of and risk factors for travel-related acquisition of extended spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E), ciprofloxacin-resistant Enterobacteriaceae (CIPR-E) and carbapenem-resistant Enterobacteriaceae. Data before and after travel were collected from 445 participants. Swabs were cultured with an enrichment broth and sub-cultured on selective agar plates for ESBL detection, and on plates with a ciprofloxacin disc. ESBL production was confirmed with the double-disc synergy test. Species identification and susceptibility testing were performed with the Vitek-2 system. All isolates were subjected to ertapenem Etest. ESBL and carbapenemase genes were characterized by PCR and sequencing. Twenty-seven out of 445 travellers (6.1%) already had ESBL-producing strains and 45 of 445 (10.1%) travellers had strains resistant to ciprofloxacin before travel. Ninety-eight out of 418 (23.4%) travellers acquired ESBL-E and 130 of 400 (32.5%) travellers acquired a ciprofloxacin-resistant strain. Of the 98 ESBL-E, predominantly Escherichia coli and predominantly blaCTX-M-15, 56% (55/98) were resistant to gentamicin, ciprofloxacin and co-trimoxazole. Multivariate analysis showed that Asia was a high-risk area for ESBL-E as well as CIPR-E acquisition. Travellers with diarrhoea combined with antimicrobial use were significantly at higher risk for acquisition of resistant strains. Only one carbapenemase-producing isolate was acquired, isolated from a participant after visiting Egypt. In conclusion, travelling to Asia and diarrhoea combined with antimicrobial use are important risk factors for acquiring ESBL-E and CIPR-E. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

DEFF Research Database (Denmark)

Joshi, Tejal; Elias, Daniel; Stenvang, Jan

2016-01-01

Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of mi......+ breast cancer patients receiving adjuvant tamoxifen mono-therapy. Our results provide new insight into the molecular mechanisms of tamoxifen resistance and may form the basis for future medical intervention for the large number of women with tamoxifen-resistant ER+ breast cancer.......RNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

Community-acquired necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus ST30-SCCmecIVc-spat019-PVL positive in San Antonio de Areco, Argentina

Directory of Open Access Journals (Sweden)

Silvina Fernández

2015-03-01

Full Text Available Community-acquired methicillin-resistant Staphylococcus aureus is the first cause of skin and soft tissue infections, but can also produce severe diseases such as bacteremia, osteomyelitis and necrotizing pneumonia. Some S. aureus lineages have been described in cases of necrotizing pneumonia worldwide, usually in young, previously healthy patients. In this work, we describe a fatal case of necrotizing pneumonia due to community-acquired methicillin-resistant S. aureus clone ST30-SCCmecIVc-spat019-PVL positive in an immunocompetent adult patient.

A horizontally gene transferred copper resistance locus confers hyper‐resistance to antibacterial copper toxicity and enables survival of community acquired methicillin resistant Staphylococcus aureus USA300 in macrophages

Science.gov (United States)

Purves, Joanne; Thomas, Jamie; Riboldi, Gustavo P.; Zapotoczna, Marta; Tarrant, Emma; Andrew, Peter W.; Londoño, Alejandra; Planet, Paul J.; Geoghegan, Joan A.; Waldron, Kevin J.

2018-01-01

Summary Excess copper is highly toxic and forms part of the host innate immune system's antibacterial arsenal, accumulating at sites of infection and acting within macrophages to kill engulfed pathogens. We show for the first time that a novel, horizontally gene transferred copper resistance locus (copXL), uniquely associated with the SCCmec elements of the highly virulent, epidemic, community acquired methicillin resistant Staphylococcus aureus (CA‐MRSA) USA300, confers copper hyper‐resistance. These genes are additional to existing core genome copper resistance mechanisms, and are not found in typical S. aureus lineages, but are increasingly identified in emerging pathogenic isolates. Our data show that CopX, a putative P1B‐3‐ATPase efflux transporter, and CopL, a novel lipoprotein, confer copper hyper‐resistance compared to typical S. aureus strains. The copXL genes form an operon that is tightly repressed in low copper environments by the copper regulator CsoR. Significantly, CopX and CopL are important for S. aureus USA300 intracellular survival within macrophages. Therefore, the emergence of new S. aureus clones with the copXL locus has significant implications for public health because these genes confer increased resistance to antibacterial copper toxicity, enhancing bacterial fitness by altering S. aureus interaction with innate immunity. PMID:29521441

Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines

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Yu-Ting Kao

2014-07-01

Full Text Available Resistance to chemotherapeutic drugs is one of the major challenges in the treatment of cancer. A better understanding of how resistance arises and what molecular alterations correlate with resistance is the key to developing novel effective therapeutic strategies. To investigate the underlying mechanisms of gemcitabine (Gem resistance and provide possible therapeutic options, three Gem-resistant urothelial carcinoma sublines were established (NG0.6, NG0.8, and NG1.0. These cells were cross-resistant to arabinofuranosyl cytidine and cisplatin, but sensitive to 5-fluorouracil. The resistant cells expressed lower values of [hENT1 × dCK/RRM1 × RRM2] mRNA ratio. Two adenosine triphosphate-binding cassette proteins ABCD1 as well as multidrug resistance protein 1 were elevated. Moreover, cyclin D1, cyclin-dependent kinases 2 and 4 were upregulated, whereas extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK activity were repressed significantly. Administration of p38 MAPK inhibitor significantly reduced the Gem sensitivity in NTUB1 cells, whereas that of an extracellular signal-regulated kinase MAPK inhibitor did not. Furthermore, the Gem-resistant sublines also exhibited higher migration ability. Forced expression of p38 MAPK impaired the cell migration activity and augmented Gem sensitivity in NG1.0 cells. Taken together, these results demonstrate that complex mechanisms were merged in acquiring Gem resistance and provide information that can be important for developing therapeutic targets for treating Gem-resistant tumors.

NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/ mTOR phosphorylation

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Sun ZH

2015-01-01

Full Text Available Zhihua Sun,2,* Qiuhui li,1,* Sheng Zhang,1 Jing Chen,1 Lili Huang,3 Jinghua Ren,1 Yu Chang,1 Yichen Liang,1 Gang Wu1 1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Oncology department, Xiangyang central Hospital, Xiangyang, Hubei, People’s Republic of China; 3Radiation Oncology Department, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People's Republic of China *These authors contributed equally to this work Background: Patients harboring activating mutations in epidermal growth factor receptors (EGFR are particularly sensitive to EGFR tyrosine kinase inhibitors (TKIs. However, most patients develop an acquired resistance after a period of about 10 months. This study focuses on the therapeutic effect of NVP-BEZ235, a dual inhibitor of phosphatidylinositol- 3-kinase/mammalian target of rapamycin (PI3K/mTOR, in gefitinib-resistant non-small cell lung cancer. Methods: H1975 cell line was validated as a gefitinib-resistant cell model by the nucleotide-sequence analysis. We used the 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay to detect the growth of H1975 cell line in vitro. H1975 cells' migration was detected by the migration assay. Xenograft models were used to investigate the growth of gefitinib-resistant non-small cell lung cancer in vivo. Western blot and immunohistochemical analysis were used to investigate the level of PI3K/protein kinase B(AKT/mTOR signaling pathway proteins. Results: We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro. Similarly, H1975 cell migration was reduced by NVP-BEZ235. Further experiments revealed that NVP-BEZ235 attenuated the phosphorylation of PI3K/AKT/mTOR signaling pathway proteins. Conclusion: Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K

Meta-Analysis of Clinical Studies Supports the Pharmacokinetic Variability Hypothesis for Acquired Drug Resistance and Failure of Antituberculosis Therapy

OpenAIRE

Pasipanodya, Jotam G.; Srivastava, Shashikant; Gumbo, Tawanda

2012-01-01

Laboratory studies have questioned nonadherence as a cause of antituberculosis drug failure and propose that between-patient pharmacokinetic variability may be the cause. This meta-analysis provides clinical evidence that pharmacokinetic variability of isoniazid alone leads to worse microbiological failure, relapse, and acquired drug resistance.

Disseminated cryptococcosis and fluconazole resistant oral candidiasis in a patient with acquired immunodeficiency syndrome (AIDS).

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Kothavade, Rajendra J; Oberai, Chetan M; Valand, Arvind G; Panthaki, Mehroo H

2010-10-28

Disseminated cryptococcosis and recurrent oral candidiasis was presented in a-heterosexual AIDS patient. Candida tropicalis (C.tropicalis) was isolated from the oral pseudomembranous plaques and Cryptococcus neoformans (C. neoformans) was isolated from maculopapular lesions on body parts (face, hands and chest) and body fluids (urine, expectorated sputum, and cerebrospinal fluid). In vitro drug susceptibility testing on the yeast isolates demonstrated resistance to fluconazole acquired by C. tropicalis which was a suggestive possible root cause of recurrent oral candidiasis in this patient.

Involvement of ethylene in lesion development and systemic acquired resistance in tobacco during the hypersensitive reaction to tobacco mosaic virus

NARCIS (Netherlands)

Knoester, M.; Linthorst, H.J.M.; Bol, J.F.; Loon, L.C. van

2001-01-01

Different approaches were taken to investigate the significance of ethylene in lesion development and systemic acquired resistance (SAR) in tobacco (Nicotiana tabacum) reacting hypersensitively to tobacco mosaic virus (TMV). Gaseous ethylene, the ethylene precursor 1-aminocyclopropane-1-carboxylic

Community-Acquired Methicillin-Resistant Staphylococcus aureus: The New Face of an Old Foe?

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Udo, Edet E.

2013-01-01

The burden of infections caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is increasing among different patient populations globally. As CA-MRSA has become established in healthcare facilities, the range of infections caused by them has also increased. Molecular characterization of CA-MRSA isolates obtained from different centers has revealed significant diversity in their genetic backgrounds. Although many CA-MRSA strains are still susceptible to non-β-lactam antibiotics, multiresistance to non-β-lactam agents has emerged in some clones, posing substantial problems for empirical and directed therapy of infections caused by these strains. Some CA-MRSA clones have acquired the capacity to spread locally and internationally. CA-MRSA belonging to ST80-MRSA-IV and ST30-MRSA-IV appear to be the dominant clones in the countries of the Gulf Cooperation Council (GCC). The emergence of pandemic CA-MRSA clones not only limits therapeutic options but also presents significant challenges for infection control. Continued monitoring of global epidemiology and emerging drug resistance data is critical for the effective management of these infections. PMID:24051949

A trade-off between natural and acquired antibody production in a reptile: implications for long-term resistance to disease

Directory of Open Access Journals (Sweden)

Franziska C. Sandmeier

2012-08-01

Vertebrate immune systems are understood to be complex and dynamic, with trade-offs among different physiological components (e.g., innate and adaptive immunity within individuals and among taxonomic lineages. Desert tortoises (Gopherus agassizii immunised with ovalbumin (OVA showed a clear trade-off between levels of natural antibodies (NAbs; innate immune function and the production of acquired antibodies (adaptive immune function. Once initiated, acquired antibody responses included a long-term elevation in antibodies persisting for more than one year. The occurrence of either (a high levels of NAbs or (b long-term elevations of acquired antibodies in individual tortoises suggests that long-term humoral resistance to pathogens may be especially important in this species, as well as in other vertebrates with slow metabolic rates, concomitantly slow primary adaptive immune responses, and long life-spans.

Update on the prevention and control of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA).

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Skov, Robert; Christiansen, Keryn; Dancer, Stephanie J; Daum, Robert S; Dryden, Matthew; Huang, Yhu-Chering; Lowy, Franklin D

2012-03-01

The rapid dissemination of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) since the early 2000s and the appearance of new successful lineages is a matter of concern. The burden of these infections varies widely between different groups of individuals and in different regions of the world. Estimating the total burden of disease is therefore problematic. Skin and soft-tissue infections, often in otherwise healthy young individuals, are the most common clinical manifestation of these infections. The antibiotic susceptibilities of these strains also vary, although they are often more susceptible to 'traditional' antibiotics than related hospital-acquired strains. Preventing the dissemination of these organisms throughout the general population requires a multifaceted approach, including screening and decolonisation, general hygiene and cleaning measures, antibiotic stewardship programmes and, in the future, vaccination. The current evidence on the prevention and control of CA-MRSA is appraised and summarised in this review. Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Bacterial Etiology and Antibiotic Resistance Profile of Community-Acquired Urinary Tract Infections in a Cameroonian City.

Science.gov (United States)

Nzalie, Rolf Nyah-Tuku; Gonsu, Hortense Kamga; Koulla-Shiro, Sinata

2016-01-01

Introduction. Community-acquired urinary tract infections (CAUTIs) are usually treated empirically. Geographical variations in etiologic agents and their antibiotic sensitivity patterns are common. Knowledge of antibiotic resistance trends is important for improving evidence-based recommendations for empirical treatment of UTIs. Our aim was to determine the major bacterial etiologies of CAUTIs and their antibiotic resistance patterns in a cosmopolitan area of Cameroon for comparison with prescription practices of local physicians. Methods. We performed a cross-sectional descriptive study at two main hospitals in Yaoundé, collecting a clean-catch mid-stream urine sample from 92 patients having a clinical diagnosis of UTI. The empirical antibiotherapy was noted, and identification of bacterial species was done on CLED agar; antibiotic susceptibility testing was performed using the Kirby-Bauer disc diffusion method. Results. A total of 55 patients had samples positive for a UTI. Ciprofloxacin and amoxicillin/clavulanic acid were the most empirically prescribed antibiotics (30.9% and 23.6%, resp.); bacterial isolates showed high prevalence of resistance to both compounds. Escherichia coli (50.9%) was the most common pathogen, followed by Klebsiella pneumoniae (16.4%). Prevalence of resistance for ciprofloxacin was higher compared to newer quinolones. Conclusions. E. coli and K. pneumoniae were the predominant bacterial etiologies; the prevalence of resistance to commonly prescribed antibiotics was high.

Loss of Nuclear Localized and Tyrosine Phosphorylated Stat5 in Breast Cancer Predicts Poor Clinical Outcome and Increased Risk of Antiestrogen Therapy Failure

Science.gov (United States)

Peck, Amy R.; Witkiewicz, Agnieszka K.; Liu, Chengbao; Stringer, Ginger A.; Klimowicz, Alexander C.; Pequignot, Edward; Freydin, Boris; Tran, Thai H.; Yang, Ning; Rosenberg, Anne L.; Hooke, Jeffrey A.; Kovatich, Albert J.; Nevalainen, Marja T.; Shriver, Craig D.; Hyslop, Terry; Sauter, Guido; Rimm, David L.; Magliocco, Anthony M.; Rui, Hallgeir

2011-01-01

Purpose To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. Patients and Methods Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. Results Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). Conclusion Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy. PMID:21576635

Cholesterol-producing transgenic Caenorhabditis elegans lives longer due to newly acquired enhanced stress resistance

International Nuclear Information System (INIS)

Lee, Eun-Young; Shim, Yhong-Hee; Chitwood, David J.; Hwang, Soon Baek; Lee, Junho; Paik, Young-Ki

2005-01-01

Because Caenorhabditis elegans lacks several components of the de novo sterol biosynthetic pathway, it requires sterol as an essential nutrient. Supplemented cholesterol undergoes extensive enzymatic modification in C. elegans to form other sterols of unknown function. 7-Dehydrocholesterol reductase (DHCR) catalyzes the reduction of the Δ 7 double bond of sterols and is suspected to be defective in C. elegans, in which the major endogenous sterol is 7-dehydrocholesterol (7DHC). We microinjected a human DHCR expression vector into C. elegans, which was then incorporated into chromosome by γ-radiation. This transgenic C. elegans was named cholegans, i.e., cholesterol-producing C. elegans, because it was able to convert 7DHC into cholesterol. We investigated the effects of changes in sterol composition on longevity and stress resistance by examining brood size, mean life span, UV resistance, and thermotolerance. Cholegans contained 80% more cholesterol than the wild-type control. The brood size of cholegans was reduced by 40% compared to the wild-type control, although the growth rate was not significantly changed. The mean life span of cholegans was increased up to 131% in sterol-deficient medium as compared to wild-type. The biochemical basis for life span extension of cholegans appears to partly result from its acquired resistance against both UV irradiation and thermal stress

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

DEFF Research Database (Denmark)

Joshi, Tejal; Elias, Daniel; Stenvang, Jan

2016-01-01

and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated. Using specific chemical inhibitors......Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA......-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

[Relationship between phenomenon of acquired activated protein C resistance and antiphospholipid antibodies in patients with systemic lupus erythematosus].

Science.gov (United States)

Hu, Y Q; Chen, F P; Xie, Q Z

2001-10-28

To determine the occurrence of activated protein C resistance (APCR), to identify APCR is associated with thrombotic events (TEs), and acquired APCR is associated with the presence of antiphospholipid antibodies (APLAs) in 30 patients with systemic lupus erythematosus (SLE). Laboratory tests included dilute Russell's viper venom time assay for LA (dRVVT-LA), ELISA assay for ACL, APC sensitivity ratio, and factor V Leiden were detected by PCR-Mnl/I digestion. Acquired APCR was presented in 14(46.67%) of 30 patients. Factor V Leiden was not found in any patients. The incidence of TEs in the APCR-positive patients was significantly higher than that in the APCR-negative patients (42.85% vs 6.25%, P TEs in the LA-positive patients was also significantly higher than that in the LA-negative patients (50% vs 11.1%, P TEs (P TEs. Acquired APCR may not reflect the interference of LAs with the protein C pathway which may represent a mechanism of LA-associated TEs.

Community-acquired necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus ST30-SCCmecIVc-spat019-PVL positive in San Antonio de Areco, Argentina.

Science.gov (United States)

Fernandez, Silvina; Murzicato, Sofía; Sandoval, Orlando; Fernández-Canigia, Liliana; Mollerach, Marta

2015-01-01

Community-acquired methicillin-resistant Staphylococcus aureus is the first cause of skin and soft tissue infections, but can also produce severe diseases such as bacteremia, osteomyelitis and necrotizing pneumonia. Some S. aureus lineages have been described in cases of necrotizing pneumonia worldwide, usually in young, previously healthy patients. In this work, we describe a fatal case of necrotizing pneumonia due to community-acquired methicillin-resistant S. aureus clone ST30-SCCmecIVc-spat019-PVL positive in an immunocompetent adult patient. Copyright © 2014 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Circumvention of inherent or acquired cytotoxic drug resistance in vitro using combinations of modulating agents.

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Cadagan, David; Merry, Stephen

2013-10-01

Modulating agents are used to circumvent drug resistance in the clinical setting. However achievable serum concentrations are often lower than those which are optimal in vitro. Combination of modulating agents with non-overlapping toxicities may overcome this obstacle. We have investigated combinations of three modulating agents (quinine, verapamil, and cinnarizine) to circumvent inherent or acquired resistance to the cytotoxic drugs doxorubicin, vincristine and paclitaxel. Dose-response curves to cytotoxic drugs in the presence/absence of modulating agents were determined using colony formation and cell proliferation assays. Doxorubicin accumulation into cell monolayers was measured by fluorescence spectrophotometry. Greater (1.9-fold) sensitisation to particular cytotoxic drugs was observed for certain combinations of modulating agents compared to individual effects. The most effective combination was quinine-plus-verapamil with the cytotoxic drug doxorubicin. This increase in sensitivity was associated with increased doxorubicin accumulation. Such enhanced activity was, however, not observed for all combinations of modulating agents or for all studied cytotoxic drugs. The findings of the present study suggest certain combinations of modulating agents to have a clinical role in circumventing drug resistance. Particular combinations of modulating agents must be carefully chosen to suit particular cytotoxic drug treatments.

Trade-offs with stability modulate innate and mutationally acquired drug-resistance in bacterial dihydrofolate reductase enzymes.

Science.gov (United States)

Matange, Nishad; Bodkhe, Swapnil; Patel, Maitri; Shah, Pooja

2018-06-05

Structural stability is a major constraint on the evolution of protein sequences. However, under strong directional selection, mutations that confer novel phenotypes but compromise structural stability of proteins may be permissible. During the evolution of antibiotic resistance, mutations that confer drug resistance often have pleiotropic effects on the structure and function of antibiotic-target proteins, usually essential metabolic enzymes. In this study, we show that trimethoprim-resistant alleles of dihydrofolate reductase from Escherichia coli (EcDHFR) harbouring the Trp30Gly, Trp30Arg or Trp30Cys mutations are significantly less stable than the wild type making them prone to aggregation and proteolysis. This destabilization is associated with lower expression level resulting in a fitness cost and negative epistasis with other TMP-resistant mutations in EcDHFR. Using structure-based mutational analysis we show that perturbation of critical stabilizing hydrophobic interactions in wild type EcDHFR enzyme explains the phenotypes of Trp30 mutants. Surprisingly, though crucial for the stability of EcDHFR, significant sequence variation is found at this site among bacterial DHFRs. Mutational and computational analyses in EcDHFR as well as in DHFR enzymes from Staphylococcus aureus and Mycobacterium tuberculosis demonstrate that natural variation at this site and its interacting hydrophobic residues, modulates TMP-resistance in other bacterial DHFRs as well, and may explain the different susceptibilities of bacterial pathogens to trimethoprim. Our study demonstrates that trade-offs between structural stability and function can influence innate drug resistance as well as the potential for mutationally acquired drug resistance of an enzyme. ©2018 The Author(s).

Bacterial Etiology and Antibiotic Resistance Profile of Community-Acquired Urinary Tract Infections in a Cameroonian City

Directory of Open Access Journals (Sweden)

Rolf Nyah-tuku Nzalie

2016-01-01

Full Text Available Introduction. Community-acquired urinary tract infections (CAUTIs are usually treated empirically. Geographical variations in etiologic agents and their antibiotic sensitivity patterns are common. Knowledge of antibiotic resistance trends is important for improving evidence-based recommendations for empirical treatment of UTIs. Our aim was to determine the major bacterial etiologies of CAUTIs and their antibiotic resistance patterns in a cosmopolitan area of Cameroon for comparison with prescription practices of local physicians. Methods. We performed a cross-sectional descriptive study at two main hospitals in Yaoundé, collecting a clean-catch mid-stream urine sample from 92 patients having a clinical diagnosis of UTI. The empirical antibiotherapy was noted, and identification of bacterial species was done on CLED agar; antibiotic susceptibility testing was performed using the Kirby-Bauer disc diffusion method. Results. A total of 55 patients had samples positive for a UTI. Ciprofloxacin and amoxicillin/clavulanic acid were the most empirically prescribed antibiotics (30.9% and 23.6%, resp.; bacterial isolates showed high prevalence of resistance to both compounds. Escherichia coli (50.9% was the most common pathogen, followed by Klebsiella pneumoniae (16.4%. Prevalence of resistance for ciprofloxacin was higher compared to newer quinolones. Conclusions. E. coli and K. pneumoniae were the predominant bacterial etiologies; the prevalence of resistance to commonly prescribed antibiotics was high.

Hospital-Acquired Methicillin-resistant Staphylococcus aureus Bacteremia Related to Medicare Antibiotic Prescriptions: A State-Level Analysis.

Science.gov (United States)

Fukunaga, Bryce T; Sumida, Wesley K; Taira, Deborah A; Davis, James W; Seto, Todd B

2016-10-01

Methicillin-resistant Staphylococcus aureus (MRSA) results in almost half of all deaths caused by antibiotic resistant organisms. Current evidence suggests that MRSA infections are associated with antibiotic use. This study examined state-level data to determine whether outpatient antibiotic use was associated with hospital-acquired MRSA (HA-MRSA) infections. The 2013 Centers for Disease Control and Prevention (CDC) Healthcare-Associated Infections Progress Report was used to obtain HA-MRSA infection rates. Data on the number of antibiotic prescriptions with activity towards methicillin-sensitive Staphylococcus aureus (MSSA) at the state level were obtained from the 2013 Medicare Provider Utilization and Payment Data: Part D Prescriber Public Use File. Pearson's correlation coefficient was used to analyze the relationship between the number of antibiotic prescriptions and HA-MRSA infection rates. The average number of HA-MRSA infections was 0.026 per 1000 persons with the highest rates concentrated in Southeastern and Northeastern states. The average number of outpatient prescriptions per capita was 0.74 with the highest rates in Southeastern states. A significant correlation (ρ = 0.64, P resistance.

Differences in microbiological profile between community-acquired, healthcare-associated and hospital-acquired infections.

Science.gov (United States)

Cardoso, Teresa; Ribeiro, Orquídea; Aragão, Irene; Costa-Pereira, Altamiro; Sarmento, António

2013-01-01

Microbiological profiles were analysed and compared for intra-abdominal, urinary, respiratory and bloodstream infections according to place of acquisition: community-acquired, with a separate analysis of healthcare-associated, and hospital-acquired. Prospective cohort study performed at a university tertiary care hospital over 1 year. Inclusion criteria were meeting the Centers for Disease Control definition of intra-abdominal, urinary, respiratory and bloodstream infections. A total of 1035 patients were included in the study. More than 25% of intra-abdominal infections were polymicrobial; multi-drug resistant gram-negatives were 38% in community-acquired, 50% in healthcare-associated and 57% in hospital-acquired. E. coli was the most prevalent among urinary infections: 69% in community-acquired, 56% in healthcare-associated and 26% in hospital-acquired; ESBL producers' pathogens were 10% in healthcare-associated and 3% in community-acquired and hospital-acquired. In respiratory infections Streptococcus pneumoniae was the most prevalent in community-acquired (54%) and MRSA in healthcare-associated (24%) and hospital-acquired (24%). A significant association was found between MRSA respiratory infection and hospitalization in the previous year (adjusted OR = 6.3), previous instrumentation (adjusted OR = 4.3) and previous antibiotic therapy (adjusted OR = 5.7); no cases were documented among patients without risk factors. Hospital mortality rate was 10% in community-acquired, 14% in healthcare-associated and 19% in hospital-acquired infection. This study shows that healthcare-associated has a different microbiologic profile than those from community or hospital acquired for the four main focus of infection. Knowledge of this fact is important because the existing guidelines for community-acquired are not entirely applicable for this group of patients.

Interpretation of deep directional resistivity measurements acquired in high-angle and horizontal wells using 3-D inversion

Science.gov (United States)

Puzyrev, Vladimir; Torres-Verdín, Carlos; Calo, Victor

2018-05-01

The interpretation of resistivity measurements acquired in high-angle and horizontal wells is a critical technical problem in formation evaluation. We develop an efficient parallel 3-D inversion method to estimate the spatial distribution of electrical resistivity in the neighbourhood of a well from deep directional electromagnetic induction measurements. The methodology places no restriction on the spatial distribution of the electrical resistivity around arbitrary well trajectories. The fast forward modelling of triaxial induction measurements performed with multiple transmitter-receiver configurations employs a parallel direct solver. The inversion uses a pre-conditioned gradient-based method whose accuracy is improved using the Wolfe conditions to estimate optimal step lengths at each iteration. The large transmitter-receiver offsets, used in the latest generation of commercial directional resistivity tools, improve the depth of investigation to over 30 m from the wellbore. Several challenging synthetic examples confirm the feasibility of the full 3-D inversion-based interpretations for these distances, hence enabling the integration of resistivity measurements with seismic amplitude data to improve the forecast of the petrophysical and fluid properties. Employing parallel direct solvers for the triaxial induction problems allows for large reductions in computational effort, thereby opening the possibility to invert multiposition 3-D data in practical CPU times.

Community-acquired methicillin-resistant Staphylococcus aureus: an emerging pathogen in orthopaedics.

Science.gov (United States)

Marcotte, Anthony L; Trzeciak, Marc A

2008-02-01

Staphylococcus aureus (S aureus) remains one of the most common pathogens for skin and soft-tissue infections encountered by the orthopaedic surgeon. Community-acquired methicillin-resistant S aureus (CA-MRSA) has become increasingly prevalent, particularly among athletes, children in day care, homeless persons, intravenous drug users, men who have sex with men, military recruits, certain minorities (ie, Alaskan Natives, Native Americans, Pacific Islanders), and prison inmates. Risk factors include antibiotic use within the preceding year, crowded living conditions, compromised skin integrity, contaminated surfaces, frequent skin-to-skin contact, shared items, and suboptimal cleanliness. When a patient presents with a skin or soft-tissue infection, the clinician should determine whether an abscess or other infection needs to be surgically incised and drained. Cultures should be performed. When the patient is a member of an at-risk group or has any of the risk factors for CA-MRSA, beta-lactam antibiotics (eg, methicillin) are no longer a reasonable choice for treatment. Empiric treatment should consist of non-beta-lactam antibiotics active against CA-MRSA.

Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus.

Science.gov (United States)

Male, C; Mitchell, L; Julian, J; Vegh, P; Joshua, P; Adams, M; David, M; Andrew, M E

2001-02-15

Acquired activated protein C resistance (APCR) has been hypothesized as a possible mechanism by which antiphospholipid antibodies (APLAs) cause thrombotic events (TEs). However, available evidence for an association of acquired APCR with APLAs is limited. More importantly, an association of acquired APCR with TEs has not been demonstrated. The objective of the study was to determine, in pediatric patients with systemic lupus erythematosus (SLE), whether (1) acquired APCR is associated with the presence of APLAs, (2) APCR is associated with TEs, and (3) there is an interaction between APCR and APLAs in association with TEs. A cross-sectional cohort study of 59 consecutive, nonselected children with SLE was conducted. Primary clinical outcomes were symptomatic TEs, confirmed by objective radiographic tests. Laboratory testing included lupus anticoagulants (LAs), anticardiolipin antibodies (ACLAs), APC ratio, protein S, protein C, and factor V Leiden. The results revealed that TEs occurred in 10 (17%) of 59 patients. Acquired APCR was present in 18 (31%) of 58 patients. Acquired APCR was significantly associated with the presence of LAs but not ACLAs. Acquired APCR was also significantly associated with TEs. There was significant interaction between APCR and LAs in the association with TEs. Presence of both APCR and LAs was associated with the highest risk of a TE. Protein S and protein C concentrations were not associated with the presence of APLAs, APCR, or TEs. Presence of acquired APCR is a marker identifying LA-positive patients at high risk of TEs. Acquired APCR may reflect interference of LAs with the protein C pathway that may represent a mechanism of LA-associated TEs. (Blood. 2001;97:844-849)

Community-acquired carbapenem-resistant Acinetobacter baumannii urinary tract infection just after marriage in a renal transplant recipient.

Science.gov (United States)

Solak, Y; Atalay, H; Turkmen, K; Biyik, Z; Genc, N; Yeksan, M

2011-12-01

Urinary tract infection (UTI) is common in renal transplant recipients and may worsen allograft and patient survival. Many risk factors such as age, female gender, immunosuppression, comorbidity, deceased-donor kidney transplantation, and uretheral catheterization are involved in development of UTI. Acinetobacter baumannii has rarely been reported as a causative agent for development of UTI. Here, we present an unusual case of a renal transplant recipient who developed community-acquired carbapenem-resistent A. baumannii UTI. © 2011 John Wiley & Sons A/S.

Antibiotic resistance in community-acquired urinary tract infections

African Journals Online (AJOL)

the treatment of other infections would inevitably lead to the development of resistance. S Afr Med J 1994; 84: 600-602. Antibiotic resistance is a major problem in developing countries.' There are many reasons for this, including antibiotic use in animal feeds, inappropriate prescribing and poor sanitation. Resistance rates in ...

High Prevalence of Multidrug-Resistant Community-Acquired Methicillin-Resistant Staphylococcus aureus at the Largest Veterinary Teaching Hospital in Costa Rica.

Science.gov (United States)

Rojas, Irene; Barquero-Calvo, Elías; van Balen, Joany C; Rojas, Norman; Muñoz-Vargas, Lohendy; Hoet, Armando E

2017-09-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen associated with severe infections in companion animals present in the community, and it is diagnosed in animals admitted to veterinary hospitals. However, reports that describe the circulation of MRSA in animal populations and veterinary settings in Latin America are scarce. Therefore, the objective of this study was to determine the prevalence and investigate the molecular epidemiology of MRSA in the environment of the largest veterinary teaching hospital in Costa Rica. Preselected contact surfaces were sampled twice within a 6-week period. Antimicrobial resistance, SCCmec type, Panton-Valentine leukocidin screening, USA type, and clonality were assessed in all recovered isolates. Overall, MRSA was isolated from 26.5% (27/102) of the surfaces sampled, with doors, desks, and examination tables most frequently contaminated. Molecular analysis demonstrated a variety of surfaces from different sections of the hospital contaminated by three highly related clones/pulsotypes. All, but one of the isolates were characterized as multidrug-resistant SCCmec type IV-USA700, a strain sporadically described in other countries and often classified as community acquired. The detection and frequency of this unique strain in this veterinary setting suggest Costa Rica has a distinctive MRSA ecology when compared with other countries/regions. The high level of environmental contamination highlights the necessity to establish and enforce standard cleaning and disinfection protocols to minimize further spread of this pathogen and reduce the risk of nosocomial and/or occupational transmission of MRSA.

Comparative genomics of community-acquired ST59 methicillin-resistant Staphylococcus aureus in Taiwan: novel mobile resistance structures with IS1216V.

Directory of Open Access Journals (Sweden)

Wei-Chun Hung

Full Text Available Methicillin-resistant Staphylococcus aureus (MRSA with ST59/SCCmecV and Panton-Valentine leukocidin gene is a major community-acquired MRSA (CA-MRSA lineage in Taiwan and has been multidrug-resistant since its initial isolation. In this study, we studied the acquisition mechanism of multidrug resistance in an ST59 CA-MRSA strain (PM1 by comparative genomics. PM1's non-β-lactam resistance was encoded by two unique genetic traits. One was a 21,832-bp composite mobile element structure (MES(PM1, which was flanked by direct repeats of enterococcal IS1216V and was inserted into the chromosomal sasK gene; the target sequence (att was 8 bp long and was duplicated at both ends of MES(PM1. MES(PM1 consisted of two regions: the 5'-end side 12.4-kb region carrying Tn551 (with ermB and Tn5405-like (with aph[3']-IIIa and aadE, similar to an Enterococcus faecalis plasmid, and the 3'-end side 6,587-bp region (MES(cat that carries cat and is flanked by inverted repeats of IS1216V. MES(cat possessed att duplication at both ends and additional two copies of IS1216V inside. MES(PM1 represents the first enterococcal IS1216V-mediated composite transposon emerged in MRSA. IS1216V-mediated deletion likely occurred in IS1216V-rich MES(PM1, resulting in distinct resistance patterns in PM1-derivative strains. Another structure was a 6,025-bp tet-carrying element (MES(tet on a 25,961-bp novel mosaic penicillinase plasmid (pPM1; MES(tet was flanked by direct repeats of IS431, but with no target sequence repeats. Moreover, the PM1 genome was deficient in a copy of the restriction and modification genes (hsdM and hsdS, which might have contributed to the acquisition of enterococcal multidrug resistance.

Antibiotic resistance in community-acquired urinary tract infections

African Journals Online (AJOL)

of community-acquired UTI organisms to amoxycillin and co-trimoxazole was .... Treatment of uncomplicated urinary tract infection in non-pregnant women. Postgrad ... Single-dose antibiotic treatment for symptomatic uri- nary tract infections in ...

Risk Factors for Acquisition of Drug Resistance during Multidrug-Resistant Tuberculosis Treatment, Arkhangelsk Oblast, Russia, 2005–2010

Science.gov (United States)

Ershova, Julia; Vlasova, Natalia; Nikishova, Elena; Tarasova, Irina; Eliseev, Platon; Maryandyshev, Andrey O.; Shemyakin, Igor G.; Kurbatova, Ekaterina; Cegielski, J. Peter

2015-01-01

Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005–2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received 3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs. PMID:25988954

Origin and evolution of European community-acquired methicillin-resistant Staphylococcus aureus.

Science.gov (United States)

Stegger, Marc; Wirth, Thierry; Andersen, Paal S; Skov, Robert L; De Grassi, Anna; Simões, Patricia Martins; Tristan, Anne; Petersen, Andreas; Aziz, Maliha; Kiil, Kristoffer; Cirković, Ivana; Udo, Edet E; del Campo, Rosa; Vuopio-Varkila, Jaana; Ahmad, Norazah; Tokajian, Sima; Peters, Georg; Schaumburg, Frieder; Olsson-Liljequist, Barbro; Givskov, Michael; Driebe, Elizabeth E; Vigh, Henrik E; Shittu, Adebayo; Ramdani-Bougessa, Nadjia; Rasigade, Jean-Philippe; Price, Lance B; Vandenesch, Francois; Larsen, Anders R; Laurent, Frederic

2014-08-26

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations. With increasing levels of CA-MRSA reported from most parts of the Western world, there is a great interest in understanding the origin and factors associated with the emergence of these epidemic lineages. To trace the origin, evolution, and dissemination pattern of the European CA-MRSA clone (CC80), we sequenced a global collection

Role of major histocompatibility complex class II in resistance of mice to naturally acquired infection with Syphacia obvelata

Science.gov (United States)

Stewart, Patricia W.; Chapes, Stephen K.

2003-01-01

Genetics plays a substantial role in host resistance in many host-parasite interactions. We examined the prevalence of naturally acquired infection with Syphacia obvelata in a number of mouse strains housed in a non-barrier facility. These mice, which included cross-bred and congenic, inbred strains on various genetic backgrounds, differ in the loci for the immune function genes--major histocompatibility complex class II (MHCII), toll-like receptor 4 (Tlr4), and solute carrier family 11, member 1 (Slc11a1)--which allowed comparisons of the impact of these genes on resistance to pinworm infection. Male and female mice of various ages were sampled over an 18-month period; infection was determined by use of the cellophane tape test. Results indicated that mice that were MHCII+/+ had a significantly lower prevalence of infection than did mice that were MHCII-/-. Differences were not seen between male and female mice. Although MHCII+/+ mice had an age-associated decrease in infection prevalence, such decrease was not seen in MHCII-/- mice. In contrast, infection prevalence in mice with the normal Tlr4 gene (Tlr4(LPS-n/LPS-n)) gene did not differ significantly compared with that in mice that were homozygous for either the point mutation (Tlr4(LPS-d/LPS-d)) or deletion (Tlr4(LPS-del/LPS-del)) of that gene. Likewise, the presence (Sle11a1r/r) or absence (Slc11a1s/s) of functional alleles for Slc11a1 had no effect on the prevalence of infection with S. obvelata. In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata. These data justify further comprehensive analyses of the immune components that are involved in pinworm resistance.

Methyl salicylate is a critical mobile signal for plant systemic acquired resistance.

Science.gov (United States)

Park, Sang-Wook; Kaimoyo, Evans; Kumar, Dhirendra; Mosher, Stephen; Klessig, Daniel F

2007-10-05

In plants, the mobile signal for systemic acquired resistance (SAR), an organism-wide state of enhanced defense to subsequent infections, has been elusive. By stimulating immune responses in mosaic tobacco plants created by grafting different genetic backgrounds, we showed that the methyl salicylate (MeSA) esterase activity of salicylic acid-binding protein 2 (SABP2), which converts MeSA into salicylic acid (SA), is required for SAR signal perception in systemic tissue, the tissue that does not receive the primary (initial) infection. Moreover, in plants expressing mutant SABP2 with unregulated MeSA esterase activity in SAR signal-generating, primary infected leaves, SAR was compromised and the associated increase in MeSA levels was suppressed in primary infected leaves, their phloem exudates, and systemic leaves. SAR was also blocked when SA methyl transferase (which converts SA to MeSA) was silenced in primary infected leaves, and MeSA treatment of lower leaves induced SAR in upper untreated leaves. Therefore, we conclude that MeSA is a SAR signal in tobacco.

Sepse por Staphylococus aureus resistente à meticilina adquirida na comunidade no sul do Brasil Sepsis due to community-acquired methicillin-resistant Staphylococcus aureus in southern Brazil

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Luciane Cristina Gelatti

2009-08-01

Full Text Available Staphylococcus aureus resistente à meticilina foi inicialmente descrito como um típico microrganismo adquirido em infecções nosocomiais. No entanto, nos últimos anos Staphylococcus aureus resistente à meticilina adquirido na comunidade é causa de infecções de pele e tecidos moles, mas infecções graves como pneumonia e sepse podem ocorrer. Este relato descreve um caso de sepse em criança, complicado com pneumonia secundária a lesão em partes moles por Staphylococcus aureus resistente à meticilina adquirido na comunidade no Sul do Brasil. O paciente foi atendido em Unidade de Emergência com história de ferimento provocado por trauma em membro inferior que evoluiu para celulite, pneumonia e sepse.Methicillin-resistant Staphylococcus aureus was initially described as a typical microorganism acquired in nosocomial infections. However, over recent years, community-acquired methicillin-resistant Staphylococcus aureus has been a cause of skin and soft-tissue infections. Serious infections such as pneumonia and sepsis can also occur. This report describes a case of sepsis in a child that was complicated by pneumonia secondary to soft tissue lesions that were due to community-acquired methicillin-resistant Staphylococcus aureus in southern Brazil. The patient was attended at the Emergency Unit with a history of injury caused by lower-limb trauma that evolved to cellulitis, pneumonia and sepsis.

An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.

Science.gov (United States)

Hanker, Ariella B; Brewer, Monica Red; Sheehan, Jonathan H; Koch, James P; Sliwoski, Gregory R; Nagy, Rebecca; Lanman, Richard; Berger, Michael F; Hyman, David M; Solit, David B; He, Jie; Miller, Vincent; Cutler, Richard E; Lalani, Alshad S; Cross, Darren; Lovly, Christine M; Meiler, Jens; Arteaga, Carlos L

2017-06-01

We report a HER2 T798I gatekeeper mutation in a patient with HER2 L869R -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2 L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3 E928G , also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2 T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 L869R but not HER2 L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2 L869R/T798I -induced signaling and cell growth. Acquisition of HER2 T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2 L869R is a driver mutation. HER2 T798I -mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2 -mutant breast cancer upon clinical progression on neratinib. We speculate that HER2 T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2 -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

Enhanced B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation contributes to ABCC1-mediated chemoresistance and glutathione-mediated survival in acquired topoisomerase II poison-resistant cancer cells.

Science.gov (United States)

Chen, Huang-Hui; Chang, Hsin-Huei; Chang, Jang-Yang; Tang, Ya-Chu; Cheng, Yung-Chi; Lin, Li-Mei; Cheng, Shu-Ying; Huang, Chih-Hsiang; Sun, Man-Wu; Chen, Chiung-Tong; Kuo, Ching-Chuan

2017-12-01

Nuclear factor erythroid-2-related factor 2 (NRF2) mainly regulates transcriptional activation through antioxidant-responsive elements (AREs) present in the promoters of NRF2 target genes. Recently, we found that NRF2 was overexpressed in a KB-derived drug-resistant cancer cell panel. In this panel, KB-7D cells, which show acquired resistance to topoisomerase II (Top II) poisons, exhibited the highest NRF2 activation. To investigate whether NRF2 directly contributed to acquired resistance against Top II poisons, we manipulated NRF2 by genetic and pharmacological approaches. The result demonstrated that silencing of NRF2 by RNA interference increased the sensitivity and treatment with NRF2 activator decreased the sensitivity of KB and KB-7D cells toward Top II poisons. Further, increased B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation activated NRF2 signaling in KB-7D cells. Moreover, increased binding of NRF2 to an ARE in the promoter of ATP-binding cassette subfamily C member 1 (ABCC1) directly contributed to Top II poison resistance. In addition, activation of NRF2 increased glutathione level and antioxidant capacity in KB-7D cells compared with that in KB cells; moreover, high glutathione level provided survival advantage to KB-7D cells. Our study is the first to show that aberrant NRF2 activation is via increased B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation, which increases the acquired resistance and promote the survival of Top II poison-resistant cancer cells. Importantly, NRF2 downstream effectors ABCC1 and glutathione directly contribute to acquired resistance and survival, respectively. These results suggest that blockade of NRF2 signaling may enhance therapeutic efficacy and reduce the survival of Top II poison-refractory tumors in clinical. Copyright © 2017 Elsevier Inc. All rights reserved.

Changing prevalence and antibiotic drug resistance pattern of pathogens seen in community-acquired pediatric urinary tract infections at a tertiary care hospital of North India

Directory of Open Access Journals (Sweden)

Vrushali Patwardhan

2017-01-01

Conclusion: Although E. coli remains the prime pathogen in pediatric UTI, the prevalence of resistance has dramatically increased over the 5-year study period. Our study highlights the emergence of community-acquired ESBL-producing uropathogens in children proclaiming treatment challenges.

High rate of mutation K103N causing resistance to nevirapine in Indian children with acquired immunodeficiency syndrome

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Sehgal S

2008-01-01

Full Text Available In north India the number of paediatric cases with acquired immunodeficiency syndrome (AIDS is on the rise. Most drug combinations used for treatment of AIDS incorporate nevirapine, resistance to which develops very fast if given singly or because of unplanned interruptions. This paper investigates presence of mutations at codon 103 and codon 215 of the HIV pol gene causing resistance to nevirapine and zidovudine (AZT respectively in 25 children with AIDS. Mutations T215Y and K103N were detected by a nested cum amplification refractory mutation system polymerase chain reaction (ARMS PCR and the results were confirmed by direct sequencing in five randomly selected cases. Nineteen patients had received nevirapine containing regimen and six were drug naive. Mutation K103N was observed in 56% (14/25 of the children while mutation T215Y was found in none. Two of the six drug naοve children also showed K103N mutation. Thus, Indian children drug naοve or treated with nevirapine containing regimens show a high rate of mutation conferring resistance to nevirapine which calls for a judicious use of nevirapine both in antenatal and postnatal setting.

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

Science.gov (United States)

Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

2014-01-01

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719

Multidrug-Resistant Candida

DEFF Research Database (Denmark)

Arendrup, Maiken Cavling; Patterson, Thomas F

2017-01-01

Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance...... can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients....... Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites...

Acquired resistance L747S mutation in an epidermal growth factor receptor-tyrosine kinase inhibitor-naïve patient: A report of three cases.

Science.gov (United States)

Yamaguchi, Fumihiro; Fukuchi, Kunihiko; Yamazaki, Yohei; Takayasu, Hiromi; Tazawa, Sakiko; Tateno, Hidetsugu; Kato, Eisuke; Wakabayashi, Aya; Fujimori, Mami; Iwasaki, Takuya; Hayashi, Makoto; Tsuchiya, Yutaka; Yamashita, Jun; Takeda, Norikazu; Kokubu, Fumio

2014-02-01

The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.

SABP2, a methyl salicylate esterase is required for the systemic acquired resistance induced by acibenzolar-S-methyl in plants.

Science.gov (United States)

Tripathi, Diwaker; Jiang, Yu-Lin; Kumar, Dhirendra

2010-08-04

Tobacco SABP2, a 29kDa protein catalyzes the conversion of methyl salicylic acid (MeSA) into salicylic acid (SA) to induce SAR. Pretreatment of plants with acibenzolar-S-methyl (ASM), a functional analog of salicylic acid induces systemic acquired resistance (SAR). Data presented in this paper suggest that SABP2 catalyzes the conversion of ASM into acibenzolar to induce SAR. Transgenic SABP2-silenced tobacco plants when treated with ASM, fail to express PR-1 proteins and do not induce robust SAR expression. When treated with acibenzolar, full SAR is induced in SABP2-silenced plants. These results show that functional SABP2 is required for ASM-mediated induction of resistance. Copyright (c) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Bacterial Aetiology and Antibiotic Resistance Pattern of Community-Acquired Urinary Tract Infections in Children in a Tertiary Care Hospital in Bangladesh

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Lazina Sharmin

2017-09-01

Full Text Available Background: Urinary tract infections (UTIs in children are among the most common bacterial infections. Community-acquired urinary tract infections (CAUTI are often treated empirically with broad-spectrum antibiotics. Pattern of aetiologic agents and their antibiotic sensitivity may vary according to geographical and regional location. So, knowledge of antibiotic resistance trends is important for improving evidence-based recommendations for empirical treatment of UTIs. Objectives: To determine the common bacterial aetiologies of CAUTIs and their antibiotic resistance patterns in a tertiary care hospital, Savar. Materials and Methods: This cross-sectional descriptive study was conducted at Enam Medical College Hospital, Savar from May 2016 to April 2017. We collected clean-catch mid-stream urine samples from 257 patients having clinical diagnosis of UTI and submitted to the clinical microbiology laboratory for culture and sensitivity. Results: A total of 120 (46.7% samples were positive for bacterial growth. Escherichia coli (79% was the most common pathogen, followed by Klebsiella spp. (14%. Bacterial isolates showed high prevalence of resistance to multiple antibiotics. Resistance against amoxicillin/clavulanic acid, co-trimoxazole and ciprofloxacin was higher compared to newer quinolones and aminoglycosides. Conclusion: Esch. coli and Klebsiella spp. were the predominant bacterial pathogens. The resistance pattern to commonly prescribed antibiotics was quite high and alarming.

Breast Cancer Stem Cells in Antiestrogen Resistance

Science.gov (United States)

2014-10-01

that several flavonoid derivatives purified from the bark of the Paper Mulberry tree (Broussonetiapapyrifera) (L.) were able to down-regulate ER...Feng et al., 2008). Various types of flavonoids are the major constituents of this plant and some of which exhibited strong tyrosinase inhibitory...mechanisms of the flavonoids from B. papyrifera in human cancer have never been studied. Recently, we purified and identified two prenylflavone derivatives

Effect of storage on radiation and antibiotic acquired stability in bacilli

International Nuclear Information System (INIS)

Tawfik, Z.S.

1991-01-01

The properties of two highly radioresistant bacterial strains namely B. laterosporous and B. firmus isolated, three years ago, from the water shielding the industrial Co-60 source of NCRRT Egypt were studied. The results showed that the studied isolates had lost their resistance to gamma irradiation as compared with their properties acquired at the time of isolation. The sensitivity test of these isolates to some antibiotics and sulpha drugs was also investigated, and was compared with tests performed on the same species isolated from tap water. The pronounced resistance of these isolates to some antibiotics acquired three years ago, had been lost by storage except for the case of the drug chemotrim. The results indicated that the acquired resistivity to both gamma irradiation and antibiotics due to the chronic exposure to gamma radiation is not stable. It is concluded that the genes controlling both phenomena, in the studied strains, fall into broad categories and the case might be a repair mechanism in the DNA during successive reproduction.2 fig., 2 tab

Acquired resistance to cetuximab is associated with the overexpression of Ras family members and the loss of radiosensitization in head and neck cancer cells

International Nuclear Information System (INIS)

Saki, Mohammad; Toulany, Mahmoud; Rodemann, H. Peter

2013-01-01

Purpose: Cetuximab in combination with radiation therapy is used to treat patients with head and neck squamous cell carcinoma (HNSCC). In the present study, the mechanism of acquired resistance to cetuximab in HNSCC cells was investigated in vitro. Material and methods: The HNSCC cell lines UT5 and SAS and UT5 cells with acquired resistance to cetuximab (UT5R9) were used. The radiotoxicity potentials of cetuximab and inhibitors of PI3K, MAPK and farnesylation were tested using a clonogenic survival assay. Western blotting was used to evaluate protein expression. The levels of EGFR ligands were detected by ELISA. Results: Cetuximab inhibited proliferation and induced radiosensitization in UT5 cells but not in SAS cells. In comparison with UT5 cells, cetuximab-resistant SAS cells markedly overexpressed the K-Ras, H-Ras and N-Ras proteins, as detected by Western blotting. Resistance in UT5R9 cells was associated with the overexpression of the K-Ras, H-Ras and N-Ras proteins as well as an increase in the autocrine production of the EGFR ligands amphiregulin and transforming growth factor α (TGFα). UT5R9 cells were significantly more radioresistant than UT5 cells. Radioresistant UT5R9 cells were not radiosensitized by cetuximab, but knocking down H-RAS and N-RAS with siRNA and targeting Ras farnesylation using the farnesyltransferase inhibitor lonafarnib induced radiosensitization in these cells. Targeting PI3K and MEK revealed that the activation of the PI3K/Akt pathway but not the MAPK/ERK pathway is associated with radioresistance in UT5R9 cells. Conclusion: Targeting Ras and PI3K activity improves the outcome of irradiation in cetuximab-resistant HNSCC cell lines in vitro

The comparative development of elevated resistance to macrolides in community-acquired pneumonia caused by Streptococcus pneumoniae

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Yayan J

2014-10-01

Full Text Available Josef Yayan Department of Internal Medicine, Division of Pulmonary, Allergy and Sleep Medicine, Saarland University Medical Center, Homburg/Saar, Germany Background: Community-acquired pneumonia (CAP is an acute inflammation of the lungs, which is often caused by Streptococcus pneumoniae. CAP is the leading cause of death by infectious disease in industrialized countries. Therefore, an immediate and effective antibiotic therapy is of great importance for the nonfatal outcome of the disease. The literature contains increasing data about the development of resistance to antibiotics that are used for the treatment of CAP caused by S. pneumoniae; this article also examines the possible development of resistance to antibiotics in S. pneumoniae in recent years.Methods: Within the study period of 2004–2014, all hospital charts from patients with CAP caused by S. pneumoniae were collected from the Department of Internal Medicine, Saarland University Medical Center, Homburg/Saar, Germany. The tracheal secretions of S. pneumoniae in CAP patients were obtained by bronchoalveolar lavage; bronchial aspirates were obtained through flexible bronchoscopy and directly from sputum, and blood cultures were examined microbiologically for microorganisms.Results: From a total of 100 patients with CAP caused by S. pneumoniae, 23 (53.49% [34.78% female], 95% confidence interval, 38.58–68.4 patients with a mean age of 59.78±15.77 years met the inclusion criteria of this investigation. These patients were compared to a total of 20 (46.51% [35% female], 95% confidence interval, 31.6–61.42 patients with a mean age of 58.9±13.36 years with CAP who were infested with S. pneumoniae. In the latter group, the streptococcal antigen was detected in pulmonary aspirations by bronchoscopy or in urine using polymerase chain reaction and a rapid pneumococcal test. Penicillin G and vancomycin had a high rate of sensitivity on the antibiogram for S. pneumoniae, which was

Study on the effect of aromatase inhibitors and antiestrogens on the sex differentiation of broiler chicks

Directory of Open Access Journals (Sweden)

E.A Valizadeh

2011-02-01

Full Text Available During the development of chick embryo, the genotype of the zygote determines the nature of the gonads, which thereafter creates the male or female phenotype. Differentiation of gonads during the period called “critical period for sexual differentiation “is accompanied with beginning of secretion of sexual hormones. Every change in the rate of steroidal hormones concentration during this critical period, affects on the structure of gonads. Therefore, injection of aromatase inhibitors (which blocks the synthesis of estrogen from testostron in 5th day of incubation into the eggs, causes the production of males with female genotype. These sex reversal females have bilateral testes with complete spermatogenesis, having normal physical appearance and behavior. In this study, 14-α-hydroxy 3,6,17, androstan-trion inhibitor (1mg/egg was injected into the eggs. Furthermore, the effect of three anti-estrogens (which blocks the estrogen receptor Tamoxifen, and Clomiphen Citrate and GAR79 were studied. Injection of aromatase inhibitors into the eggs during incubation period caused statistically significant (p

Antimicrobial resistance of thermophilic Campylobacter

DEFF Research Database (Denmark)

Aarestrup, Frank Møller; Engberg, J.

2001-01-01

Campylobacter has become the leading cause of zoonotic enteric infections in developed and developing countries world-wide. Antimicrobial resistance has emerged among Campylobacter mainly as a consequence of the use of antimicrobial agents in food animal production. Resistance to drugs of choice...... for the treatment of infections, macrolides and fluoroquinolones has emerged as a clinical problem and interventions to reduce this are recommended. Resistance to fluoroquinolones and macrolides is mediated by chromosomal mutations. Resistance to other relevant antimicrobial agents, mediated by acquired resistance...... genes, has not become widespread so far. However, resistance genes originating from both Gram-positive and Gram-negative bacterial species have been found, showing the potential for acquired resistance to emerge in Campylobacter....

Principles of Antibiotic Management of Community-Acquired Pneumonia.

Science.gov (United States)

Bender, Michael T; Niederman, Michael S

2016-12-01

Community-acquired pneumonia (CAP) encompasses a broad spectrum of disease severity and may require outpatient, inpatient, or intensive care management. Successful treatment hinges on expedient delivery of appropriate antibiotic therapy tailored to both the likely offending pathogens and the severity of disease. This review summarizes key principles in starting treatment and provides recommended empiric therapy regimens for each site of care. In addition, we discuss the antimicrobial and anti-inflammatory role macrolides play in CAP, as well as specific information for managing individual CAP pathogens such as community-acquired methicillin-resistant Staphylococcus aureus and drug-resistant Streptococcus pneumoniae . We also examine several novel antibiotics being developed for CAP and review the evidence guiding duration of therapy and current best practices for the transition of hospitalized patients from intravenous antibiotics to oral therapy. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Antibiotic resistant enterococci—Tales of a drug resistance gene trafficker

DEFF Research Database (Denmark)

Werner, Guido; Coque, Teresa M.; Franz, Charles M.A.P.

2013-01-01

Enterococci have been recognized as important hospital-acquired pathogens in recent years, and isolates of E. faecalis and E. faecium are the third- to fourth-most prevalent nosocomial pathogen worldwide. Acquired resistances, especially against penicilin/ampicillin, aminoglycosides (high-level) ...

Changing prevalence and antibiotic drug resistance pattern of pathogens seen in community-acquired pediatric urinary tract infections at a tertiary care hospital of North India.

Science.gov (United States)

Patwardhan, Vrushali; Kumar, Dinesh; Goel, Varun; Singh, Sarman

2017-01-01

The aim and objective of this study was to assess the temporal changes in the microbiological profiles and antimicrobial resistance patterns of uropathogens in pediatric community-acquired UTI. This is a retrospective analysis of data collected over a Scattered period of 5 years. The baseline data collected were from January to December 2009, and the second period considered for comparison was from January to December 2014. Urine specimens from children (Antibiotic sensitivity was put up by Kirby-Bauer disc diffusion method as per the Clinical and Laboratory Standard Institute guidelines. In the year 2009, 340 of 2104 (16.15%) urine specimens yielded significant colony count, whereas in 2014, it was 407 of 2212 (18.39%) ( P = 0.051). Escherichia coli was the predominant pathogen and was significantly more prevalent in girls than in boys ( P resistance to ampicillin (from 40.29% to 58.72%), amoxyclav (from 26.17% to 40.54%), nitrofurantoin (from 28.82% to 39.06%), and norfloxacin (from 30% to 41.42%). However, the maximum increase in the resistance was noted for co-trimoxazole from 35.58% in 2009 to 63.39% in 2014 ( P = 0.0000058). The prevalence of extended-spectrum beta-lactamases (ESBLs) has also significantly increased from 21.7% to 33.16% ( P = 0.0045). Although E. coli remains the prime pathogen in pediatric UTI, the prevalence of resistance has dramatically increased over the 5-year study period. Our study highlights the emergence of community-acquired ESBL-producing uropathogens in children proclaiming treatment challenges.

Functional cooperation between HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR.

Science.gov (United States)

Meng, Shuyan; Wang, Guorui; Lu, Yang; Fan, Zhen

2018-07-01

Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are important transcription factors regulating expression of genes involved in cell survival. HIF-1α and c-Jun are key components of HIF-1 and AP-1, respectively, and are regulated by epidermal growth factor receptor (EGFR)-mediated cell signaling and tumor microenvironmental cues. The roles of HIF-1α and c-Jun in development of resistance to EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) with activating mutation of EGFR have not been explored. In this study, we investigated the roles of HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR. Changes in HIF-1α protein and in total and phosphorylated c-Jun levels in relation to changes in total and phosphorylated EGFR levels before and after gefitinib treatment were measured using Western blot analysis in NSCLC cells sensitive or resistant to gefitinib. The impact of overexpression of a constitutively expressed HIF-1α (HIF-1α/ΔODD) or a constitutively active c-Jun upstream regulator (SEK1 S220E/T224D mutant) on cell response to gefitinib was also examined. The effect of pharmacological inhibition of SEK1-JNK-c-Jun pathway on cell response to gefitinib was evaluated. Downregulation of HIF-1α and total and phosphorylated c-Jun levels correlated with cell inhibitory response to gefitinib better than decrease in phosphorylated EGFR did in NSCLC cells with intrinsic or acquired resistance to gefitinib. Overexpression of HIF-1α/ΔODD or SEK1 S220E/T224D mutant conferred resistance to gefitinib. There exists a positive feed-forward regulation loop between HIF-1 and c-Jun. The JNK inhibitor SP600125 sensitized gefitinib-resistant NSCLC cells to gefitinib. HIF-1α and c-Jun functionally cooperate in development of resistance to gefitinib in NSCLC cells. The translational value of inhibiting HIF-1α/c-Jun cooperation in overcoming resistance to EGFR TKI

Infectious caused by community-acquired Methicillin-Resistant Staphylococcus aureus (CA-MRSA: three-years experience of an universitary hospital in Rome

Directory of Open Access Journals (Sweden)

Anna Altieri

2010-06-01

Full Text Available To date methicillin-resistant Staphylococcus aureus (MRSA is one of the most common pathogens causing nosocomial infections(1. In Europe the proportion of MRSA is increasing sharply and the distribution varies from country to country. In recent years there has, in various parts of the world, the emergence of infection with strains of S. aureus methicillin-resistant community-acquired (CA-MRSA than those circulating in hospitals(2. These strains contain a gene that confers resistance to methicillin (mec A SSC mec IV which is usually associated with the gene for Leukocidin Panton Valentine (PVL toxin responsible for necrosis of skin and soft tissue (3. In 2006-2008, at the Laboratory of Bacteriology PolyclinicTor Vergata,were isolated a total of 738 strains of S. aureus from biological samples of different nature (oral, vaginal secretions, wound swab, secreted headset, etc ... of patients related to our surgeries.The identification and study of drug sensitivity of strains were performed with the automatic VITEK2 (bioMérieux. Of the 738 strains of S. aureus identified 212 (28.7% were resistant to methicillin (MRSA, with an increasing trend over the years: 46 isolates, respectively, in 2006, 76 in 2007 and 90 in 2008. The highest frequency of MRSA (varying between 85% and 95% was detected in wound swabs from the dispensary and diabetes (diabetic foot.

Patients' Hand Washing and Reducing Hospital-Acquired Infection.

Science.gov (United States)

Haverstick, Stacy; Goodrich, Cara; Freeman, Regi; James, Shandra; Kullar, Rajkiran; Ahrens, Melissa

2017-06-01

Hand hygiene is important to prevent hospital-acquired infections. Patients' hand hygiene is just as important as hospital workers' hand hygiene. Hospital-acquired infection rates remain a concern across health centers. To improve patients' hand hygiene through the promotion and use of hand washing with soap and water, hand sanitizer, or both and improve patients' education to reduce hospital-acquired infections. In August 2013, patients in a cardiothoracic postsurgical step-down unit were provided with individual bottles of hand sanitizer. Nurses and nursing technicians provided hand hygiene education to each patient. Patients completed a 6-question survey before the intervention, at hospital discharge and 1, 2, and 3 months after the intervention. Hospital-acquired infection data were tracked monthly by infection prevention staff. Significant correlations were found between hand hygiene and rates of infection with vancomycin-resistant enterococci ( P = .003) and methicillin-resistant Staphylococcus aureus ( P = .01) after the intervention. After the implementation of hand hygiene interventions, rates of both infections declined significantly and patients reported more staff offering opportunities for and encouraging hand hygiene. This quality improvement project demonstrates that increased hand hygiene compliance by patients can influence infection rates in an adult cardiothoracic step-down unit. The decreased infection rates and increased compliance with hand hygiene among the patients may be attributed to the implementation of patient education and the increased accessibility and use of hand sanitizer. ©2017 American Association of Critical-Care Nurses.

Antibiotic resistance patterns of pediatric community-acquired urinary infections

OpenAIRE

Guidoni, Eliana Biondi Medeiros; Berezin, Eitan N.; Nigro, Stanley; Santiago, Nataly A; Benini, Vanda; Toporovski, Julio

2008-01-01

Knowledge about antimicrobial resistance patterns of the etiological agents of urinary tract infections (UTIs) is essential for appropriate therapy. Urinary isolates from symptomatic UTI cases attended at Santa Casa University Hospital of São Paulo from August 1986 to December 1989 and August 2004 to December 2005 were identified by conventional methods. Antimicrobial resistance testing was performed by Kirby Bauer's disc diffusion method. Among the 257 children, E. coli was found in 77%. A h...

Differential induction of progestin-binding sites in uterine cell types by estrogen and antiestrogen

International Nuclear Information System (INIS)

Ennis, B.W.; Stumpf, W.E.

1988-01-01

Effects of antiestrogen on progestin binding in uterine cell types were determined and compared to those of estrogen. Effects on uterine morphology were also studied. Immature rats were treated with four daily sc injections of 100 micrograms hydroxytamoxifen [TAM(OH)], 5 micrograms estradiol (E2), or oil. On day 5 the rats were injected iv with 1 microgram of the synthetic progestin [ 3 H]Org 2058, and 1 h later uteri were excised, weighed, and processed for thaw-mount autoradiography. Treatment with TAM(OH) or E2 resulted in uterine weight gain, which was greater in animals treated with E2. E2 treatment resulted in cellular hypertrophy in all tissue compartments, especially in the luminal epithelium and myometrium, but TAM(OH) treatment resulted in hypertrophy of only the luminal epithelium. Treatment with TAM(OH) or E2 changed the pattern and intensity of nuclear binding of [ 3 H]Org 2058 from that in oil-treated controls. E2 increased progestin binding in stroma and myometrium and decreased it in luminal epithelium. TAM(OH), similarly, decreased progestin binding in the luminal epithelium and increased it, albeit less than E2, in the myometrium, but left it unchanged in the stroma. The results indicate that E2 and TAM(OH) differentially effect progestin binding among the uterine tissue compartments

Adherence to anti-estrogen therapy in seniors with breast cancer: how well are we doing?

Science.gov (United States)

Trabulsi, Nora; Riedel, Kristen; Winslade, Nancy; Gregoire, Jean-Pierre; Meterissian, Sarkis; Abrahamovicz, Michal; Tamblyn, Robyn; Mayo, Nancy; Meguerditchian, Ari

2014-01-01

A third of breast cancers (BC) occur in women ≥65 years (seniors). Anti-estrogen therapy (AET) significantly reduces BC recurrence and death. This study characterizes determinants of adherence to AET in seniors with BC. Provincial cancer registry and administrative claims data were accessed for all non-metastatic BC diagnosed in Quebec (1998-2005) to identify seniors treated for 5 years with AET. Multivariate linear regression was used to assess the association with patient, disease, and physician characteristics and the 5-year medication possession ratio (MPR) for each patient. 4,715 women were included (mean age: 72.9). Mean MPR was 83.5%, 79% of patients reached a 5-year MPR of ≥80%, and 34% discontinued AET at some point during treatment. The cumulative probability of discontinuation was 33.8% (mean time to discontinuation 2.3 years). The MPR decreased with increasing age and non-BC related hospitalizations, p seniors with BC remained a challenge and medication discontinuation rates were high. Advanced age, increasing number of hospitalizations, in situ disease, baseline use of antidepressants, Tamoxifen (versus aromatase inhibitors), early switches of AET type, and newly added medications significantly reduced the MPR. © 2014 Wiley Periodicals, Inc.

Study on drug resistance of mycobacterium tuberculosis in patients with pulmonary tuberculosis by drug resistance gene detecting

International Nuclear Information System (INIS)

Wang Wei; Li Hongmin; Wu Xueqiong; Wang Ansheng; Ye Yixiu; Wang Zhongyuan; Liu Jinwei; Chen Hongbing; Lin Minggui; Wang Jinhe; Li Sumei; Jiang Ping; Feng Bai; Chen Dongjing

2004-01-01

To investigate drug resistance of mycobacterium tuberculosis in different age group, compare detecting effect of two methods and evaluate their the clinical application value, all of the strains of mycobacterium tuberculosis were tested for resistance to RFP, INH SM PZA and EMB by the absolute concentration method on Lowenstein-Jensen medium and the mutation of the rpoB, katG, rpsL, pncA and embB resistance genes in M. tuberculosis was tested by PCR-SSCP. In youth, middle and old age group, the rate of acquired drug resistance was 89.2%, 85.3% and 67.6% respectively, the gene mutation rate was 76.2%, 81.3% and 63.2% respectively. The rate of acquired drug resistance and multiple drug resistance in youth group was much higher than those in other groups. The gene mutation was correlated with drug resistance level of mycobacterium tuberculosis. The gene mutation rate was higher in strains isolated from high concentration resistance than those in strains isolated from low concentration resistance. The more irregular treatment was longer, the rate of drug resistance was higher. Acquired drug resistance varies in different age group. It suggested that surveillance of drug resistence in different age group should be taken seriously, especially in youth group. PCR - SSCP is a sensitive and specific method for rapid detecting rpoB, katG, rpsL, pncA and embB genes mutations of MTB. (authors)

Changing prevalence and antibiotic drug resistance pattern of pathogens seen in community-acquired pediatric urinary tract infections at a tertiary care hospital of North India

OpenAIRE

Patwardhan, Vrushali; Kumar, Dinesh; Goel, Varun; Singh, Sarman

2017-01-01

b>Introduction: Timely treatment of urinary tract infection (UTI) with appropriate antibiotic administration is of immense importance in children to reduce the consequences. Aims and Objectives: The aim and objective of this study was to assess the temporal changes in the microbiological profiles and antimicrobial resistance patterns of uropathogens in pediatric community-acquired UTI. Materials and Methods: This is a retrospective analysis of data collected over a Scattered period of 5...

Novel pharmacotherapy for the treatment of hospital-acquired and ventilator-associated pneumonia caused by resistant gram-negative bacteria.

Science.gov (United States)

Kidd, James M; Kuti, Joseph L; Nicolau, David P

2018-03-01

Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are among the most prevalent infections in hospitalized patients, particularly those in the intensive care unit. Importantly, the frequency of multidrug resistant (MDR) Gram-negative (GN) bacteria as the bacteriologic cause of HABP/VABP is increasing. These include MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem resistant Enterobacteriaceae (CRE). Few antibiotics are currently available when such MDR Gram-negatives are encountered and older agents such as polymyxin B, colistin (polymyxin E), and tigecycline have typically performed poorly in HABP/VABP. Areas covered: In this review, the authors summarize novel antibiotics which have reached phase 3 clinical trials including patients with HABP/VABP. For each agent, the spectrum of activity, pertinent pharmacological characteristics, clinical trial data, and potential utility in the treatment of MDR-GN HABP/VABP is discussed. Expert opinion: Novel antibiotics currently available, and those soon to be, will expand opportunities to treat HABP/VABP caused by MDR-GN organisms and minimize the use of more toxic, less effective drugs. However, with sparse clinical data available, defining the appropriate role for each of the new agents is challenging. In order to maximize the utility of these antibiotics, combination therapy and the role of therapeutic drug monitoring should be investigated.

Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions

Science.gov (United States)

Sucker, Antje; Zhao, Fang; Pieper, Natalia; Heeke, Christina; Maltaner, Raffaela; Stadtler, Nadine; Real, Birgit; Bielefeld, Nicola; Howe, Sebastian; Weide, Benjamin; Gutzmer, Ralf; Utikal, Jochen; Loquai, Carmen; Gogas, Helen; Klein-Hitpass, Ludger; Zeschnigk, Michael; Westendorf, Astrid M.; Trilling, Mirko; Horn, Susanne; Schilling, Bastian; Schadendorf, Dirk; Griewank, Klaus G.; Paschen, Annette

2017-01-01

Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8+ T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making. PMID:28561041

Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease.

Science.gov (United States)

Wardell, Suzanne E; Nelson, Erik R; Chao, Christina A; McDonnell, Donald P

2013-05-01

There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-α) antagonists, or that downregulate the expression of ER-α, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-α pharmacology, that there may already exist among the most recently developed selective estrogen receptor modulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-α conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. The high-affinity SERM bazedoxifene was shown to function as a pure ER-α antagonist in cellular models of breast cancer and effectively inhibited the growth of both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-α that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist efficacy. Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer. ©2013 AACR.

c-Met Overexpression Contributes to the Acquired Apoptotic Resistance of Nonadherent Ovarian Cancer Cells through a Cross Talk Mediated by Phosphatidylinositol 3-Kinase and Extracellular Signal-Regulated Kinase 1/2

Directory of Open Access Journals (Sweden)

Maggie K.S. Tang

2010-02-01

Full Text Available Ovarian cancer is the most lethal gynecologic cancer mainly because of widespread peritoneal dissemination and malignant ascites. Key to this is the capacity of tumor cells to escape suspension-induced apoptosis (anoikis, which also underlies their resistance to chemotherapy. Here, we used a nonadherent cell culture model to investigate the molecular mechanisms of apoptotic resistance of ovarian cancer cells that may mimic the chemoresistance found in solid tumors. We found that ovarian cancer cells acquired a remarkable resistance to anoikis and apoptosis induced by exposure to clinically relevant doses of two front-line chemotherapeutic drugs cisplatin and paclitaxel when grown in three-dimensional than monolayer cultures. Inhibition of the hepatocyte growth factor (HGF receptor c-Met, which is frequently overexpressed in ovarian cancer, by a specific inhibitor or small interfering RNA blocked the acquired anoikis resistance and restored chemosensitivity in three-dimensional not in two-dimensional cultures. These effects were found to be dependent on both phosphatidylinositol 3-kinase (PI3K/Akt and extracellular signal-regulated kinase (ERK 1/2 signaling pathways. Inhibitors of PI3K/Akt abrogated ERK1/2 activation and its associated anoikis resistance in response to HGF, suggesting a signaling relay between these two pathways. Furthermore, we identified a central role of Ras as a mechanism of this cross talk. Interestingly, Ras did not lie upstream of PI3K/Akt, whereas PI3K/Akt signaling to ERK1/2 involved Ras. These findings shed new light on the apoptotic resistance mechanism of nonadherent ovarian cancer ascites cells and may have important clinical implications.

[Ceftaroline fosamil in community-acquired and nosocomial pneumonia].

Science.gov (United States)

Calbo, Esther; Zaragoza, Rafael

2014-03-01

Community-acquired pneumonia (CAP) is a common infection in developed countries and causes a large number of hospital admissions and deaths. In recent years, the incidence of this disease has increased, caused by progressive population aging. Following the introduction of the conjugate vaccine against Streptococcus pneumoniae, there have been significant epidemiological changes that require close monitoring because of the possible emergence of new patterns of resistance. This article aims to review the role of ceftaroline fosamil, a new parenteral cephalosporin with antibacterial activity against Gram-negative and Gram-positive pathogens, in the treatment of pneumonia. Several in vitro and in vivo studies have shown the efficacy of ceftaroline fosamil against penicillin-resistant S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). Additionally, ceftaroline has shown similar efficacy and safety to ceftriaxone in the treatment of community-acquired pneumonia with severe prognosis (prognostic severity index III and IV) in two phase III clinical trials. Although a non-inferiority design was used for these clinical trials, some data suggest a superior efficacy of ceftaroline, with earlier clinical response and higher cure rate in infections caused by S. pneumoniae, making this drug particularly interesting for critically-ill patients admitted to the intensive care unit. Ceftaroline may also be considered for empirical and directed treatment of MRSA pneumonia. Copyright © 2014 Elsevier España, S.L. All rights reserved.

Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan

Directory of Open Access Journals (Sweden)

Hiscox Stephen

2012-10-01

Full Text Available Abstract Background Acquired resistance to endocrine therapy in breast cancer is a significant problem with relapse being associated with local and/or regional recurrence and frequent distant metastases. Breast cancer cell models reveal that endocrine resistance is accompanied by a gain in aggressive behaviour driven in part through altered growth factor receptor signalling, particularly involving erbB family receptors. Recently we identified that CD44, a transmembrane cell adhesion receptor known to interact with growth factor receptors, is upregulated in tamoxifen-resistant (TamR MCF7 breast cancer cells. The purpose of this study was to explore the consequences of CD44 upregulation in an MCF7 cell model of acquired tamoxifen resistance, specifically with respect to the hypothesis that CD44 may influence erbB activity to promote an adverse phenotype. Methods CD44 expression in MCF7 and TamR cells was assessed by RT-PCR, Western blotting and immunocytochemistry. Immunofluorescence and immunoprecipitation studies revealed CD44-erbB associations. TamR cells (± siRNA-mediated CD44 suppression or MCF7 cells (± transfection with the CD44 gene were treated with the CD44 ligand, hyaluronon (HA, or heregulin and their in vitro growth (MTT, migration (Boyden chamber and wound healing and invasion (Matrigel transwell migration determined. erbB signalling was assessed using Western blotting. The effect of HA on erbB family dimerisation in TamR cells was determined by immunoprecipitation in the presence or absence of CD44 siRNA. Results TamR cells overexpressed CD44 where it was seen to associate with erbB2 at the cell surface. siRNA-mediated suppression of CD44 in TamR cells significantly attenuated their response to heregulin, inhibiting heregulin-induced cell migration and invasion. Furthermore, TamR cells exhibited enhanced sensitivity to HA, with HA treatment resulting in modulation of erbB dimerisation, ligand-independent activation of erbB2

Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan

International Nuclear Information System (INIS)

Hiscox, Stephen; Gee, Julia; Baruha, Bedanta; Smith, Chris; Bellerby, Rebecca; Goddard, Lindy; Jordan, Nicola; Poghosyan, Zaruhi; Nicholson, Robert I; Barrett-Lee, Peter

2012-01-01

Acquired resistance to endocrine therapy in breast cancer is a significant problem with relapse being associated with local and/or regional recurrence and frequent distant metastases. Breast cancer cell models reveal that endocrine resistance is accompanied by a gain in aggressive behaviour driven in part through altered growth factor receptor signalling, particularly involving erbB family receptors. Recently we identified that CD44, a transmembrane cell adhesion receptor known to interact with growth factor receptors, is upregulated in tamoxifen-resistant (TamR) MCF7 breast cancer cells. The purpose of this study was to explore the consequences of CD44 upregulation in an MCF7 cell model of acquired tamoxifen resistance, specifically with respect to the hypothesis that CD44 may influence erbB activity to promote an adverse phenotype. CD44 expression in MCF7 and TamR cells was assessed by RT-PCR, Western blotting and immunocytochemistry. Immunofluorescence and immunoprecipitation studies revealed CD44-erbB associations. TamR cells (± siRNA-mediated CD44 suppression) or MCF7 cells (± transfection with the CD44 gene) were treated with the CD44 ligand, hyaluronon (HA), or heregulin and their in vitro growth (MTT), migration (Boyden chamber and wound healing) and invasion (Matrigel transwell migration) determined. erbB signalling was assessed using Western blotting. The effect of HA on erbB family dimerisation in TamR cells was determined by immunoprecipitation in the presence or absence of CD44 siRNA. TamR cells overexpressed CD44 where it was seen to associate with erbB2 at the cell surface. siRNA-mediated suppression of CD44 in TamR cells significantly attenuated their response to heregulin, inhibiting heregulin-induced cell migration and invasion. Furthermore, TamR cells exhibited enhanced sensitivity to HA, with HA treatment resulting in modulation of erbB dimerisation, ligand-independent activation of erbB2 and EGFR and induction of cell migration

Systemic resistance induced by rhizosphere bacteria

NARCIS (Netherlands)

Loon, L.C. van; Bakker, P.A.H.M.; Pieterse, C.M.J.

1998-01-01

Nonpathogenic rhizobacteria can induce a systemic resistance in plants that is phenotypically similar to pathogen-induced systemic acquired resistance (SAR). Rhizobacteria-mediated induced systemic resistance (ISR) has been demonstrated against fungi, bacteria, and viruses in Arabidopsis, bean,

Methicillin-resistant Staphylococcus aureus (MRSA)

Science.gov (United States)

Methicillin-resistant Staphylococcus aureus; Hospital-acquired MRSA (HA-MRSA); Staph - MRSA; Staphylococcal - MRSA ... Centers for Disease Control and Prevention website. Methicillin-resistant Staphylococcus aureus (MRSA). www.cdc.gov/mrsa/index.html . Updated ...

Spread of community-acquired meticillin-resistant Staphylococcus aureus skin and soft-tissue infection within a family: implications for antibiotic therapy and prevention.

LENUS (Irish Health Repository)

Amir, N H

2010-04-01

Outbreaks or clusters of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) within families have been reported. We describe a family cluster of CA-MRSA skin and soft-tissue infection where CA-MRSA was suspected because of recurrent infections which failed to respond to flucloxacillin. While the prevalence of CA-MRSA is low worldwide, CA-MRSA should be considered in certain circumstances depending on clinical presentation and risk assessment. Surveillance cultures of family contacts of patients with MRSA should be considered to help establish the prevalence of CA-MRSA and to inform the optimal choice of empiric antibiotic treatment.

Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses

Science.gov (United States)

Sundaresan, Tilak K.; Sequist, Lecia V.; Heymach, John V.; Riely, Gregory J.; Jänne, Pasi A.; Koch, Walter H.; Sullivan, James P.; Fox, Douglas B.; Maher, Robert; Muzikansky, Alona; Webb, Andrew; Tran, Hai T.; Giri, Uma; Fleisher, Martin; Yu, Helena A.; Wei, Wen; Johnson, Bruce E.; Barber, Thomas A.; Walsh, John R.; Engelman, Jeffrey A.; Stott, Shannon L.; Kapur, Ravi; Maheswaran, Shyamala; Toner, Mehmet

2015-01-01

Purpose The T790M gatekeeper mutation in the Epidermal Growth Factor Receptor (EGFR) is acquired by some EGFR-mutant non-small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKIs). As third generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management. Experimental Design As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy. We compared the T790M genotype from tumor biopsies with analysis of simultaneously collected circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Results T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples and 32 (80%) ctDNA samples. The resistance-associated mutation was detected in 47–50% of patients using each of the genotyping assays, with concordance among them ranging from 57–74%. While CTC- and ctDNA-based genotyping were each unsuccessful in 20–30% of cases, the two assays together enabled genotyping in all patients with an available blood sample, and they identified the T790M mutation in 14 (35%) patients in whom the concurrent biopsy was negative or indeterminate. Conclusion Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient’s cancer, which should be validated in predicting response to T790M-targeted inhibitors. PMID:26446944

Community-acquired multidrug-resistant Gram-negative bacterial infective endocarditis.

Science.gov (United States)

Naha, Sowjanya; Naha, Kushal; Acharya, Vasudev; Hande, H Manjunath; Vivek, G

2014-08-05

We describe two cases of bacterial endocarditis secondary to multidrug-resistant Gram-negative organisms. In both cases, the diagnosis was made in accordance with the modified Duke's criteria and confirmed by histopathological analysis. Furthermore, in both instances there were no identifiable sources of bacteraemia and no history of contact with hospital or other medical services prior to the onset of symptoms. The patients were managed in similar fashion with prolonged broad-spectrum antibiotic therapy and surgical intervention and made complete recoveries. These cases highlight Gram-negative organisms as potential agents for endocarditis, as well as expose the dissemination of such multidrug-resistant bacteria into the community. The application of an integrated medical and surgical approach and therapeutic dilemmas encountered in managing these cases are described. 2014 BMJ Publishing Group Ltd.

PI3Kδ inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse large B cell lymphoma with acquired resistance to PI3Kδ and BTK inhibitors.

Directory of Open Access Journals (Sweden)

Anella Yahiaoui

Full Text Available Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3Kδ and Bruton's tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton's tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*, which led to a loss of A20 protein, and increased p-IκBα. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton's tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to

Nasal carriage of a single clone of community-acquired methicillin-resistant Staphylococcus aureus among kindergarten attendees in northern Taiwan

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Lee Shih-Yi

2007-06-01

Full Text Available Abstract Background: To evaluate the prevalence and microbiological characterization of community-acquired (CA methicillin-resistant Staphylococcus aureus (MRSA nasal carriage in a kindergarten. Methods: Point prevalence study. Nasal swabs were collected from healthy children younger than 7 years of age who were attending a kindergarten in Taipei, Taiwan. A parent questionnaire regarding MRSA risk factors was administered simultaneously. All CA-MRSA colonization isolates were archived for subsequent antimicrobial susceptibility and molecular typing. Results: Of the 68 children who participated in the study, 17 (25% had S. aureus isolated from nasal swabs. Nine (13.2% of the 68 children had CA-MRSA carriage, and none of them had any identified risk factors. Antimicrobial susceptibility testing revealed all of the 9 CA-MRSA colonization isolates had uniformly high resistance (100% to both clindamycin and erythromycin, the macrolide-lincosamide-streptogramin-constitutive phenotype and the ermB gene. Pulsed-field gel electrophoresis revealed 8 (88.9% of 9 CA-MRSA colonization isolates were genetically related and multilocus sequence typing revealed all isolates had sequence type 59. All of the colonization isolates carried the staphylococcal cassette chromosome mec type IV, but none were positive for the Panton-Valentine leukocidin genes. Conclusion: The results of this study suggest that a single predominant CA-MRSA colonization strain featuring high clindamycin resistance circulated in this kindergarten. Additionally, due to the established transmissibility of colonization isolates, the high prevalence of nasal carriage of CA-MRSA among healthy attendees in kindergartens may indicate the accelerated spread of CA-MRSA in the community.

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

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Iida, Mari; Bahrar, Harsh; Brand, Toni M; Pearson, Hannah E; Coan, John P; Orbuch, Rachel A; Flanigan, Bailey G; Swick, Adam D; Prabakaran, Prashanth; Lantto, Johan; Horak, Ivan D.; Kragh, Michael; Salgia, Ravi; Kimple, Randy J; Wheeler, Deric L

2016-01-01

Cetuximab, an antibody against the Epidermal Growth Factor Receptor (EGFR) has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do initially respond become refractory, highlighting both intrinsic and acquired resistance to cetuximab as significant clinical problems. To understand mechanistically how cancerous cells acquire resistance, we previously developed models of acquired resistance using the H226 NSCLC and UM-SCC1 HNSCC cell lines. Cetuximab-resistant clones showed a robust upregulation and dependency on the HER family receptors EGFR, HER2 and HER3. Here, we examined Pan-HER, a mixture of six antibodies targeting these receptors on cetuximab-resistant clones. In cells exhibiting acquired or intrinsic resistance to cetuximab, Pan-HER treatment decreased all three receptors’ protein levels and down-stream activation of AKT and MAPK. This correlated with decreased cell proliferation in cetuximab-resistant clones. To determine whether Pan-HER had a therapeutic benefit in vivo, we established de novo cetuximab-resistant mouse xenografts and treated resistant tumors with Pan-HER. This regimen resulted in a superior growth delay of cetuximab-resistant xenografts compared to mice continued on cetuximab. Furthermore, intrinsically cetuximab-resistant HNSCC patient-derived xenograft tumors treated with Pan-HER exhibited significant growth delay compared to vehicle/cetuximab controls. These results suggest that targeting HER family receptors simultaneously with Pan-HER is a promising treatment strategy for tumors displaying intrinsic or acquired resistance to cetuximab. PMID:27422810

The increasing importance of community-acquired methicillin-resistant Staphylococcus aureus infections.

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Agostino, Jason W; Ferguson, John K; Eastwood, Keith; Kirk, Martyn D

2017-11-06

To identify groups at risk of methicillin-resistant Staphylococcus aureus (MRSA) infection, patterns of antimicrobial resistance, and the proportion of patients with MRSA infections but no history of recent hospitalisation. Case series of 39 231 patients with S. aureus isolates from specimens processed by the Hunter New England Local Health District (HNELHD) public pathology provider during 2008-2014. Proportion of MRSA infections among people with S. aureus isolates; antimicrobial susceptibility of MRSA isolates; origin of MRSA infections (community- or health care-associated); demographic factors associated with community-associated MRSA infections. There were 71 736 S. aureus-positive specimens during the study period and MRSA was isolated from 19.3% of first positive specimens. Most patients (56.9%) from whom MRSA was isolated had not been admitted to a public hospital in the past year. Multiple regression identified that patients with community-associated MRSA were more likely to be younger (under 40), Indigenous Australians (odds ratio [OR], 2.6; 95% CI, 2.3-2.8), or a resident of an aged care facility (OR, 4.7; 95% CI, 3.8-5.8). The proportion of MRSA isolates that included the dominant multi-resistant strain (AUS-2/3-like) declined from 29.6% to 3.4% during the study period (P resistant strain decreased, new strategies for controlling infections in the community are needed to reduce the prevalence of non-multi-resistant strains.

The Gut as Reservoir of Antibiotic Resistance: Microbial Diversity of Tetracycline Resistance in Mother and Infant

DEFF Research Database (Denmark)

de Vries, Lisbeth Elvira; Valles, Yvonne; Agersø, Yvonne

2011-01-01

The microbiota in the human gastrointestinal tract (GIT) is highly exposed to antibiotics, and may be an important reservoir of resistant strains and transferable resistance genes. Maternal GIT strains can be transmitted to the offspring, and resistances could be acquired from birth. This is a ca...

Global Fluoroquinolone Resistance Epidemiology and Implictions for Clinical Use

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Dalhoff, Axel

2012-01-01

This paper on the fluoroquinolone resistance epidemiology stratifies the data according to the different prescription patterns by either primary or tertiary caregivers and by indication. Global surveillance studies demonstrate that fluoroquinolone resistance rates increased in the past years in almost all bacterial species except S. pneumoniae and H. influenzae, causing community-acquired respiratory tract infections. However, 10 to 30% of these isolates harbored first-step mutations conferring low level fluoroquinolone resistance. Fluoroquinolone resistance increased in Enterobacteriaceae causing community acquired or healthcare associated urinary tract infections and intraabdominal infections, exceeding 50% in some parts of the world, particularly in Asia. One to two-thirds of Enterobacteriaceae producing extended spectrum β-lactamases were fluoroquinolone resistant too. Furthermore, fluoroquinolones select for methicillin resistance in Staphylococci. Neisseria gonorrhoeae acquired fluoroquinolone resistance rapidly; actual resistance rates are highly variable and can be as high as almost 100%, particularly in Asia, whereas resistance rates in Europe and North America range from 30% in established sexual networks. In general, the continued increase in fluoroquinolone resistance affects patient management and necessitates changes in some guidelines, for example, treatment of urinary tract, intra-abdominal, skin and skin structure infections, and traveller's diarrhea, or even precludes the use in indications like sexually transmitted diseases and enteric fever. PMID:23097666

Prevalence and invasiveness of community-acquired methicillin-resistant Staphylococcus aureus: A meta-analysis

Directory of Open Access Journals (Sweden)

Shipeng Li

2014-01-01

Full Text Available Background: Reports suggest that the prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA has increased, and that CA-MRSA is more virulent than healthcare-associated (HA-MRSA. Aims: The aim of this study is to gain a better understanding of the invasiveness and prevalence of CA-MRSA in patients; we systematically reviewed the literature by conducting a meta-analysis. Materials and Methods: We searched the MEDLINE and PUBMED databases from the year these databases were established to January 2013. Results: The pooled CA-MRSA prevalence among 50,737 patients from 33 studies was 39.0% (range, 30.8-47.8%. The pooled CA-MRSA prevalence rates among pediatric and adult patients with MRSA infection were 50.2% (range, 37.5-62.8% and 42.3% (range, 16.4-73.3%, respectively. The pooled CA-MRSA prevalence rates of MRSA-infected patients in Asia, Europe, and North America were 23.1% (range, 12.0-39.8%, 37.4% (range, 21.1-56.4%, and 47.4% (range, 35.8-59.4%, respectively. Using the random effects model, we determined that the pooled odds ratio of invasive infections in CA- and HA-MRSA was 0.30 (95% confidence interval: 0.08-1.10; P = 0.07, test for heterogeneity P < 0.00001. Conclusions: The prevalence of CA-MRSA in MRSA infection varied with area and population. No difference in the ability to cause invasive infections was found between CA- and HA-MRSA. This finding challenges the view that CA-MRSA is more virulent than HA-MRSA.

Antibiotic Resistance in Pediatric Urinary Tract Infections.

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Stultz, Jeremy S; Doern, Christopher D; Godbout, Emily

2016-12-01

Urinary tract infections (UTIs) are a common problem in pediatric patients. Resistance to common antibiotic agents appears to be increasing over time, although resistance rates may vary based on geographic region or country. Prior antibiotic exposure is a pertinent risk factor for acquiring resistant organisms during a first UTI and recurrent UTI. Judicious prescribing of antibiotics for common pediatric conditions is needed to prevent additional resistance from occurring. Complex pediatric patients with histories of hospitalizations, prior antibiotic exposure, and recurrent UTIs are also at high risk for acquiring UTIs due to extended spectrum beta-lactamase-producing organisms. Data regarding the impact of in vitro antibiotic susceptibility testing interpretation on UTI treatment outcomes is lacking.

Chemotherapeutics-resistance "arms" race: An update on mechanisms involved in resistance limiting EGFR inhibitors in lung cancer.

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Singh, Pankaj Kumar; Silakari, Om

2017-10-01

Clinical reports suggest that EGFR-mutated lung cancer usually respond significantly towards small molecule tyrosine kinase inhibitors. Same studies also report the eventual development of acquired resistance within a median time interval of 9 to 14months. One of the major mechanisms involved in this acquired resistance was found to be a secondary point mutation at gate-keeper residue, EGFR T790M. However, there are other recent studies which disclose the role of few other novel key players such as, ZEB1, TOPK etc., in the development of tolerance towards the EGFR TKI's, along with other commonly known mechanisms, such as amplification of signalling pathways such as, c-MET, Erbb2, AXL, additional acquired secondary mutations (PIK3CA, BRAF), or phenotypic transformation (small cell or epithelial to mesenchymal transitions). Interestingly, a recent study showed development of resistance via another point mutation, C797S, in case of tumors which were previously resistant and were administered agents capable of overcoming T790M gatekeeper mutation based resistance. Thus, raising serious concern over the direction of drug development involving tyrosine kinases such as EGFR. Current approaches focussing on development of third generation inhibitors, dual inhibitors or inhibitors of HSP90 have shown significant activity but do not answer the long term question of resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy of a hospital-wide environmental cleaning protocol on hospital-acquired methicillin-resistant Staphylococcus aureus rates.

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Watson, Paul Andrew; Watson, Luke Robert; Torress-Cook, Alfonso

2016-07-01

Environmental contamination has been associated with over half of methicillin-resistant Staphylococcus aureus (MRSA) outbreaks in hospitals. We explored if a hospital-wide environmental and patient cleaning protocol would lower hospital acquired MRSA rates and associated costs. This study evaluates the impact of implementing a hospital-wide environmental and patient cleaning protocol on the rate of MRSA infection and the potential cost benefit of the intervention. A retrospective, pre-post interventional study design was used. The intervention comprised a combination of enhanced environmental cleaning of high touch surfaces, daily washing of patients with benzalkonium chloride, and targeted isolation of patients with active infection. The rate of MRSA infection per 1000 patient days (PD) was compared with the rate after the intervention (Steiros Algorithm ® ) was implemented. A cost-benefit analysis based on the number of MRSA infections avoided was conducted. The MRSA rates decreased by 96% from 3.04 per 1000 PD to 0.11 per 1000 PD ( P reduction in MRSA infections, avoided an estimated $1,655,143 in healthcare costs. Implementation of this hospital-wide protocol appears to be associated with a reduction in the rate of MRSA infection and therefore a reduction in associated healthcare costs.

Antimicrobial Resistance in Invasive Bacterial Infections in Hospitalized Children, Cambodia, 2007-2016.

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Fox-Lewis, Andrew; Takata, Junko; Miliya, Thyl; Lubell, Yoel; Soeng, Sona; Sar, Poda; Rith, Kolthida; McKellar, Gregor; Wuthiekanun, Vanaporn; McGonagle, Erin; Stoesser, Nicole; Moore, Catrin E; Parry, Christopher M; Turner, Claudia; Day, Nicholas P J; Cooper, Ben S; Turner, Paul

2018-05-01

To determine trends, mortality rates, and costs of antimicrobial resistance in invasive bacterial infections in hospitalized children, we analyzed data from Angkor Hospital for Children, Siem Reap, Cambodia, for 2007-2016. A total of 39,050 cultures yielded 1,341 target pathogens. Resistance rates were high; 82% each of Escherichia coli and Klebsiella pneumoniae isolates were multidrug resistant. Hospital-acquired isolates were more often resistant than community-acquired isolates; resistance trends over time were heterogeneous. K. pneumoniae isolates from neonates were more likely than those from nonneonates to be resistant to ampicillin-gentamicin and third-generation cephalosporins. In patients with community-acquired gram-negative bacteremia, third-generation cephalosporin resistance was associated with increased mortality rates, increased intensive care unit admissions, and 2.26-fold increased healthcare costs among survivors. High antimicrobial resistance in this setting is a threat to human life and the economy. In similar low-resource settings, our methods could be reproduced as a robust surveillance model for antimicrobial resistance.

GLP-1 responses are heritable and blunted in acquired obesity with high liver fat and insulin resistance

DEFF Research Database (Denmark)

Matikainen, Niina; Bogl, Leonie H; Hakkarainen, Antti

2014-01-01

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for o...... Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults....... under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min...... GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS...

The Complete Genome and Phenome of a Community-Acquired Acinetobacter baumannii

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Farrugia, Daniel N.; Elbourne, Liam D. H.; Hassan, Karl A.; Eijkelkamp, Bart A.; Tetu, Sasha G.; Brown, Melissa H.; Shah, Bhumika S.; Peleg, Anton Y.; Mabbutt, Bridget C.; Paulsen, Ian T.

2013-01-01

Many sequenced strains of Acinetobacter baumannii are established nosocomial pathogens capable of resistance to multiple antimicrobials. Community-acquired A. baumannii in contrast, comprise a minor proportion of all A. baumannii infections and are highly susceptible to antimicrobial treatment. However, these infections also present acute clinical manifestations associated with high reported rates of mortality. We report the complete 3.70 Mbp genome of A. baumannii D1279779, previously isolated from the bacteraemic infection of an Indigenous Australian; this strain represents the first community-acquired A. baumannii to be sequenced. Comparative analysis of currently published A. baumannii genomes identified twenty-four accessory gene clusters present in D1279779. These accessory elements were predicted to encode a range of functions including polysaccharide biosynthesis, type I DNA restriction-modification, and the metabolism of novel carbonaceous and nitrogenous compounds. Conversely, twenty genomic regions present in previously sequenced A. baumannii strains were absent in D1279779, including gene clusters involved in the catabolism of 4-hydroxybenzoate and glucarate, and the A. baumannii antibiotic resistance island, known to bestow resistance to multiple antimicrobials in nosocomial strains. Phenomic analysis utilising the Biolog Phenotype Microarray system indicated that A. baumannii D1279779 can utilise a broader range of carbon and nitrogen sources than international clone I and clone II nosocomial isolates. However, D1279779 was more sensitive to antimicrobial compounds, particularly beta-lactams, tetracyclines and sulphonamides. The combined genomic and phenomic analyses have provided insight into the features distinguishing A. baumannii isolated from community-acquired and nosocomial infections. PMID:23527001

New Fks hot spot for acquired echinocandin resistance in Saccharomyces cerevisiae and its contribution to intrinsic resistance of Scedosporium species.

Science.gov (United States)

Johnson, Michael E; Katiyar, Santosh K; Edlind, Thomas D

2011-08-01

Echinocandins represent a new antifungal group with potent activity against Candida species. These lipopeptides inhibit the synthesis of β-1,3-glucan, the major cell wall polysaccharide. Acquired resistance or reduced echinocandin susceptibility (RES) is rare and associated with mutations in two "hot spot" regions of Fks1 or Fks2, the probable β-1,3-glucan synthases. In contrast, many fungi demonstrate intrinsic RES for reasons that remain unclear. We are using Saccharomyces cerevisiae to understand the basis for RES by modeling echinocandin-Fks interaction. Previously characterized mutations confer cross-RES; we screened for mutations conferring differential RES, implying direct interaction of that Fks residue with a variable echinocandin side chain. One mutant (in an fks1Δ background) exhibited ≥16-fold micafungin and anidulafungin versus caspofungin RES. Sequencing identified a novel Fks2 mutation, W714L/Y715N. Equivalent W695L/Y696N and related W695L/F/C mutations in Fks1 generated by site-directed mutagenesis and the isolation of a W695L-equivalent mutation in Candida glabrata confirmed the role of the new "hot spot 3" in RES. Further mutagenesis expanded hot spot 3 to Fks1 residues 690 to 700, yielding phenotypes ranging from cross-RES to differential hypersusceptibility. Fks1 sequences from intrinsically RES Scedosporium species revealed W695F-equivalent substitutions; Fks1 hybrids expressing Scedosporium prolificans hot spot 3 confirmed that this substitution imparts RES.

New Fks Hot Spot for Acquired Echinocandin Resistance in Saccharomyces cerevisiae and Its Contribution to Intrinsic Resistance of Scedosporium Species▿

Science.gov (United States)

Johnson, Michael E.; Katiyar, Santosh K.; Edlind, Thomas D.

2011-01-01

Echinocandins represent a new antifungal group with potent activity against Candida species. These lipopeptides inhibit the synthesis of β-1,3-glucan, the major cell wall polysaccharide. Acquired resistance or reduced echinocandin susceptibility (RES) is rare and associated with mutations in two “hot spot” regions of Fks1 or Fks2, the probable β-1,3-glucan synthases. In contrast, many fungi demonstrate intrinsic RES for reasons that remain unclear. We are using Saccharomyces cerevisiae to understand the basis for RES by modeling echinocandin-Fks interaction. Previously characterized mutations confer cross-RES; we screened for mutations conferring differential RES, implying direct interaction of that Fks residue with a variable echinocandin side chain. One mutant (in an fks1Δ background) exhibited ≥16-fold micafungin and anidulafungin versus caspofungin RES. Sequencing identified a novel Fks2 mutation, W714L/Y715N. Equivalent W695L/Y696N and related W695L/F/C mutations in Fks1 generated by site-directed mutagenesis and the isolation of a W695L-equivalent mutation in Candida glabrata confirmed the role of the new “hot spot 3” in RES. Further mutagenesis expanded hot spot 3 to Fks1 residues 690 to 700, yielding phenotypes ranging from cross-RES to differential hypersusceptibility. Fks1 sequences from intrinsically RES Scedosporium species revealed W695F-equivalent substitutions; Fks1 hybrids expressing Scedosporium prolificans hot spot 3 confirmed that this substitution imparts RES. PMID:21576441

[Cetuximab in combination with icotinib overcomes the acquired resistance caused by EGFR T790M mutation in non-small cell lung cancer].

Science.gov (United States)

Wang, Meng; Zhang, Lianmin; Zhao, Xiaoliang; Liu, Jun; Chen, Yulong; Wang, Changli

2014-09-01

The aim of this study was to investigate the effects of combination of icotinib and cetuximab on the acquired drug resistance caused by T790M mutation of EGFR in NSCLC, and provide experimental evidence for rational treatment of NSCLC. The effects of these two agents on cell proliferation, apoptosis, and EGFR-dependent signaling were evaluated using 3-(4, 5-dimethylthiazol-2-yl)- 5-diphenyltetrazolium bromide (MTT) assay, annexin V staining, and Western blotting. The expression of molecular markers of tumor proliferation PCNA and Ki-67 protein was further examined by immunohistochemistry, and the expression of EGFR-signaling-related proteins in tissue sections taken from H1975 tumor xenografts was assessed by Western blot assay. Sensitivity to EGFR inhibitors was detected in human H1975 tumor xenograft in nude mice. The in vitro experiment showed that the proliferative ability of H1975 cells was inhibited in a dose-dependent manner, along with the increasing doses of cetuximab and icotinib, and the combination of cetuximab with icotinib resulted in a more pronounced growth inhibition of the H1975 cells. The apoptosis rate of H1975 cells after treatment with 0.5 µmol/L icotinib and 1 µg/ml cetuximab was (22.03 ± 2.41)% and that after treatment with 5 µmol/L icotinib and 10 µg/ml cetuximab was (42.75 ± 2.49)%, both were significantly higher than that after treatment with the same dose of icotinib or cetuximab alone (P icotinib treatment, but (30.8 ± 2.0) mm(3) in the cetuximab treatment group and 0 mm(3) in the cetuximab combined with icotinib group. There was a significantly decreased expression of Ki-67 and PCNA proteins and down-regulation of phosphorylation of EGFR signaling-related proteins in the cetuximab combined with icotinib group. The combination of icotinib with cetuximab can exert synergistic inhibitory effect on the acquired drug resistance caused by T790M mutation of EGFR in NSCLC H1975 cells, interrupts the EGFR-downstream signaling pathway

Leucine supplementation improves acquired growth hormone resistance in rats with protein-energy malnutrition.

Science.gov (United States)

Gao, Xuejin; Tian, Feng; Wang, Xinying; Zhao, Jie; Wan, Xiao; Zhang, Li; Wu, Chao; Li, Ning; Li, Jieshou

2015-01-01

-CON group. Our data are the first to demonstrate that long-term supplementation with leucine improved acquired growth hormone resistance in rats with protein-energy malnutrition. Leucine might promote skeletal muscle protein synthesis by regulating downstream anabolic signaling transduction.

Infection control implications of heterogeneous resistance mechanisms in carbapenem-resistant Enterobacteriaceae (CRE).

Science.gov (United States)

Goodman, K E; Simner, P J; Tamma, P D; Milstone, A M

2016-01-01

The Centers for Disease Control and Prevention (CDC) defines carbapenem-resistant Enterobacteriaceae (CRE) based upon a phenotypic demonstration of carbapenem resistance. However, considerable heterogeneity exists within this definitional umbrella. CRE may mechanistically differ by whether they do or do not produce carbapenemases. Moreover, patients can acquire CRE through multiple pathways: endogenously through antibiotic selective pressure on intestinal microbiota, exogenously through horizontal transmission or through a combination of these factors. Some evidence suggests that non-carbapenemase-producing CRE may be more frequently acquired by antibiotic exposure and carbapenemase-producing CRE via horizontal transmission, but definitive data are lacking. This review examines types of CRE resistance mechanisms, antibiotic exposure and horizontal transmission pathways of CRE acquisition, and the implications of these heterogeneities to the development of evidence-based CRE healthcare epidemiology policies. In our Expert Commentary & Five-Year View, we outline specific nosocomial CRE knowledge gaps and potential methodological approaches for their resolution.

Emergence of community-acquired methicillin-resistant Staphylococcus aureus in an Iranian referral paediatric hospital.

Science.gov (United States)

Mamishi, S; Mahmoudi, S; Bahador, A; Matini, H; Movahedi, Z; Sadeghi, R H; Pourakbari, B

2015-01-01

The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals has been changed in recent years due to the arrival of community-associated MRSA (CA-MRSA) strains into healthcare settings. The aim of this study is to investigate the distribution of staphylococcal cassette chromosome mec (SCCmec) type V as well as SCCmec IV subtypes, which have been associated with community-acquired infection among healthcare-associated MRSA (HA-MRSA) isolates. Antimicrobial susceptibility, SCCmec type, spa type and the presence of Panton-Valentine leukocidin (PVL) genes were determined for all HA-MRSA isolates in an Iranian referral hospital. In this study of 48 HA-MRSA isolates, 13 (27%), three (6.2%), five (10.4%) and one (2%) belonged to SCCmec subtypes IVa, IVb, IVc and IVd, respectively. Only two isolates (4.2%) belonged to SCCmec types V Notably, one isolate was found to harbour concurrent SCCmec subtypes IVb and IVd. MRSA containing SCCmec subtype IVb, IVc and IVd as well as type V isolates were all susceptible to chloramphenicol, clindamycin and rifampicin, while the sensitivity to these antibiotics was lower among MRSA containing SCCmec subtype IVa. The most frequently observed spa ttype was t037, accounting for 88% (22/25). Three other spa type was t002, t1816 and t4478. Large reservoirs of MRSA containing type IV subtypes and type V now exist in patients in this Iranian hospital. Therefore, effective infection control management in order to control the spread of CA-MRSA is highly recommended.

Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222.

Science.gov (United States)

Yu, Dan-Dan; Wu, Ying; Zhang, Xiao-Hui; Lv, Meng-Meng; Chen, Wei-Xian; Chen, Xiu; Yang, Su-Jin; Shen, Hongyu; Zhong, Shan-Liang; Tang, Jin-Hai; Zhao, Jian-Hua

2016-03-01

Breast cancer (BCa) is one of the major deadly cancers in women. However, treatment of BCa is still hindered by the acquired-drug resistance. It is increasingly reported that exosomes take part in the development, metastasis, and drug resistance of BCa. However, the specific role of exosomes in drug resistance of BCa is poorly understood. In this study, we investigate whether exosomes transmit drug resistance through delivering miR-222. We established an adriamycin-resistant variant of Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line (MCF-7/Adr) from a drug-sensitive variant (MCF-7/S). Exosomes were isolated from cell supernatant by ultracentrifugation. Cell viability was assessed by MTT assay and apoptosis assay. Individual miR-222 molecules in BCa cells were detected by fluorescence in situ hybridization (FISH). Then, FISH was combined with locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH). Individual miR-222 could be detected as bright photostable fluorescent spots and then the quantity of miR-222 per cell could be counted. Stained exosomes were taken in by the receipt cells. MCF-7/S acquired drug resistance after co-culture with exosomes from MCF-7/Adr (A/exo) but did not after co-culture with exosomes from MCF-7/S (S/exo). The quantity of miR-222 in A/exo-treated MCF-7/S was significantly greater than in S/exo-treated MCF-7/S. MCF-7/S transfected with miR-222 mimics acquired adriamycin resistance while MCF-7/S transfected with miR-222 inhibitors lost resistance. In conclusion, exosomes are effective in transmitting drug resistance and the delivery of miR-222 via exosomes may be a mechanism.

METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA ...

African Journals Online (AJOL)

Nosocomial infections caused by methicillin-resistant strains of Staphylococcus aureus often pose therapeutic dilemma to the clinicians because of the multi resistant nature of these strains of Staphylococcus aureus. Outbreaks of both nosocomial and community acquired infections are also frequent and difficult to control.

Characteristics and specificity of acquired immunologic memory to Mycobacterium tuberculosis infection

International Nuclear Information System (INIS)

Orme, I.M.

1988-01-01

The results herein show that mice infected with Mycobacterium tuberculosis and then exposed to a protracted course of isoniazid chemotherapy possess a heightened state of acquired resistance to subsequent challenge with the homologous organism. Our results provide the first evidence, moreover, that this resistance is mediated by a long-lived, cyclophosphamide- and irradiation-resistant L3T4+ Lyt-2- lymphocyte capable of giving rise to an accelerated re-emergence of resistance in the animal upon rechallenge. Evidence is also provided to show that triggering of this memory-immune T cell population in the re-challenged host was associated with the rapid emergence of non-specific resistance to secondary bacterial infection; however, the accelerated emergence of this population was only observed if the challenge inoculum consisted of the living organism. The relevance of this latter finding to strategies for vaccine development is discussed

Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters

International Nuclear Information System (INIS)

Němcová-Fürstová, Vlasta; Kopperová, Dana; Balušíková, Kamila; Ehrlichová, Marie; Brynychová, Veronika; Václavíková, Radka; Daniel, Petr; Souček, Pavel; Kovář, Jan

2016-01-01

Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to

Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters

Energy Technology Data Exchange (ETDEWEB)

Němcová-Fürstová, Vlasta, E-mail: vlasta.furstova@lf3.cuni.cz [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Kopperová, Dana; Balušíková, Kamila [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Ehrlichová, Marie; Brynychová, Veronika; Václavíková, Radka [Toxicogenomics Unit, National Institute of Public Health, Prague (Czech Republic); Daniel, Petr [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Souček, Pavel [Toxicogenomics Unit, National Institute of Public Health, Prague (Czech Republic); Kovář, Jan [Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic)

2016-11-01

Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to

Endocrine resistance in breast cancer – an overview and update

Science.gov (United States)

Clarke, Robert; Tyson, John J.; Dixon, J. Michael

2015-01-01

Tumors that express detectable levels of the product of the ESR1 gene (estrogen receptor-α; ERα) represent the single largest molecular subtype of breast cancer. More women eventually die from ERα+ breast cancer than from either HER2+ disease (almost half of which also express ERα) and/or from triple negative breast cancer (ERα-negative, progesterone receptor-negative, and HER2-negative). Antiestrogens and aromatase inhibitors are largely indistinguishable from each other in their abilities to improve overall survival and almost 50% of ERα+ breast cancers will eventually fail one or more of these endocrine interventions. The precise reasons why these therapies fail in ERα+ breast cancer remain largely unknown. Pharmacogenetic explanations for Tamoxifen resistance are controversial. The role of ERα mutations in endocrine resistance remains unclear. Targeting the growth factors and oncogenes most strongly correlated with endocrine resistance has proven mostly disappointing in their abilities to improve overall survival substantially, particularly in the metastatic setting. Nonetheless, there are new concepts in endocrine resistance that integrate molecular signaling, cellular metabolism, and stress responses including endoplasmic reticulum stress and the unfolded protein response (UPR) that provide novel insights and suggest innovative therapeutic targets. Encouraging evidence that drug combinations with CDK4/CDK6 inhibitors can extend recurrence free survival may yet translate to improvements in overall survival. Whether the improvements seen with immunotherapy in other cancers can be achieved in breast cancer remains to be determined, particularly for ERα+ breast cancers. This review explores the basic mechanisms of resistance to endocrine therapies, concluding with some new insights from systems biology approaches further implicating autophagy and the UPR in detail, and a brief discussion of exciting new avenues and future prospects. PMID:26455641

Community-acquired pneumonia caused by methicillin-resistant Staphylococcus aureus in critically-ill patients: systematic review

Directory of Open Access Journals (Sweden)

Nuria Carballo

2017-03-01

Full Text Available Introduction: Community-acquired pneumonia (CAP is associated with high morbidity and mortality rates. Despite methicillin-resistant Staphylococcus aureus (MRSA having often been associated with nosocomial pneumonia, the condition of some MRSA CAP patients is severe enough to warrant their being admitted to ICU. Objective: The purpose of this study is to conduct a systematic review of the literature on antibiotic treatment of MRSA CAP in critically-ill patients. Material and methods: An online search was conducted for locating articles on MRSA CAP in critically ill patients. Relevant publications were identified in PUBMED, the BestPractice database, UpToDate database and the Cochrane Library for articles published in English within the December 2001 - April 2016 time frame. Results: A total of 70 articles were found to have been published, 13 (18.8% having been included and 57 (81.4% excluded. Cohort studies were predominant, having totaled 16 in number (20.7% as compared to one sole cross-sectional study (3.5%. Conclusions: The experience in the treatment of MRSA CAP in patients requiring admission to ICU is quite limited. Vancomycin or linezolid seem to be the treatments of choice for MRSA CAP, although there not be any specific recommendation in this regard. It may be useful to use alternative routes, such as administration via aerosolized antibiotics, continuous infusion or in association with other antibiotics.

Mechanisms and circumvention of cellular resistance to cisplatin.

NARCIS (Netherlands)

Hospers, Geesiena Alberdina Petronella

1989-01-01

Cisplatin (CDDP) is an active cytostatic agent. A limitation to its effectiveness initially or appearing during cystatic treatment is the occurrence of resistance. This thesis describes mechanisms wich are responsible for acquired cellular CDDP resistance. To investigate cellular CDDP resistance, a

Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study.

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Sharma, Aditya; Hill, Andrew; Kurbatova, Ekaterina; van der Walt, Martie; Kvasnovsky, Charlotte; Tupasi, Thelma E; Caoili, Janice C; Gler, Maria Tarcela; Volchenkov, Grigory V; Kazennyy, Boris Y; Demikhova, Olga V; Bayona, Jaime; Contreras, Carmen; Yagui, Martin; Leimane, Vaira; Cho, Sang Nae; Kim, Hee Jin; Kliiman, Kai; Akksilp, Somsak; Jou, Ruwen; Ershova, Julia; Dalton, Tracy; Cegielski, Peter

2017-07-01

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are emerging worldwide. The Green Light Committee initiative supported programmatic management of drug-resistant tuberculosis in 90 countries. We used estimates from the Preserving Effective TB Treatment Study to predict MDR and XDR tuberculosis trends in four countries with a high burden of MDR tuberculosis: India, the Philippines, Russia, and South Africa. We calibrated a compartmental model to data from drug resistance surveys and WHO tuberculosis reports to forecast estimates of incident MDR and XDR tuberculosis and the percentage of incident MDR and XDR tuberculosis caused by acquired drug resistance, assuming no fitness cost of resistance from 2000 to 2040 in India, the Philippines, Russia, and South Africa. The model forecasted the percentage of MDR tuberculosis among incident cases of tuberculosis to increase, reaching 12·4% (95% prediction interval 9·4-16·2) in India, 8·9% (4·5-11·7) in the Philippines, 32·5% (27·0-35·8) in Russia, and 5·7% (3·0-7·6) in South Africa in 2040. It also predicted the percentage of XDR tuberculosis among incident MDR tuberculosis to increase, reaching 8·9% (95% prediction interval 5·1-12·9) in India, 9·0% (4·0-14·7) in the Philippines, 9·0% (4·8-14·2) in Russia, and 8·5% (2·5-14·7) in South Africa in 2040. Acquired drug resistance would cause less than 30% of incident MDR tuberculosis during 2000-40. Acquired drug resistance caused 80% of incident XDR tuberculosis in 2000, but this estimate would decrease to less than 50% by 2040. MDR and XDR tuberculosis were forecast to increase in all four countries despite improvements in acquired drug resistance shown by the Green Light Committee-supported programmatic management of drug-resistant tuberculosis. Additional control efforts beyond improving acquired drug resistance rates are needed to stop the spread of MDR and XDR tuberculosis in countries with a high burden of MDR

Resistance to treatment in gastrointestinal stromal tumours: What radiologists should know

International Nuclear Information System (INIS)

Tirumani, S.H.; Jagannathan, J.P.; Hornick, J.L.; Ramaiya, N.H.

2013-01-01

Gastrointestinal stromal tumour resistance to treatment with imatinib occurs due to pre-existing or acquired mutations. Computed tomography and positron-emission tomography play an essential role in prompt recognition of resistance to treatment. Primary resistance to treatment, which is encountered in the first 6 months of treatment, is associated with specific mutations. Imaging of these tumours shows no anatomical or metabolic response to treatment. Secondary resistance to treatment, which develops after an initial response, is associated with a variety of mutations acquired after the start of treatment. Imaging findings of secondary resistance are of disease progression

Whole genome analysis of linezolid resistance in Streptococcus pneumoniae reveals resistance and compensatory mutations

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Légaré Danielle

2011-10-01

Full Text Available Abstract Background Several mutations were present in the genome of Streptococcus pneumoniae linezolid-resistant strains but the role of several of these mutations had not been experimentally tested. To analyze the role of these mutations, we reconstituted resistance by serial whole genome transformation of a novel resistant isolate into two strains with sensitive background. We sequenced the parent mutant and two independent transformants exhibiting similar minimum inhibitory concentration to linezolid. Results Comparative genomic analyses revealed that transformants acquired G2576T transversions in every gene copy of 23S rRNA and that the number of altered copies correlated with the level of linezolid resistance and cross-resistance to florfenicol and chloramphenicol. One of the transformants also acquired a mutation present in the parent mutant leading to the overexpression of an ABC transporter (spr1021. The acquisition of these mutations conferred a fitness cost however, which was further enhanced by the acquisition of a mutation in a RNA methyltransferase implicated in resistance. Interestingly, the fitness of the transformants could be restored in part by the acquisition of altered copies of the L3 and L16 ribosomal proteins and by mutations leading to the overexpression of the spr1887 ABC transporter that were present in the original linezolid-resistant mutant. Conclusions Our results demonstrate the usefulness of whole genome approaches at detecting major determinants of resistance as well as compensatory mutations that alleviate the fitness cost associated with resistance.

Cutaneous community-acquired methicillin-resistant Staphylococcus aureus infection in participants of athletic activities.

Science.gov (United States)

Cohen, Philip R

2005-06-01

Cutaneous community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) has been identified in otherwise healthy individuals either with or without methicillin-resistant S. aureus (MRSA)-associated risk factors who participate in athletic activities. The purpose of this study was to describe the clinical features of CAMRSA skin infection that occurred in university student athletes, evaluate the potential mechanisms for the transmission of MRSA infection of the skin in participants of athletic activities, and review the measures for preventing the spread of cutaneous CAMRSA infection in athletes. A retrospective chart review of the student athletes from the University of Houston whose skin lesions were evaluated at the Health Center and grew MRSA was performed. The clinical characteristics and the postulated mechanisms of cutaneous MRSA infection in the athletes were compared with those previously published in reports of CAMRSA skin infection outbreaks in other sports participants. Cutaneous CAMRSA infection occurred in seven student athletes (four women and three men) who were either weight lifters (three students) or members of a varsity sports team: volleyball (two women), basketball (one woman), and football (one man). The MRSA skin infection presented as solitary or multiple, tender, erythematous, fluctuant abscesses with surrounding cellulitis. The lesions were most frequently located in the axillary region (three weight lifters), on the buttocks (two women), or on the thighs (two women). The drainage from all of the skin lesions grew MRSA, which was susceptible to clindamycin, gentamicin, rifampin, trimethoprim/sulfamethoxazole, and vancomycin; five of the isolates were also susceptible to ciprofloxacin and levofloxacin. All of the bacterial strains were resistant to erythromycin, oxacillin, and penicillin. The cutaneous MRSA infections persisted or worsened in the six athletes who were empirically treated for methicillin-sensitive S. aureus at

Approaches to drug resistance in solid tumors : with emphasis on lung cancer

NARCIS (Netherlands)

Bakker, Marleen

2005-01-01

De novo or acquired resistance of tumor cells to anticancer agents remains a major problem for the therapeutic efficacy of chemotherapeutic drugs. Most solid tumors are intrinsically insensitive or acquire resistance after initial response to chemotherapy. Different mechanisms seem to play a role in

Radiological findings of community-acquired methicillin-resistant and methicillin-susceptible staphylococcus aureus pediatric pneumonia in Hawaii

International Nuclear Information System (INIS)

Erdem, Guliz; Bergert, Lora; Len, Kyra; Melish, Marian; Kon, Kevin; DiMauro, Robert

2010-01-01

Community-acquired Staphylococcus aureus (CA-SA) infections are common among pediatric patients in Hawaii. We wanted to characterize the radiological features of methicillin-susceptible (CA-MSSA) and methicillin-resistant (CA-MRSA) staphylococcal pneumonia in Hawaiian children. We retrospectively reviewed medical records and imaging studies of children with SA pneumonia identified from 1996 through 2007. Of 40 children, 26 (65%) had CA-MRSA pneumonia and 14 patients (35%) had CA-MSSA pneumonia. CA-MRSA patients were significantly younger than CA-MSSA patients (65% younger than 1 year vs. 36% older). In a majority (62%) of CA-MRSA patients, the consolidation was unilateral; in most of the CA-MSSA cases (79%), the consolidation was bilateral. Fifty percent of the patients with CA-MRSA and 21% of those with CA-MSSA had pneumatoceles (P = 0.1). CA-MRSA patients more commonly had pleural effusions (85% vs. 64% for CA-MSSA) and pleural thickening (50% vs. 36% for CA-MSSA). This case series describes the radiologic characteristics of CA-MRSA and CA-MSSA pneumonia in children in a highly endemic area. We found that CA-MRSA pneumonias are unilateral in a majority of pediatric pneumonia cases, are more common in children 1 year or younger, and have higher rates of complications in comparison to CA-MSSA patients. (orig.)

Radiological findings of community-acquired methicillin-resistant and methicillin-susceptible staphylococcus aureus pediatric pneumonia in Hawaii

Energy Technology Data Exchange (ETDEWEB)

Erdem, Guliz; Bergert, Lora; Len, Kyra; Melish, Marian [University of Hawaii, John A. Burns School of Medicine, Department of Pediatrics, Honolulu, HI (United States); Kon, Kevin; DiMauro, Robert [Kapiolani Medical Center for Women and Children, Department of Radiology, Honolulu, HI (United States)

2010-11-15

Community-acquired Staphylococcus aureus (CA-SA) infections are common among pediatric patients in Hawaii. We wanted to characterize the radiological features of methicillin-susceptible (CA-MSSA) and methicillin-resistant (CA-MRSA) staphylococcal pneumonia in Hawaiian children. We retrospectively reviewed medical records and imaging studies of children with SA pneumonia identified from 1996 through 2007. Of 40 children, 26 (65%) had CA-MRSA pneumonia and 14 patients (35%) had CA-MSSA pneumonia. CA-MRSA patients were significantly younger than CA-MSSA patients (65% younger than 1 year vs. 36% older). In a majority (62%) of CA-MRSA patients, the consolidation was unilateral; in most of the CA-MSSA cases (79%), the consolidation was bilateral. Fifty percent of the patients with CA-MRSA and 21% of those with CA-MSSA had pneumatoceles (P = 0.1). CA-MRSA patients more commonly had pleural effusions (85% vs. 64% for CA-MSSA) and pleural thickening (50% vs. 36% for CA-MSSA). This case series describes the radiologic characteristics of CA-MRSA and CA-MSSA pneumonia in children in a highly endemic area. We found that CA-MRSA pneumonias are unilateral in a majority of pediatric pneumonia cases, are more common in children 1 year or younger, and have higher rates of complications in comparison to CA-MSSA patients. (orig.)

Non-Escherichia coli versus Escherichia coli community-acquired urinary tract infections in children hospitalized in a tertiary center: relative frequency, risk factors, antimicrobial resistance and outcome.

Science.gov (United States)

Marcus, Nir; Ashkenazi, Shai; Yaari, Arnon; Samra, Zmira; Livni, Gilat

2005-07-01

Currently hospitalization for children with urinary tract infections (UTIs) is reserved for severe or complicated cases. Changes may have taken place in the characteristics and causative uropathogens of hospital-treated community-acquired UTI. To study children hospitalized in a tertiary center with community-acquired UTI, compare Escherichia coli and non-E. coli UTI, define predictors for non-E. coli UTI and elucidate the appropriate therapeutic approach. A prospective clinical and laboratory study from 2001 through 2002 in a tertiary pediatric medical center. Patients were divided by results of the urine culture into E. coli and non-E. coli UTI groups, which were compared. Of 175 episodes of culture-proved UTI, 70 (40%) were caused by non-E. coli pathogens. Non-E. coli UTI was more commonly found in children who were male (P = 0.005), who had underlying renal abnormalities (P = 0.0085) and who had received antibiotic therapy in the prior month (P = 0.0009). Non-E. coli uropathogens were often resistant to antibiotics usually recommended for initial therapy for UTI, including cephalosporins and aminoglycosides; 19% were initially treated with inappropriate empiric intravenous antibiotics (compared with 2% for E. coli UTI, P = 0.0001), with a longer hospitalization. Current treatment routines are often inappropriate for hospitalized children with non-E. coli UTI, which is relatively common in this population. The defined risk factors associated with non-E. coli UTIs and its antimicrobial resistance patterns should be considered to improve empiric antibiotic therapy for these infections.

Positron emission tomography of tumour [{sup 18}F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

Energy Technology Data Exchange (ETDEWEB)

Kruchten, Michel van; Schroeder, Carolien P.; Vries, Elisabeth G.E. de; Hospers, Geke A.P. [University of Groningen, Department of Medical Oncology, University Medical Centre Groningen (Netherlands); Glaudemans, Andor W.J.M.; Vries, Erik F.J. de [University of Groningen, Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen (Netherlands)

2015-10-15

Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Up-regulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16α-[{sup 18}F]fluoro-17β-oestradiol ({sup 18}F-FES) as potential marker to select breast cancer patients for oestradiol therapy. Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after ≥2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent {sup 18}F-FES-PET/CT imaging at baseline. Tumour {sup 18}F-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUV{sub max}). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression ≥24 weeks. {sup 18}F-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value (PPV/NPV) of {sup 18}F-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUV{sub max} >1.5. {sup 18}F-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy. (orig.)

Testing of SNS-032 in a Panel of Human Neuroblastoma Cell Lines with Acquired Resistance to a Broad Range of Drugs12

Science.gov (United States)

Löschmann, Nadine; Michaelis, Martin; Rothweiler, Florian; Zehner, Richard; Cinatl, Jaroslav; Voges, Yvonne; Sharifi, Mohsen; Riecken, Kristoffer; Meyer, Jochen; von Deimling, Andreas; Fichtner, Iduna; Ghafourian, Taravat; Westermann, Frank; Cinatl, Jindrich

2013-01-01

Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3rCDDP1000 in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases. PMID:24466371

Molecular conformation, receptor binding, and hormone action of natural and synthetic estrogens and antiestrogens.

Science.gov (United States)

Duax, W L; Griffin, J F; Weeks, C M; Korach, K S

1985-01-01

The X-ray crystallographic structural determinations of synthetic estrogens and antiestrogens provide reliable information on the global minimum energy conformation of these molecules or a local minimum energy conformation that is within 1 or 2 kcal/mole of the global minimum. In favorable cases, state-of-the-art molecular mechanics calculations provide quantitative agreement with X-ray results and information on the relative energy of other local minimum energy conformations not observed crystallographically. Because the conformation of diethylstilbestrol (DES) observed in solvated crystals has an overall conformation and dipole moment more similar to estradiol it is the form more likely to bind to the receptor and produce hormone activity. Either phenol ring of DES can successfully mimic the estradiol A-ring in binding to the receptor. Indenestrol A (INDA) and indenestrol B (INDB) have nearly identical fully extended planar conformations. Either the alpha or gamma rings of these compounds may mimic the A ring of estradiol and compete for the estrogen receptor. Although there are eight distinct ways in which molecules of a racemic mixture of INDA or INDB can bind to the receptor, not all of them may be able to elicit a hormonal response. This may account for the reduced biological activity of the compounds despite their successful competition for receptor binding. The minimum energy conformations of Z-pseudodiethylstilbestrol (ZPD) and E-pseudodiethylstilbestrol (EPD) are bent in a fashion similar to that of indanestrol (INDC). These molecules have good binding affinity suggesting that the receptor does not require a flat molecule. Therefore these conformations would appear to be compatible with receptor binding, but only the Z isomer has an energetically allowed extended conformation that accounts for its observed biological activity relative to DES. PMID:3905370

Comparative genomics of multidrug resistance in Acinetobacter baumannii.

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Pierre-Edouard Fournier

2006-01-01

Full Text Available Acinetobacter baumannii is a species of nonfermentative gram-negative bacteria commonly found in water and soil. This organism was susceptible to most antibiotics in the 1970s. It has now become a major cause of hospital-acquired infections worldwide due to its remarkable propensity to rapidly acquire resistance determinants to a wide range of antibacterial agents. Here we use a comparative genomic approach to identify the complete repertoire of resistance genes exhibited by the multidrug-resistant A. baumannii strain AYE, which is epidemic in France, as well as to investigate the mechanisms of their acquisition by comparison with the fully susceptible A. baumannii strain SDF, which is associated with human body lice. The assembly of the whole shotgun genome sequences of the strains AYE and SDF gave an estimated size of 3.9 and 3.2 Mb, respectively. A. baumannii strain AYE exhibits an 86-kb genomic region termed a resistance island--the largest identified to date--in which 45 resistance genes are clustered. At the homologous location, the SDF strain exhibits a 20 kb-genomic island flanked by transposases but devoid of resistance markers. Such a switching genomic structure might be a hotspot that could explain the rapid acquisition of resistance markers under antimicrobial pressure. Sequence similarity and phylogenetic analyses confirm that most of the resistance genes found in the A. baumannii strain AYE have been recently acquired from bacteria of the genera Pseudomonas, Salmonella, or Escherichia. This study also resulted in the discovery of 19 new putative resistance genes. Whole-genome sequencing appears to be a fast and efficient approach to the exhaustive identification of resistance genes in epidemic infectious agents of clinical significance.

Comparative Genomics of Multidrug Resistance in Acinetobacter baumannii.

Directory of Open Access Journals (Sweden)

2006-01-01

Full Text Available Acinetobacter baumannii is a species of nonfermentative gram-negative bacteria commonly found in water and soil. This organism was susceptible to most antibiotics in the 1970s. It has now become a major cause of hospital-acquired infections worldwide due to its remarkable propensity to rapidly acquire resistance determinants to a wide range of antibacterial agents. Here we use a comparative genomic approach to identify the complete repertoire of resistance genes exhibited by the multidrug-resistant A. baumannii strain AYE, which is epidemic in France, as well as to investigate the mechanisms of their acquisition by comparison with the fully susceptible A. baumannii strain SDF, which is associated with human body lice. The assembly of the whole shotgun genome sequences of the strains AYE and SDF gave an estimated size of 3.9 and 3.2 Mb, respectively. A. baumannii strain AYE exhibits an 86-kb genomic region termed a resistance island-the largest identified to date-in which 45 resistance genes are clustered. At the homologous location, the SDF strain exhibits a 20 kb-genomic island flanked by transposases but devoid of resistance markers. Such a switching genomic structure might be a hotspot that could explain the rapid acquisition of resistance markers under antimicrobial pressure. Sequence similarity and phylogenetic analyses confirm that most of the resistance genes found in the A. baumannii strain AYE have been recently acquired from bacteria of the genera Pseudomonas, Salmonella, or Escherichia. This study also resulted in the discovery of 19 new putative resistance genes. Whole-genome sequencing appears to be a fast and efficient approach to the exhaustive identification of resistance genes in epidemic infectious agents of clinical significance.

Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4

OpenAIRE

Breslin, Susan; Lowry, Michelle C; O'Driscoll, Lorraine

2017-01-01

Background: Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance. Methods: Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to nerat...

Modulation of P-glycoprotein-mediated multidrug resistance in K562 leukemic cells by indole-3-carbinol

International Nuclear Information System (INIS)

Arora, Annu; Seth, Kavita; Kalra, Neetu; Shukla, Yogeshwer

2005-01-01

Resistance to chemotherapeutic drugs is one of the major problems in the treatment of cancer. P-glycoprotein (P-gp) encoded by the mdr gene is a highly conserved protein, acts as a multidrug transporter, and has a major role in multiple drug resistance (MDR). Targeting of P-gp by naturally occurring compounds is an effective strategy to overcome MDR. Indole-3-carbinol (I3C), a glucosinolates present in cruciferous vegetables, is a promising chemopreventive agent as it is reported to possess antimutagenic, antitumorigenic, and antiestrogenic properties in experimental studies. In the present investigation, the potential of I3C to modulate P-gp expression was evaluated in vinblastine (VBL)-resistant K562 human leukemic cells. The resistant K562 cells (K562/R10) were found to be cross-resistant to vincristine (VCR), doxorubicin (DXR), and other antineoplastic agents. I3C at a nontoxic dose (10 x 10 -3 M) enhanced the cytotoxic effects of VBL time dependently in VBL-resistant human leukemia (K562/R10) cells but had no effect on parent-sensitive cells (K562/S). The Western blot analysis of K 562/R 10 cells showed that I3C downregulates the induced levels of P-gp in resistant cells near to normal levels. The quantitation of immunocytochemically stained K562/R10 cells showed 24%, 48%, and 80% decrease in the levels of P-gp by I3C for 24, 48, and 72 h of incubation. The above features thus indicate that I3C could be used as a novel modulator of P-gp-mediated multidrug resistance in vitro and may be effective as a dietary adjuvant in the treatment of MDR cancers

Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer

Science.gov (United States)

Dauchy, Robert T.; Xiang, Shulin; Mao, Lulu; Brimer, Samantha; Wren, Melissa A.; Yuan, Lin; Anbalagan, Muralidharan; Hauch, Adam; Frasch, Tripp; Rowan, Brian G.; Blask, David E.; Hill, Steven M.

2014-01-01

Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to anti-estrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of ERα+ MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speeds the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characters were not produced in animals where circadian rhythms were not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to re-establish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen. PMID:25062775

ANTIBIOTIC RESISTANCE IN THE OPPORTUNISTIC PATHOGEN STENOTROPHOMONAS MALTOPHILIA

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María Blanca Sánchez

2015-06-01

Full Text Available Stenotrophomonas maltophilia is an environmental bacterium found in the soil, associated with plants and animals, and in aquatic environments. It is also an opportunistic pathogen now causing an increasing number of nosocomial infections. The treatment of S. maltophilia is quite difficult given its intrinsic resistance to a number of antibiotics, and because it is able to acquire new resistances via horizontal gene transfer and mutations. Certainly, strains resistant to quinolones, cotrimoxale and/or cephalosporins - antibiotics commonly used to treat S. maltophilia infections - have emerged. The increasing number of available S. maltophilia genomes has allowed the identification and annotation of a large number of antimicrobial and heavy metal resistance genes. Most encode inactivating enzymes and efflux pumps, but information on their role in intrinsic and acquired resistance is limited. Non-typical antibiotic resistance mechanisms that also form part of the intrinsic resistome have been identified via mutant library screening. These include non-typical antibiotic resistance genes, such as bacterial metabolism genes, and non-inheritable resistant phenotypes, such as biofilm formation and persistence. Their relationships with resistance are complex and require further study.

Neurosis of acquired helplessness and role of hypoxia in the formation of this disorder in rats.

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Vvedenskaya, O Yu; Avrushchenko, M A; Bol'shakova, T D; Khitrov, N K; Moroz, V V

2003-04-01

Acquisition of instrumental defense response with pain reinforcement uncertainty (25% reinforcement) induced the development of acquired helplessness in 50% rats. Acquired helplessness is characterized by the absence of responses to conditioned (light) and unconditioned stimuli (pain), minor response of plasma corticosterone to learning, gas markers of circulatory cerebral hypoxia (Delta A/V pO2 carotid artery/jugular vein), low sensitivity to severe hypobaric conditions, and high resistance of Purkinje cells in the cerebellum. Piracetam improved learning and prevented the development of acquired helplessness. Local changes in cerebral blood flow and energy deficit in neurons responsible for emotional stress during acquired helplessness impair adaptive capacity, but reduce energy consumption and protect neuronal structures.

Prevalence of Genotypes That Determine Resistance of Staphylococci to Macrolides and Lincosamides in Serbia

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Milena Mišić

2017-08-01

Full Text Available Macrolides, lincosamides, and streptogramins (MLS resistance genes are responsible for resistance to these antibiotics in Staphylococcus infections. The purpose of the study was to analyze the distribution of the MLS resistance genes in community- and hospital-acquired Staphylococcus isolates. The MLS resistance phenotypes [constitutive resistance to macrolide–lincosamide–streptogramin B (cMLSb, inducible resistance to macrolide–lincosamide–streptogramin B (iMLSb, resistance to macrolide/macrolide–streptogramin B (M/MSb, and resistance to lincosamide–streptogramin A/streptogramin B (LSa/b] were determined by double-disc diffusion method. The presence of the MLS resistance genes (ermA, ermB, ermC, msrA/B, lnuA, lnuB, and lsaA were determined by end-point polymerase chain reaction in 179 isolates of staphylococci collected during 1-year period at the Center for Microbiology of Public Health Institute in Vranje. The most frequent MLS phenotype among staphylococcal isolates, both community-acquired and hospital-acquired, was iMLSb (33.4%. The second most frequent was M/MSb (17.6% with statistically significantly higher number of hospital-acquired staphylococcal isolates (p < 0.05. MLS resistance was mostly determined by the presence of msrA/B (35.0% and ermC (20.8% genes. Examined phenotypes were mostly determined by the presence of one gene, especially by msrA/B (26.3% and ermC (14.5%, but 15.6% was determined by a combination of two or more genes. M/MSb phenotype was the most frequently encoded by msrA/B (95.6% gene, LSa/b phenotype by lnuA (56.3% gene, and iMLSb phenotype by ermC (29.4% and ermA (25.5% genes. Although cMLSb phenotype was mostly determined by the presence of ermC (28.9%, combinations of two or more genes have been present too. This pattern was particularly recorded in methicillin-resistant Staphylococcus aureus (MRSA (58.3% and methicillin-resistant coagulase-negative staphylococci (MRCNS (90.9% isolates with c

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

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Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

2013-10-01

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.

Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol.

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Pearson, Hannah E; Iida, Mari; Orbuch, Rachel A; McDaniel, Nellie K; Nickel, Kwangok P; Kimple, Randall J; Arbiser, Jack L; Wheeler, Deric L

2018-01-01

Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204-14. ©2017 AACR . ©2017 American Association for Cancer Research.

Surveillance of drug resistance for tuberculosis control: why and how?

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Chaulet, P; Boulahbal, F; Grosset, J

1995-12-01

The resistance of Mycobacterium tuberculosis to antibiotics, which reflects the quality of the chemotherapy applied in the community, is one of the elements of epidemiological surveillance used in national tuberculosis programmes. Measurement of drug resistance poses problems for biologists in standardization of laboratory methods and quality control. The definition of rates of acquired and primary drug resistance also necessitates standardization in the methods used to collect information transmitted by clinicians. Finally, the significance of the rates calculated depends on the choice of the patients sample on which sensitivity tests have been performed. National surveys of drug resistance therefore require multidisciplinary participation in order to select the only useful indicators: rates of primary resistance and of acquired resistance. These indicators, gathered in representative groups of patients over a long period, are a measurement of the impact of modern chemotherapy regimens on bacterial ecology.

The Impact of a Universal Decolonization Protocol on Hospital-Acquired Methicillin-Resistant Staphylococcus aureus in a Burn Population.

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Johnson, Arthur T; Nygaard, Rachel M; Cohen, Ellie M; Fey, Ryan M; Wagner, Anne Lambert

Hospital-acquired (HA) methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of HA infections and a significant concern for burn centers. The use of 2% chlorhexidine-impregnated wipes and nasal mupirocin significantly decreases the rate of HA-MRSA in adult intensive care units. The aim of this study was to examine the impact of universal decolonization on the rate of MRSA conversion in an American Burn Association verified adult and pediatric burn center. Universal decolonization protocol consisting of daily chlorhexidine baths and a 5-day course of nasal mupirocin was implemented in the burn unit. MRSA screening both on admission and weekly and contact isolation practices were in place in pre-decolonization and post-decolonization periods. Patient data were analyzed 2 years before and 1 year after implementation of the protocol. The incidence rate of MRSA was significantly decreased after the implementation of the decolonization protocol (11.8 vs 1.0 per 1000 patient days, P burn patients are at greater risk for invasive infection leading to severe complications and death. The prevalence of HA-MRSA at our institution's burn center was significantly decreased after the implementation of a universal decolonization protocol.

IGF-IR cooperates with ERα to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules

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Afratis, Nikolaos A; Bouris, Panagiotis; Skandalis, Spyros S

2017-01-01

IGF-IR is highly associated with the behaviour of breast cancer cells. In ERα-positive breast cancer, IGF-IR is present at high levels. In clinical practice, prolonged treatment with anti-estrogen agents results in resistance to the therapy with activation of alternative signaling pathways. Recep...

Antimicrobial resistance patterns in community acquired urinary tract infections

International Nuclear Information System (INIS)

Gilani, S.Y.H; Ahmad, N.; Shah, S.R.A.

2016-01-01

Urinary tract infection (UTI) is the most frequent disease for which patients seek medical care. The antimicrobial agents causing UTI and their sensitivity patterns have remarkably changed throughout the world over the past few years. Hence, the present study was designed to explore the uropathogens and their susceptibility to various molecules in our region. Methods: This descriptive cross sectional study was conducted at Medical C Unit of Ayub Teaching Hospital, Abbottabad from January 2015 to January 2016. Patients with clinical features of UTI were evaluated using Urine R/E and Urine culture and sensitivity. Ten antibiotics were checked for susceptibility. Results were analysed using SPSS 17. Results: A total of 630 patients presented with urinary complaints. Of these, 236 patients had more than 8-10 pus cells on urine R/E. They were further evaluated using culture and sensitivity and positive culture was obtained in 75 patients. Of these 34 (45.3%) were males and 41 (54.7%) were females. E Coli was the predominant isolate being present in 49 (65.3%) patients. This was followed by Klebsiella in 9 (12%) patients. Tazobactam-piperacillin and cefoperazone-sulbactam were the most sensitive drugs having overall sensitivity of 96% and 93.3% respectively. The isolates were highly resistant to Fluoroquinolones 77.3% followed by Penicillins 72% and TMP-SMX 69.3%.Conclusion: Antibiotic sensitivity patterns have enormously changed over the past decade. Newer agents are quite efficacious but their use should be highly judicious to prevent the development of resistance to these molecules. (author)

Ancestral genes can control the ability of horizontally acquired loci to confer new traits.

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H Deborah Chen

2011-07-01

Full Text Available Horizontally acquired genes typically function as autonomous units conferring new abilities when introduced into different species. However, we reasoned that proteins preexisting in an organism might constrain the functionality of a horizontally acquired gene product if it operates on an ancestral pathway. Here, we determine how the horizontally acquired pmrD gene product activates the ancestral PmrA/PmrB two-component system in Salmonella enterica but not in the closely related bacterium Escherichia coli. The Salmonella PmrD protein binds to the phosphorylated PmrA protein (PmrA-P, protecting it from dephosphorylation by the PmrB protein. This results in transcription of PmrA-dependent genes, including those conferring polymyxin B resistance. We now report that the E. coli PmrD protein can activate the PmrA/PmrB system in Salmonella even though it cannot do it in E. coli, suggesting that these two species differ in an additional component controlling PmrA-P levels. We establish that the E. coli PmrB displays higher phosphatase activity towards PmrA-P than the Salmonella PmrB, and we identified a PmrB subdomain responsible for this property. Replacement of the E. coli pmrB gene with the Salmonella homolog was sufficient to render E. coli resistant to polymyxin B under PmrD-inducing conditions. Our findings provide a singular example whereby quantitative differences in the biochemical activities of orthologous ancestral proteins dictate the ability of a horizontally acquired gene product to confer species-specific traits. And they suggest that horizontally acquired genes can potentiate selection at ancestral loci.

Translocation of integron-associated resistance in a natural system: Acquisition of resistance determinants by Inc P and Inc W Plasmids from Salmonella enterica Typhimurium DT104

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Sandvang, Dorthe; Diggle, M.; Platt, D.J.

2002-01-01

to determinate the genetic content. Translocation to R751 and R388 was associated with the loss of the indigenous trimethoprim cassette to both plasmids and also acquisition of sulfonamide resistance by R751 and RP4::Tn7, which indicated movement of the 3' terminus of one or both of the DT104 integrons......Salmonella enterica Typhimurium DT104, 961368, a veterinary field isolate that encodes a chromosomal cluster of resistance genes as well as two integrons, was used to study the mobility of resistance cassettes (aadA2 and pse-1) and nonintegron-associated resistance determinants (chloramphenicol...... and tetracycline). A range of natural plasmids was used as targets for the translocation of resistance. Plasmids that acquired resistance from the DT104 chromosome were segregated by conjugation into Escherichia coli K12. Plasmids R751, R388, and RP4::Tn7 acquired several combinations of resistance determinant...

[Antibiotic therapy of hospital-acquired pneumonia and its pharmacoeconomics].

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Kolář, Milan; Htoutou Sedláková, Miroslava; Urbánek, Karel; Uvízl, Radomír; Adamus, Milan; Imwensi, O P

2016-03-01

Important hospital-acquired infections include pneumonia, mainly because of the increasing resistance of bacterial pathogens to antimicrobials and the associated potential failure of antibiotic therapy. The present study aimed at determining the most frequent etiological agents of hospital-acquired pneumonia (HAP) and assessing the relationship between 30-day mortality and adequacy of antibiotic therapy. Based on the obtained information, optimal patterns of antibiotic therapy were to be defined, including a pharmacoeconomic perspective. In patients with clinically confirmed HAP, bacterial etiological agents were identified, their susceptibility to antimicrobials was determined and statistical methods were used to assess the relationship between adequacy of antibiotic therapy and 30-day mortality. The study comprised 68 patients with clinically confirmed HAP. The most common etiological agents were strains of Pseudomonas aeruginosa (30.8 %), Klebsiella pneumoniae (23.1 %) and Burkholderia cepacia complex (15.4 %). Gram-negative bacteria accounted for 86.5 % of all bacterial pathogens. The overall mortality reached 42.5 %. In the subgroup of patients with inadequate antibiotic therapy, 30-day mortality was significantly higher (83.3 %) than in the subgroup with adequate therapy (30.0 %; p = 0.002). The risk for 30-day mortality was 2.78 times higher in case of inadequate antibiotic therapy (95%CI: 1.52-5.07). The proportion of Pseudomonas aeruginosa strains was significantly higher in the subgroup of patients with inadequate antibiotic therapy than in those with adequate therapy (67 % vs. 27 %; p = 0.032). Results of the present study suggest a significant relationship between mortality of patients with HAP and ineffective antibiotic therapy due to resistance of the bacterial pathogen. Thus, it is clear that initial antibiotic therapy must be based on qualified assumption of sufficient activity against the most common bacterial pathogens and results of surveillance

Radiation-resistant asporogenic bacteria

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Yano, K [Tokyo Univ. (Japan). Faculty of Agriculture

1975-09-01

This paper reports the biological and ecological examinations on the radiation-resistant asporogenic bacteria (mainly concerning Micrococcus radiodurans). Radiation-resistant asporogenic bacteria were isolated from the irradiated areas of the natural world as well as from the general areas and from the Rn waters in the Misasa hot spring. The acquiring of the tolerance to radiation in bacteria was also examined. In addition, the future problems of microbiological treatment with irradiation were mentioned.

Radiation-resistant asporogenic bacteria

International Nuclear Information System (INIS)

Yano, Keiji

1975-01-01

This paper reports the biological and ecological examinations on the radiation-resistant asporogenic bacteria (mainly concerning Micrococcus radiodurans). Radiation-resistant asporogenic bacteria were isolated from the irradiated areas of the natural world as well as from the general areas and from the Rn waters in the Misasa hot spring. The acquiring of the tolerance to radiation in bacteria was also examined. In addition, the future problems of microbiological treatment with irradiation were mentioned. (Tsukamoto, Y.)

Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples

International Nuclear Information System (INIS)

Spanswick, Victoria J; Hartley, John A; Lowe, Helen L; Newton, Claire; Bingham, John P; Bagnobianchi, Alessia; Kiakos, Konstantinos; Craddock, Charles; Ledermann, Jonathan A; Hochhauser, Daniel

2012-01-01

DNA interstrand cross-links (ICLs) are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma) and solid tumours (ovarian cancer) that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the ‘unhooking’ step is common to all ICLs. Using a modification of the single cell gel electrophoresis (Comet) assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The RAD51 foci response was both drug and cell line

Acquired resistance of malarial parasites against artemisinin-based drugs: social and economic impacts

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Johanna M Porter-Kelley

2010-08-01

Full Text Available Johanna M Porter-Kelley1, Joann Cofie2, Sophonie Jean2, Mark E Brooks1, Mia Lassiter1, DC Ghislaine Mayer21Life Sciences Department, ­Winston-Salem State University, Winston Salem, NC, USA; 2Department of Biology, Virginia Commonwealth University, Richmond, VA, USAAbstract: Malaria, a disease of poverty and high morbidity and mortality in the tropical world, has led to a worldwide search for control measures. To that end, good antimalarial chemotherapies have been difficult to find in the global market and those that seem to be most effective are rapidly becoming ineffective due to the emergence and spread of drug resistance. Artemisinin, a very effective yet expensive antimalarial, has quickly become the recommended drug of choice when all other possibilities fail. However, for all its promise as the next great antimalarial, the outlook is bleak. Resistance is developing to artemisinin while another effective antimalarial is not in sight. Malaria endemic areas which are mostly in developing countries must deal with the multifaceted process of changing and implementing new national malaria treatment guidelines. This requires complex interactions between several sectors of the affected society which in some cases take place within the context of political instability. Moreover, the cost associated with preventing and containing the spread of antimalarial resistance is detrimental to economic progress. This review addresses the impact of artemisinin resistance on the socioeconomic structure of malaria endemic countries.Keywords: artemisinin-based drugs, social, economic, malarial parasite resistance

[Resistance to target-based therapy and its circumvention].

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Nishio, Kazuto

2004-07-01

Intrinsic and acquired resistance to molecular target therapy critically limits the outcome of cancer treatments. Target levels including quantitative and gene alteration should be determinants for the resistance. Downstream of the target molecules, drug metabolism, and drug transport influences the tumor sensitivity to molecular target therapy. The mechanisms of resistance to antibody therapy have not been fully clarified. Correlative clinical studies using these biomarkers of resistance are extremely important for circumvention of clinical resistance to target based therapy.

Online continuing interprofessional education on hospital-acquired infections for Latin America.

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Medina-Presentado, Julio C; Margolis, Alvaro; Teixeira, Lucia; Lorier, Leticia; Gales, Ana C; Pérez-Sartori, Graciela; Oliveira, Maura S; Seija, Verónica; Paciel, Daniela; Vignoli, Rafael; Guerra, Silvia; Albornoz, Henry; Arteta, Zaida; Lopez-Arredondo, Antonio; García, Sofía

Latin America is a large and diverse region, comprising more than 600 million inhabitants and one million physicians in over 20 countries. Resistance to antibacterial drugs is particularly important in the region. This paper describes the design, implementation and results of an international bi-lingual (Spanish and Portuguese) online continuing interprofessional interactive educational program on hospital-acquired infections and antimicrobial resistance for Latin America, supported by the American Society for Microbiology. Participation, satisfaction and knowledge gain (through pre and post tests) were used. Moreover, commitment to change statements were requested from participants at the end of the course and three months later. There were 1169 participants from 19 Latin American countries who registered: 57% were physicians and 43% were other health care professionals. Of those, 1126 participated in the course, 46% received a certificate of completion and 54% a certificate of participation. There was a significant increase in knowledge between before and after the course. Of 535 participants who took both tests, the grade increased from 59 to 81%. Commitments to change were aligned with course objectives. Implementation of this educational program showed the feasibility of a continent-wide interprofessional massive course on hospital acquired-infections in Latin America, in the two main languages spoken in the region. Next steps included a new edition of this course and a "New Challenges" course on hospital-acquired infections, which were successfully implemented in the second semester of 2015 by the same institutions. Copyright © 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

Molecular Characterization of Streptococcus agalactiae Causing Community- and Hospital-acquired Infections in Shanghai, China

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Haoqin Jiang

2016-08-01

Full Text Available Streptococcus agalactiae, a colonizing agent in pregnant women and the main cause of neonatal sepsis and meningitis, has been increasingly associated with invasive disease in nonpregnant adults. We collected a total of 87 non-repetitive S. agalactiae isolates causing community-acquired (CA and hospital-acquired (HA infections in nonpregnant adults from a teaching hospital in Shanghai between 2009 and 2013. We identified and characterized their antibiotic resistance, sequence type (ST, serotype, virulence, and biofilm formation. The most frequent STs were ST19 (29.9%, ST23 (16.1%, ST12 (13.8%, and ST1 (12.6%. ST19 had significantly different distributions between CA- and HA-group B Streptococci (GBS isolates. The most frequent serotypes were III (32.2%, Ia (26.4%, V (14.9%, Ib (13.8%, and II (5.7%. Serotype III/ST19 was significantly associated with levofloxacin resistance in all isoates. The HA-GBS multidrug resistant rate was much higher than that of CA-GBS. Virulence genes pavA, cfb were found in all isolates. Strong correlations exist between serotype Ib (CA and HA and surface protein genes spb1 and bac, serotype III (HA and surface protein gene cps and GBS pilus cluster. The serotype, epidemic clone, PFGE-based genotype, and virulence gene are closely related between CA-GBS and HA-GBS, and certain serotypes and clone types were significantly associated with antibiotic resistance. However, CA-GBS and HA-GBS still had significant differences in their distribution of clone types, antibiotic resistance, and specific virulence genes, which may provide a basis for infection control.

New principle of chemotherapy resistance

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A laboratory study has revealed an entirely unexpected process for acquiring drug resistance that bypasses the need to re-establish DNA damage repair in breast cancers that have mutant BRCA1 or BRCA2 genes.

Burden of Hospital Acquired Infections and Antimicrobial Use in Vietnamese Adult Intensive Care Units.

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Vu Dinh Phu

Full Text Available Vietnam is a lower middle-income country with no national surveillance system for hospital-acquired infections (HAIs. We assessed the prevalence of hospital-acquired infections and antimicrobial use in adult intensive care units (ICUs across Vietnam.Monthly repeated point prevalence surveys were systematically conducted to assess HAI prevalence and antimicrobial use in 15 adult ICUs across Vietnam. Adults admitted to participating ICUs before 08:00 a.m. on the survey day were included.Among 3287 patients enrolled, the HAI prevalence was 29.5% (965/3266 patients, 21 missing. Pneumonia accounted for 79.4% (804/1012 of HAIs Most HAIs (84.5% [855/1012] were acquired in the survey hospital with 42.5% (363/855 acquired prior to ICU admission and 57.5% (492/855 developed during ICU admission. In multivariate analysis, the strongest risk factors for HAI acquired in ICU were: intubation (OR 2.76, urinary catheter (OR 2.12, no involvement of a family member in patient care (OR 1.94, and surgery after admission (OR 1.66. 726 bacterial isolates were cultured from 622/1012 HAIs, most frequently Acinetobacter baumannii (177/726 [24.4%], Pseudomonas aeruginosa (100/726 [13.8%], and Klebsiella pneumoniae (84/726 [11.6%], with carbapenem resistance rates of 89.2%, 55.7%, and 14.9% respectively. Antimicrobials were prescribed for 84.8% (2787/3287 patients, with 73.7% of patients receiving two or more. The most common antimicrobial groups were third generation cephalosporins, fluoroquinolones, and carbapenems (20.1%, 19.4%, and 14.1% of total antimicrobials, respectively.A high prevalence of HAIs was observed, mainly caused by Gram-negative bacteria with high carbapenem resistance rates. This in combination with a high rate of antimicrobial use illustrates the urgent need to improve rational antimicrobial use and infection control efforts.

Genetic makeup of amantadine-resistant and oseltamivir-resistant human influenza A/H1N1 viruses.

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Zaraket, Hassan; Saito, Reiko; Suzuki, Yasushi; Baranovich, Tatiana; Dapat, Clyde; Caperig-Dapat, Isolde; Suzuki, Hiroshi

2010-04-01

The emergence and widespread occurrence of antiviral drug-resistant seasonal human influenza A viruses, especially oseltamivir-resistant A/H1N1 virus, are major concerns. To understand the genetic background of antiviral drug-resistant A/H1N1 viruses, we performed full genome sequencing of prepandemic A/H1N1 strains. Seasonal influenza A/H1N1 viruses, including antiviral-susceptible viruses, amantadine-resistant viruses, and oseltamivir-resistant viruses, obtained from several areas in Japan during the 2007-2008 and 2008-2009 influenza seasons were analyzed. Sequencing of the full genomes of these viruses was performed, and the phylogenetic relationships among the sequences of each individual genome segment were inferred. Reference genome sequences from the Influenza Virus Resource database were included to determine the closest ancestor for each segment. Phylogenetic analysis revealed that the oseltamivir-resistant strain evolved from a reassortant oseltamivir-susceptible strain (clade 2B) which circulated in the 2007-2008 season by acquiring the H275Y resistance-conferring mutation in the NA gene. The oseltamivir-resistant lineage (corresponding to the Northern European resistant lineage) represented 100% of the H1N1 isolates from the 2008-2009 season and further acquired at least one mutation in each of the polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), hemagglutinin (HA), and neuraminidase (NA) genes. Therefore, a reassortment event involving two distinct oseltamivir-susceptible lineages, followed by the H275Y substitution in the NA gene and other mutations elsewhere in the genome, contributed to the emergence of the oseltamivir-resistant lineage. In contrast, amantadine-resistant viruses from the 2007-2008 season distinctly clustered in clade 2C and were characterized by extensive amino acid substitutions across their genomes, suggesting that a fitness gap among its genetic components might have driven these mutations to maintain it in the

Identification and Determination of Drug Resistant of Candida species isolated from Hospital Acquired Infections

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Kambiz Diba

2015-01-01

Full Text Available Background & aim: Currently, the use of antifungal azole group and yeasts resistant to these drugs is increasing. The aim of this study was to isolate and identify the yeasts obtained from candidiasis patients and furthermore determining thier antifungal resistance. Methods: In the present descriptive study, infections samples were collected from 256 patients with suspected nosocomial candidiasis, then direct exam and culture were performed. Yeast colonies were identified using phenotypic methods, polymerase chain reaction method and enzyme digestion. Data were analyzed using Descriptive statistical tests. Results: Of sixty isolated yeast, thirty-seven cases of Candida albicans (61.6%, seven cases of C. krusei and C. glabrata (11.6% each, five cases of C. dubliniensis (8.3% and four cases of C. tropicalis (6.6% were indicated. The study showed that the sensitivity of C. albicans and C. cruise species to amphotericin B was negligible in disk diffusion and very sensitve in microdilution. Conclusion: Inspite of the results of antifungal susceptibility test of strains studied did not show high resistance, but screening for drug-resistant Candida isolates in Candida infection by disk diffusion and microdilution methods for new cases of drug resistance is reasonable.

A case of community-acquired Acinetobacter baumannii meningitis - has the threat moved beyond the hospital?

NARCIS (Netherlands)

Lowman, Warren; Kalk, Thomas; Menezes, Colin N.; John, Melanie A.; Grobusch, Martin P.

2008-01-01

Acinetobacter baumannii is a prolific nosocomial pathogen renowned for its multidrug-resistant nature. We report a case of community-acquired meningitis due to A. baumannii. The case highlights the potential pathogenicity of this organism and raises concerns that this highly adaptable organism may

The prolyl isomerase Pin1 acts synergistically with CDK2 to regulate the basal activity of estrogen receptor α in breast cancer.

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Chiara Lucchetti

Full Text Available In hormone receptor-positive breast cancers, most tumors in the early stages of development depend on the activity of the estrogen receptor and its ligand, estradiol. Anti-estrogens, such as tamoxifen, have been used as the first line of therapy for over three decades due to the fact that they elicit cell cycle arrest. Unfortunately, after an initial period, most cells become resistant to hormonal therapy. Peptidylprolyl isomerase 1 (Pin1, a protein overexpressed in many tumor types including breast, has been demonstrated to modulate ERalpha activity and is involved in resistance to hormonal therapy. Here we show a new mechanism through which CDK2 drives an ERalpha-Pin1 interaction under hormone- and growth factor-free conditions. The PI3K/AKT pathway is necessary to activate CDK2, which phosphorylates ERalphaSer294, and mediates the binding between Pin1 and ERalpha. Site-directed mutagenesis demonstrated that ERalphaSer294 is essential for Pin1-ERalpha interaction and modulates ERalpha phosphorylation on Ser118 and Ser167, dimerization and activity. These results open up new drug treatment opportunities for breast cancer patients who are resistant to anti-estrogen therapy.

Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment.

Science.gov (United States)

Arendrup, Maiken Cavling; Patterson, Thomas F

2017-08-15

Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

AXL mediates resistance to cetuximab therapy.

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Brand, Toni M; Iida, Mari; Stein, Andrew P; Corrigan, Kelsey L; Braverman, Cara M; Luthar, Neha; Toulany, Mahmoud; Gill, Parkash S; Salgia, Ravi; Kimple, Randall J; Wheeler, Deric L

2014-09-15

The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical outcome. In this study, we show that overexpression of the oncogenic receptor tyrosine kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated, and tightly associated with EGFR expression in cells resistant to cetuximab (Ctx(R) cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in Ctx(R) cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in Ctx(R) cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft models, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL-targeting drugs to treat cetuximab-resistant cancers. Cancer Res; 74(18); 5152-64. ©2014 AACR. ©2014 American Association for Cancer Research.

Circumvention of acquired resistance to doxorubicin in K562 human leukemia cells by oxatomide.

Science.gov (United States)

Ishikawa, M; Fujita, R; Furusawa, S; Takayanagi, M; Sasaki, K; Satoh, S

2001-10-01

We studied the effect of oxatomide, an antiallergic drug, on the resistance of K562 cells to doxorubicin. Oxatomide synergistically potentiated the cytotoxicity of doxorubicin in doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 1-10 microM, but had hardly any synergistic effect on the parental cell line (K562) at the same concentration. Oxatomide inhibit P-glycoprotein pump-efflux activity and the binding of [3H]-azidopine to the cell-surface protein P-glycoprotein, in a dose-related manner. These results indicate that oxatomide reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.

Community-acquired urinary tract infections in children: pathogens, antibiotic susceptibility and seasonal changes.

Science.gov (United States)

Yolbaş, I; Tekin, R; Kelekci, S; Tekin, A; Okur, M H; Ece, A; Gunes, A; Sen, V

2013-04-01

Urinary tract infections (UTIs) are common infections affecting children. The aim of our study is to determine microorganisms that cause community-acquired urinary tract infections and their antibiotic susceptibility in children. Our investigation includes 150 cases which has positive urine culture. The cases are detected at Pediatric Polyclinics of Dicle University between June 2010 and June 2011. The study included 118 (78.7%) female and 32 (21.3%) male children. Urinary tract infections were seen in autumn 10.7% (n = 16), summer 35.3% (n = 53), winter 30.7% (n = 46) and spring 23.3% (n = 35). The culture results indicated 75.3% (n = 113) Escherichia coli; 20.7% (n = 31) Klebsiella; 2.7% (n = 4) Proteus and % 1.3 (n = 2) Pseudomonas. The antibiotic resistance against Escherichia coli was found out is amikacin (3%), ertapenem (7%), imipenem (0%), meropenem (0%), nitrofurantoin (9%), trimethoprim/sulfamethoxazole (58%), piperacillin (83%), amoxicillin/clavulanate (50%), ampicillin/sulbactam (65%), cefazolin (54%), cefotaxime (51%), cefuroxime sodium (51% ) and tetracycline (68%). The resistance ratios of Klebsiella are amikacin (0%), imipenem (0%), levofloxacin (0%), meropenem (0%), amoxicillin/clavulanate (57%), ampicillin/sulbactam (79%), ceftriaxone (68%), cefuroxime sodium (74%) and trimethoprim/sulfamethoxazole (61%). The results represent the increasing antibiotic resistance against microorganisms among the community-acquired UTI patients in a developing country such as Turkey. So, the physicians should consider resistance status of the infectious agent and choose effective antibiotics which are nitrofurantoin and cefoxitin for their empirical antibiotic treatment. Furthermore, they should be trained about selection of more effective antibiotics and check the regional studies regularly.

Efflux Pump-mediated Drug Resistance in Burkholderia

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Nicole L Podnecky

2015-04-01

Full Text Available Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in B. cenocepacia and B. pseudomallei. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance.

High-levels of acquired drug resistance in adult patients failing first-line antiretroviral therapy in a rural HIV treatment programme in KwaZulu-Natal, South Africa.

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Justen Manasa

Full Text Available To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa.Cross-sectional study nested within HIV treatment programme.Adult (≥ 18 years HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART regimen and with evidence of virological failure (one viral load >1000 copies/ml were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms.A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%; and stavudine, lamivudine and nevirapine (24%. Median duration of ART was 42 months (interquartile range (IQR 32-53 and median duration of antiretroviral failure was 27 months (IQR 17-40. One hundred and ninety one (86% had at least one drug resistance mutation. For 34 individuals (15%, the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR 5.70, 95% confidence interval (CI 2.60-12.49.There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved.

Antimicrobial resistance in the 21st century: a multifaceted challenge.

Science.gov (United States)

Nolte, O

2014-04-01

Antimicrobial resistance, the ability of (pathogenic) bacteria to withstand the action of antibiotic drugs, has recently been rated of having an impact on humans similar to that of global climate change. Indeed, during the last years medicine has faced the development of highly resistant bacterial strains, which were, as a consequence of worldwide travel activity, dispersed all over the globe. This is even more astonishing if taking into account that antibiotics were introduced into human medicine not even hundred years ago. Resistance covers different principle aspects, natural resistance, acquired resistance and clinical resistance. In the modern microbiology laboratory, antimicrobial resistance is determined by measuring the susceptibility of micro-organisms in vitro in the presence of antimicrobials. However, since the efficacy of an antibiotic depends on its pharmacokinetic and pharmacodynamics properties, breakpoints are provided to translate minimal inhibitory concentration to categorical efficacy (i.e. susceptible or resistant). Resistance in one microorganism against one particular drug may drive treatment decisions of clinicians, thereby fostering selection pressure to resistance development against another antibiotic. Thereby, bacteria may acquire more and more resistance traits, ending up with multi-resistance. To this end, antimicrobial resistance becomes a public health concern, not only in terms of limited treatment options but also due to its economic burden. The current paper provides a summary of the main topics associated with antimicrobial resistance as an introduction to this special issue.

Transcriptomics and knockout mutant analysis of rhizobacteria-mediated induced systemic resistance in Arabidopsis

NARCIS (Netherlands)

Verhagen, B.W.M.

2004-01-01

A classic example of induced resistance is triggered after infection by a necrotizing pathogen, rendering uninfected,distal parts more resistant to subsequent pathogen attack, and is often referred to as systemic acquired resistance (SAR). A phenotypically comparable type of induced resistance is

Advances in the causes and management of community acquired pneumonia in adults.

Science.gov (United States)

Wunderink, Richard G; Waterer, Grant

2017-07-10

Community acquired pneumonia remains a common cause of morbidity and mortality. Usually, the causal organism is not identified and treatment remains empiric. Recent computed tomography and magnetic resonance imaging studies have challenged the accuracy of the clinical diagnosis of pneumonia, and epidemiologic studies are changing our perspective of what causes community acquired pneumonia, especially the role of viral pathogens and the frequent finding of multiple pathogens. The past decade has seen increasing overuse of empiric coverage of meticillin resistant Staphylococcus aureus and antibiotic resistant Gram negative pathogens owing to inappropriate application of guidelines for healthcare associated pneumonia. Optimal treatment remains a matter for debate, especially in very sick patients, including the role of combination antibiotic therapy and corticosteroids. Pneumonia care bundles are being defined to improve outcomes. Increased recognition of both acute and long term cardiac complications is shifting our concept of pneumonia from an acute lung disease to a multisystem problem with adverse chronic health consequences. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Identification of Systemic Acquired Resistance–Related Volatile Organic Compounds and their Role in Plant Immunity

OpenAIRE

Bichlmeier, Marlies

2017-01-01

Systemic acquired resistance (SAR) is an inducible immune response that depends on ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1), which is essential for SAR signalling. In contrast to SAR, local resistance remains intact in Arabidopsis (Arabidopsis thaliana) eds1-2 mutant plants in response to Pseudomonas syringae delivering the effector protein AvrRpm1. I utilized the SAR-specific phenotype of the eds1-2 mutant to identify volatile organic compounds (VOCs) related to SAR. To this end, SAR was indu...

An allele of an ancestral transcription factor dependent on a horizontally acquired gene product.

Science.gov (United States)

Chen, H Deborah; Jewett, Mollie W; Groisman, Eduardo A

2012-01-01

Changes in gene regulatory circuits often give rise to phenotypic differences among closely related organisms. In bacteria, these changes can result from alterations in the ancestral genome and/or be brought about by genes acquired by horizontal transfer. Here, we identify an allele of the ancestral transcription factor PmrA that requires the horizontally acquired pmrD gene product to promote gene expression. We determined that a single amino acid difference between the PmrA proteins from the human adapted Salmonella enterica serovar Paratyphi B and the broad host range S. enterica serovar Typhimurium rendered transcription of PmrA-activated genes dependent on the PmrD protein in the former but not the latter serovar. Bacteria harboring the serovar Typhimurium allele exhibited polymyxin B resistance under PmrA- or under PmrA- and PmrD-inducing conditions. By contrast, isogenic strains with the serovar Paratyphi B allele displayed PmrA-regulated polymyxin B resistance only when experiencing activating conditions for both PmrA and PmrD. We establish that the two PmrA orthologs display quantitative differences in several biochemical properties. Strains harboring the serovar Paratyphi B allele showed enhanced biofilm formation, a property that might promote serovar Paratyphi B's chronic infection of the gallbladder. Our findings illustrate how subtle differences in ancestral genes can impact the ability of horizontally acquired genes to confer new properties.

Drug-resistance in Streptococcus pneumoniae isolates among Spanish middle aged and older adults with community-acquired pneumonia

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Raga-Luria Xavier

2009-03-01

Full Text Available Abstract Background Pneumococcal diseases remain a major cause of morbidity and mortality worldwide. Updated data on drug-resistance from different populations may be important to recognize changes in disease patterns. This study assessed current levels of penicilin resistance among Streptococcus Pneumoniae causing pneumonia in Spanish middle age and older adults. Methods Antimicrobial susceptibility was tested for 104 consecutive isolates of Streptococcus pneumoniae recovered from patients 50 years or older with radiographically confirmed pneumonia in the region of Tarragona (Spain between 2002 and 2007. According to the minimum inhibitory concentration of tested antimicrobials (penicillin, erythromycin, cefotaxime and levofloxacin strains were classified as susceptible or resistant. Antimicrobial resistance was determined for early cases (2002–2004 and contemporary cases (2005–2007. Results Twenty-seven (25.9% were penicillin-resistant strains (19 strains with intermediate resistance and 8 strains with high resistance. Penicillin-resistance was higher in 2002–2004 than in 2005–2007 (39.5% vs 18.2%, p = 0.017. Of 27 penicillin-resistant strains, 10 (37% were resistant to erythromycin, 8 (29.6% to cefotaxime, 2 (7.4% to levofloxacin, and 4 (14.8% were identified as multidrug resistant. Case-fatality rate was higher among those patients who had an infection caused by any penicillin susceptible strain (16.9% than in those with infections due to penicillin-resistant strains. Conclusion Resistance to penicillin among Streptococcus pneumoniae remains high, but such resistance does not result in increased mortality in patients with pneumococcal pneumonia.

Options for modulation of drug resistance in ovarian cancer

NARCIS (Netherlands)

Arts, HJG; Van der Zee, AGJ; De Jong, S; De Vries, EGE

2000-01-01

The objective of this paper is to present an update of mechanisms responsible for drug resistance in ovarian cancer and the possible therapeutic options to modulate this resistance using literature review with emphasis on data acquired in studies comprising ovarian tumor samples. The classic

Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples

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Spanswick Victoria J

2012-09-01

Full Text Available Abstract Background DNA interstrand cross-links (ICLs are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma and solid tumours (ovarian cancer that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the ‘unhooking’ step is common to all ICLs. Methods Using a modification of the single cell gel electrophoresis (Comet assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. Results Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The

Identification of genes involved in rhizobacteria-mediated induced systemic resistance in Arabidopsis

NARCIS (Netherlands)

Léon-Kloosterziel, K.M.; Verhagen, B.W.M.; Keurentjes, J.J.B.; Loon, L.C. van; Pieterse, C.M.J.

2002-01-01

Different forms of biologically induced disease resistance have been identified in plants. Following attack by a necrotizing pathogen systemic acquired resistance (SAR) is induced, leading to a broad-spectrum disease resistance that is associated with an increase in salicylic acid (SA) levels

Resistance trends in gram-negative bacteria: surveillance results from two Mexican hospitals, 2005–2010

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Morfin-Otero Rayo

2012-06-01

Full Text Available Abstract Background Hospital-acquired infections caused by multiresistant gram-negative bacteria are difficult to treat and cause high rates of morbidity and mortality. The analysis of antimicrobial resistance trends of gram-negative pathogens isolated from hospital-acquired infections is important for the development of antimicrobial stewardship programs. The information obtained from antimicrobial resistant programs from two hospitals from Mexico will be helpful in the selection of empiric therapy for hospital-acquired gram-negative infections. Findings Two thousand one hundred thirty two gram-negative bacteria collected between January 2005 and December 2010 from hospital-acquired infections occurring in two teaching hospitals in Mexico were evaluated. Escherichia coli was the most frequently isolated gram-negative bacteria, with >50% of strains resistant to ciprofloxacin and levofloxacin. Klebsiella spp. showed resistance rates similar to Escherichia coli for ceftazidime (33.1% vs 33.2%, but exhibited lower rates for levofloxacin (18.2% vs 56%. Of the samples collected for the third most common gram-negative bacteria, Pseudomonas aeruginosa, >12.8% were resistant to the carbapenems, imipenem and meropenem. The highest overall resistance was found in Acinetobacter spp. Enterobacter spp. showed high susceptibility to carbapenems. Conclusions E. coli was the most common nosocomial gram-negative bacilli isolated in this study and was found to have the second-highest resistance to fluoroquinolones (>57.9%, after Acinetobacter spp. 81.2%. This finding represents a disturbing development in a common nosocomial and community pathogen.

Pipecolic Acid Orchestrates Plant Systemic Acquired Resistance and Defense Priming via Salicylic Acid-Dependent and -Independent Pathways.

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Bernsdorff, Friederike; Döring, Anne-Christin; Gruner, Katrin; Schuck, Stefan; Bräutigam, Andrea; Zeier, Jürgen

2016-01-01

We investigated the relationships of the two immune-regulatory plant metabolites, salicylic acid (SA) and pipecolic acid (Pip), in the establishment of plant systemic acquired resistance (SAR), SAR-associated defense priming, and basal immunity. Using SA-deficient sid2, Pip-deficient ald1, and sid2 ald1 plants deficient in both SA and Pip, we show that SA and Pip act both independently from each other and synergistically in Arabidopsis thaliana basal immunity to Pseudomonas syringae. Transcriptome analyses reveal that SAR establishment in Arabidopsis is characterized by a strong transcriptional response systemically induced in the foliage that prepares plants for future pathogen attack by preactivating multiple stages of defense signaling and that SA accumulation upon SAR activation leads to the downregulation of photosynthesis and attenuated jasmonate responses systemically within the plant. Whereas systemic Pip elevations are indispensable for SAR and necessary for virtually the whole transcriptional SAR response, a moderate but significant SA-independent component of SAR activation and SAR gene expression is revealed. During SAR, Pip orchestrates SA-dependent and SA-independent priming of pathogen responses in a FLAVIN-DEPENDENT-MONOOXYGENASE1 (FMO1)-dependent manner. We conclude that a Pip/FMO1 signaling module acts as an indispensable switch for the activation of SAR and associated defense priming events and that SA amplifies Pip-triggered responses to different degrees in the distal tissue of SAR-activated plants. © 2016 American Society of Plant Biologists. All rights reserved.

Acquired multi-azole resistance in Candida tropicalis during persistent urinary tract infection in a dog

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Sergio Álvarez-Pérez

2016-03-01

Full Text Available Multi-azole resistance acquisition by Candida tropicalis after prolonged antifungal therapy in a dog with urinary candidiasis is reported. Pre- and post-azole treatment isolates were clonally related and had identical silent mutations in the ERG11 gene, but the latter displayed increased azole minimum inhibitory concentrations. A novel frameshift mutation in ERG3 was found in some isolates recovered after resistance development, so it appears unlikely that this mutation is responsible for multi-azole resistance.

Phenotypic and molecular characterization of Klebsiella spp. isolates causing community-acquired infections

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U. Garza-Ramos

2018-05-01

Full Text Available Klebsiella spp. isolates from community-acquired infections were characterized. A total of 39 Klebsiella spp. isolates were obtained from outpatients at four rural hospitals in Mexico (2013–2014. The biochemical tests identified all as being K. pneumoniae. The molecular multiplex-PCR test identified 36 (92.4% K. pneumoniae isolates and one (2.5% K. variicola isolate, and phylogenetic analysis of the rpoB gene identified two isolates (5.1% belonging to K. quasipneumoniae subsp. quasipneumoniae and K. quasivariicola. The last one was confirmed by phylogenetic analysis of six-loci concatenated genes. Mostly the isolates were multidrug resistant; however, a minority were extended-spectrum β-lactamase producing (10.2%. The extended-spectrum β-lactamase CTX-M-15 gene was identified in these isolates. Analysis of biofilm production and the hypermucoviscosity phenotype showed a total of 35 (92.3% and seven (17.9% of the isolates were positive for these phenotypes respectively. The K2 (4/39, 10.2%, K5 (2/39, 5.1% and K54 (1/39, 2.5% serotypes were identified in seven (17.9% of the isolates, and only 28.5% (2/7 hypermucoviscous isolates were positive for the K2 and K5 serotypes. In general, the sequence type (ST analysis and phylogenetic analysis of seven multilocus sequence typing loci were heterogeneous; however, ST29 was the most prevalent ST in the analysed isolates, accounting for 19% (4/21 of the total isolates. Two of the four ST29 isolates had the hypermucoviscosity phenotype. The virulence factors for fimbriae were the most prevalent, followed by siderophores. Community-acquired infections are caused by various species from Klebsiella genus, with different profiles of antibiotic resistance and heterogeneous virulence factors. Keywords: Antimicrobial susceptibility, Bacterial resistance, Cephalosporin resistance, Community infection, ESBL, Hypermucoviscosity

Experimental Studies on the Changes in Resistivity and Its Anisotropy Using Electrical Resistivity Tomography

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Tao Zhu

2012-01-01

Full Text Available Three measuring lines were arranged on one of free planes of magnetite cuboid samples. Apparent resistivity data were acquired by MIR-2007 resistivity meter when samples were under uniaxial compression of servocontrol YAW-5000F loadingmachine in laboratory. Then we constructed the residual resistivity images using electrical resistivity tomography (ERT and plotted the diagrams of apparent resistivity anisotropy coefficient (ARAC λ∗ and the included angle α between the major axis of apparent resistivity anisotropy ellipse and the axis of load with pressure and effective depth. Our results show that with increasing pressure, resistivity and the decreased (D region and increased (I region resistivity regions have complex behaviors, but when pressure is higher than a certain value, the average resistivity decrease and the area of D region expand gradually in all time with the increase of pressure, which may be significant to the monitoring and prediction of earthquake, volcanic activities, and large-scale geologic motions. The effects of pressure on λ∗ and α are not very outstanding for dry magnetite samples.

Knowledge transfer process of Brazilian multinationals: comparing acquired subsidiaries to the greenfield ones

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Natacha Bertoia Silva

2012-07-01

Full Text Available The main purpose of this study was to explore the knowledge transfer process between the subsidiaries and the headquarter of Brazilian multinationals, and to identify the most used mechanisms for transferring knowledge. This paper also aims to point out existing barriers in this process, comparing acquired subsidiaries to the greenfield ones. International studies have shown differences in the process of knowledge transfer due to the origin of foreign units (entry mode. We surveyed in 2006 and 2007 a sample of 66 Brazilian subsidiaries of multinationals with overseas activities. As a result, the knowledge transfer from the headquarter to the subsidiary has occurred through meetings with top executives and the reception of Brazilian executives in both types of units. The barriers to knowledge transfer are bland, being clearer in acquired subsidiaries. Cultural resistance is the most prominent. When we focus on the acquired units, the hierarchical structure is seen as a barrier, probably reflecting the centralized attitude by the headquarters. At the same time, the lack of incentives for sharing knowledge is more evident in greenfield units. Also, the syndrome of not invented here is a perceived barrier by acquired units.

Learning-by-Being-Acquired

DEFF Research Database (Denmark)

Colombo, Massimo Gaetano; Moreira, Solon; Rabbiosi, Larissa

2016-01-01

In horizontal acquisitions, the post-acquisition integration of the R&D function often damages the inventive labor force and results in lower innovative productivity of acquired inventors. In this paper we study post-acquisition integration in terms of R&D team reorganization-i.e., the creation...... of new teams with both inventors of the acquiring and acquired firms-and assess the impact of this integration action in the period that immediately follows the acquisition. Drawing on social identity and self-categorization theories, we argue that R&D team reorganization increases the acquired inventors...

The Growing Resistance of Klebsiella pneumonia ; the Need to ...

African Journals Online (AJOL)

During the course of her treatment she acquired various infections that led to her exposure to antimicrobials from almost all classes at various times; including bacteremia due to a pan-drug resistant Klebsiella pneumoniae and multi-drug resistant Acinetobacter baumannii. She was successfully treated with a combination of ...

Invasive Community-Acquired Methicillin-Resistant Staphylococcus aureus in a Japanese Girl with Disseminating Multiple Organ Infection: A Case Report and Review of Japanese Pediatric Cases

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Ryuta Yonezawa

2015-01-01

Full Text Available Pediatric invasive community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA infection is very serious and occasionally fatal. This infectious disease is still a relatively rare and unfamiliar infectious disease in Japan. We report a positive outcome in a 23-month-old Japanese girl with meningitis, osteomyelitis, fasciitis, necrotizing pneumonia, urinary tract infection, and bacteremia due to CA-MRSA treated with linezolid. PCR testing of the CA-MRSA strain was positive for PVL and staphylococcal enterotoxin b and negative for ACME. SCC mec was type IVa. This case underscores the selection of effective combinations of antimicrobial agents for its treatment. We need to be aware of invasive CA-MRSA infection, which rapidly progresses with a serious clinical course, because the incidence of the disease may be increasing in Japan.

Transposon characterization of vancomycin-resistant Enterococcus faecium (VREF) and dissemination of resistance associated with transferable plasmids

DEFF Research Database (Denmark)

Migura, Lourdes Garcia; Liebana, Ernesto; Jensen, Lars Bogø

2007-01-01

Objectives: VanA glycopeptide resistance has persisted on broiler farms in the UK despite the absence of the antimicrobial selective pressure, avoparcin. This study aimed to investigate the contribution of horizontal gene transfer of Tn 1546 versus clonal spread in the dissemination of the resist......Objectives: VanA glycopeptide resistance has persisted on broiler farms in the UK despite the absence of the antimicrobial selective pressure, avoparcin. This study aimed to investigate the contribution of horizontal gene transfer of Tn 1546 versus clonal spread in the dissemination...... plasmid replicons, associated with antimicrobial resistance on several unrelated farms. Conclusions: Horizontal transfer of vancomycin resistance may play a more important role in the persistence of antimicrobial resistance than clonal spread. The presence of different plasmid replicons, associated...... with antimicrobial resistance on several unrelated farms, illustrates the ability of these enterococci to acquire and disseminate mobile genetic elements within integrated livestock systems....

An Update on the Management Of Hospital-Acquired Pneumonia in the Elderly

Directory of Open Access Journals (Sweden)

Chao-Hsien Lee

2008-12-01

Full Text Available Pneumonia is the leading cause of infection-related death and represents the fifth cause of mortality in the elderly. There are several reported risk factors for acquiring pneumonia at an older age, such as alcoholism, lung and heart diseases, nursing home residence, and swallowing disorders. Hospital-acquired pneumonia (HAP is reviewed, with an emphasis on multidrug-resistant (MDR bacterial pathogens, such as Pseudomonas aeruginosa, Acinetobacter species, and methicillin-resistant Staphylococcus aureus. The clinical characteristics of pneumonia in the elderly differ substantially compared with younger patients, and the severity of the disease is strongly associated with increased age and age-related comorbid disorders. Streptococcus pneumoniae is the pathogen most frequently responsible for pneumonia in the elderly with early HAP without risk factors for MDR; enteric Gram-negative rods should be considered in nursing home-associated pneumonia, as well as anaerobes in patients with aspiration pneumonia. Special attention should be given to preventive measures such as vaccination, oral care, and nutrition. The management of HAP should be instituted early with: appropriate use of antibiotics in adequate doses; avoidance of excessive use of antibiotics by de-escalation of initial antibiotic therapy, based on microbiologic cultures and the clinical response of the patient; and reduction of the duration of treatment to the minimum effective period.

Candidate genes for cross-resistance against DNA-damaging drugs

DEFF Research Database (Denmark)

Wittig, Rainer; Nessling, Michelle; Will, Rainer D

2002-01-01

Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA...... as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs....

Identification of a Non-Gatekeeper Hot Spot for Drug-Resistant Mutations in mTOR Kinase.

Science.gov (United States)

Wu, Tzung-Ju; Wang, Xiaowen; Zhang, Yanjie; Meng, Linghua; Kerrigan, John E; Burley, Stephen K; Zheng, X F Steven

2015-04-21

Protein kinases are therapeutic targets for human cancer. However, "gatekeeper" mutations in tyrosine kinases cause acquired clinical resistance, limiting long-term treatment benefits. mTOR is a key cancer driver and drug target. Numerous small-molecule mTOR kinase inhibitors have been developed, with some already in human clinical trials. Given our clinical experience with targeted therapeutics, acquired drug resistance in mTOR is thought likely, but not yet documented. Herein, we describe identification of a hot spot (L2185) for drug-resistant mutations, which is distinct from the gatekeeper site, and a chemical scaffold refractory to drug-resistant mutations. We also provide new insights into mTOR kinase structure and function. The hot spot mutations are potentially useful as surrogate biomarkers for acquired drug resistance in ongoing clinical trials and future treatments and for the design of the next generation of mTOR-targeted drugs. Our study provides a foundation for further research into mTOR kinase function and targeting. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Acquired neuropathies.

Science.gov (United States)

Lozeron, Pierre; Trocello, Jean-Marc; Kubis, Nathalie

2013-09-01

Acquired neuropathies represent most of the neuropathies encountered in clinical practice. Hundreds of causes have been identified even though up to 41% of patients are still classified as idiopathic (Rajabally and Shah in J Neurol 258:1431-1436, 1). Routine evaluation relies on comprehensive medical history taking, clinical examination, nerve conduction studies and laboratory tests. Other investigations such as nerve biopsy or nerve or muscle imaging are performed in specific settings. This review focuses on recent advances in acquired neuropathies.

[Antituberculosis-drug resistance in the border of Brazil with Paraguay and Bolivia].

Science.gov (United States)

Marques, Marli; Cunha, Eunice Atsuko Totumi; Evangelista, Maria do Socorro Nantua; Basta, Paulo Cesar; Marques, Ana Maria Campos; Croda, Julio; de Andrade, Sonia Maria Oliveira

2017-04-20

To estimate the rate of drug resistance among pulmonary tuberculosis (PTB) cases in the state of Mato Grosso do Sul, Brazil, and specifically in the border areas with Paraguay and Bolivia, as well as to identify associated risk factors. The present cross-sectional, epidemiological study focused on PTB cases recorded between January 2007 and December 2010 in the State Reportable Disease Information System with results of susceptibility tests to rifampicin, isoniazid, ethambutol, and streptomycin. Dependent variables were development of resistance to a single drug or any combination of drugs. Independent variables were being a new or treated case, living in border areas, presence/absence of diabetes, and history of alcoholism. There were 789 TBP cases with susceptibility testing. The following characteristics were associated with resistance: treated case (P = 0.0001), border region (P = 0.0142), alcoholism (P = 0.0451), and diabetes (P = 0.0708). The rates of combined, primary, and acquired resistance for the state were 16.3%, 10.6%, and 39.0%, vs. 22.3%, 19.2%, and 37.5% for the border region. The rates of combined, primary, and acquired multidrug resistance for the state were 1.8%, 0.6%, and 6.3%, vs. 3.1%, 1.2%, and 12.5% for the border region. In the border region, the state should investigate drug resistance in all patients with respiratory symptoms, determine the pattern of resistance in confirmed cases, adopt directly observed treatment for cases of PTB, and develop health actions together with neighboring countries. Across the state, the levels of acquired resistance should be monitored, with investigation of resistance in all treated cases and implementation of directly observed treatment especially among patients with diabetes or alcoholism.

Plasmid-Mediated Antibiotic Resistance and Virulence in Gram-negatives: the Klebsiella pneumoniae Paradigm.

Science.gov (United States)

Ramirez, Maria S; Traglia, German M; Lin, David L; Tran, Tung; Tolmasky, Marcelo E

Plasmids harbor genes coding for specific functions including virulence factors and antibiotic resistance that permit bacteria to survive the hostile environment found in the host and resist treatment. Together with other genetic elements such as integrons and transposons, and using a variety of mechanisms, plasmids participate in the dissemination of these traits resulting in the virtual elimination of barriers among different kinds of bacteria. In this article we review the current information about physiology and role in virulence and antibiotic resistance of plasmids from the gram-negative opportunistic pathogen Klebsiella pneumoniae . This bacterium has acquired multidrug resistance and is the causative agent of serious communityand hospital-acquired infections. It is also included in the recently defined ESKAPE group of bacteria that cause most of US hospital infections.

Differential effectiveness of salicylate-dependent and jasmonate/ethylene-dependent induced resistance in Arabidopsis

NARCIS (Netherlands)

Ton, J.; Pelt, J.A. van; Loon, L.C. van; Pieterse, C.M.J.

2002-01-01

Salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) are each involved in the regulation of basal resistance against different pathogens. These three signals play important roles in induced resistance as well. SA is a key regulator of pathogen-induced systemic acquired resistance (SAR),

Why sensitive bacteria are resistant to hospital infection control

Science.gov (United States)

van Kleef, Esther; Luangasanatip, Nantasit; Bonten, Marc J; Cooper, Ben S

2017-01-01

Background: Large reductions in the incidence of antibiotic-resistant strains of Staphylococcus aureus and Clostridium difficile have been observed in response to multifaceted hospital-based interventions. Reductions in antibiotic-sensitive strains have been smaller or non-existent. It has been argued that since infection control measures, such as hand hygiene, should affect resistant and sensitive strains equally, observed changes must have largely resulted from other factors, including changes in antibiotic use. We used a mathematical model to test the validity of this reasoning. Methods: We developed a mechanistic model of resistant and sensitive strains in a hospital and its catchment area. We assumed the resistant strain had a competitive advantage in the hospital and the sensitive strain an advantage in the community. We simulated a hospital hand hygiene intervention that directly affected resistant and sensitive strains equally. The annual incidence rate ratio ( IRR) associated with the intervention was calculated for hospital- and community-acquired infections of both strains. Results: For the resistant strain, there were large reductions in hospital-acquired infections (0.1 ≤ IRR ≤ 0.6) and smaller reductions in community-acquired infections (0.2 ≤ IRR ≤  0.9). These reductions increased in line with increasing importance of nosocomial transmission of the strain. For the sensitive strain, reductions in hospital acquisitions were much smaller (0.6 ≤ IRR ≤ 0.9), while communityacquisitions could increase or decrease (0.9 ≤ IRR ≤ 1.2). The greater the importance of the community environment for the transmission of the sensitive strain, the smaller the reductions. Conclusions: Counter-intuitively, infection control interventions, including hand hygiene, can have strikingly discordant effects on resistant and sensitive strains even though they target them equally, following differences in their adaptation to hospital and community

Why sensitive bacteria are resistant to hospital infection control.

Science.gov (United States)

van Kleef, Esther; Luangasanatip, Nantasit; Bonten, Marc J; Cooper, Ben S

2017-01-01

Large reductions in the incidence of antibiotic-resistant strains of Staphylococcus aureus and Clostridium difficile have been observed in response to multifaceted hospital-based interventions. Reductions in antibiotic-sensitive strains have been smaller or non-existent. It has been argued that since infection control measures, such as hand hygiene, should affect resistant and sensitive strains equally, observed changes must have largely resulted from other factors, including changes in antibiotic use. We used a mathematical model to test the validity of this reasoning. We developed a mechanistic model of resistant and sensitive strains in a hospital and its catchment area. We assumed the resistant strain had a competitive advantage in the hospital and the sensitive strain an advantage in the community. We simulated a hospital hand hygiene intervention that directly affected resistant and sensitive strains equally. The annual incidence rate ratio (IRR) associated with the intervention was calculated for hospital- and community-acquired infections of both strains. For the resistant strain, there were large reductions in hospital-acquired infections (0.1 ≤ IRR ≤ 0.6) and smaller reductions in community-acquired infections (0.2 ≤ IRR ≤ 0.9). These reductions increased in line with increasing importance of nosocomial transmission of the strain. For the sensitive strain, reductions in hospital acquisitions were much smaller (0.6 ≤ IRR ≤ 0.9), while community acquisitions could increase or decrease (0.9 ≤ IRR ≤ 1.2). The greater the importance of the community environment for the transmission of the sensitive strain, the smaller the reductions. Counter-intuitively, infection control interventions, including hand hygiene, can have strikingly discordant effects on resistant and sensitive strains even though they target them equally. This follows from differences in their adaptation to hospital- and community-based transmission. Observed lack of

The Challenging Diagnosis of Non-Community-Acquired Pneumonia in Non-Mechanically Ventilated Subjects: Value of Microbiological Investigation.

Science.gov (United States)

Messika, Jonathan; Stoclin, Annabelle; Bouvard, Eric; Fulgencio, Jean-Pierre; Ridel, Christophe; Muresan, Ioan-Paul; Boffa, Jean-Jacques; Bachmeyer, Claude; Denis, Michel; Gounant, Valérie; Esteso, Adoracion; Loi, Valeria; Verdet, Charlotte; Prigent, Hélène; Parrot, Antoine; Fartoukh, Muriel

2016-02-01

Early recognition and an attempt at obtaining microbiological documentation are recommended in patients with non-community-acquired pneumonia (NCAP), whether hospital-acquired (HAP) or health care-associated (HCAP). We aimed to characterize the clinical features and microbial etiologies of NCAP to assess the impact of microbiological investigation on their management. This was a prospective 1-y study in a university hospital with 141 non-mechanically ventilated subjects suspected of having HAP (n = 110) or HCAP (n = 31). Clinical criteria alone poorly identified pneumonia (misdiagnosis in 50% of cases). Microbiological confirmation was achievable in 80 subjects (57%). Among 79 microorganisms isolated, 28 were multidrug-resistant aerobic Gram-negative bacilli and group III Enterobacteriaceae and 6 were methicillin-resistant Staphylococcus aureus. Multidrug-resistant aerobic Gram-negative bacilli accounted for one third of the microorganisms in early-onset HAP and for 50% in late-onset HAP. Methicillin-resistant S. aureus was most often recovered from subjects with HCAP. Inappropriate empirical antibiotics were administered to 36% of subjects with confirmed pneumonia. Forty subjects were admitted to the ICU, 13 (33%) of whom died. Overall, 39 subjects (28%) died in the hospital. Integrating the microbiological investigation in the complex clinical diagnostic workup of patients suspected of having NCAP is mandatory. Respiratory tract specimens should be obtained whenever possible for appropriate management. Copyright © 2016 by Daedalus Enterprises.

Prevalence of Methicillin–Resistant Staphylococcus aureus (MRSA ...

African Journals Online (AJOL)

Prof. Ogunji

hospital–acquired postoperative wound infections, otitis media etc. which are difficult to ... resistance does not cause the organism to be more intrinsically virulent than ..... with a diagnosis of pneumonia: analysis of results from the SENTRY ...

Antifolate resistance and its circumvention by new analogues.

Science.gov (United States)

Takemura, Y; Kobayashi, H; Miyachi, H

2001-09-01

We have established human leukemia cell lines made resistant to various antifolate drugs and analyzed resistance mechanisms developed in these cells at the cellular and molecular levels. The cells acquired resistance to antifolate drug(s) through: (1) impaired drug uptake via the reduced folate carrier, (2) increased activity of the target enzymes[dihydrofolate reductase(DHFR) or thymidylate synthase(TS)] resulted from a concomitant amplification and overexpression of their gene, (3) induction of a variant DHFR with a low affinity for antifolate drug(s) used for the selection of resistance, and (4) defective polyglutamation. Each resistance mechanism was not necessarily induced at random, but appeared to relate to the biochemical and pharmacological properties of the drug exposed, biological dispositions of the cells, drug-exposure manners to, or culture conditions of the cells. Since it has been shown that a minor modification at the specified position of the folate structure resulted in a drastic change in its pharmacological properties, many new compounds have been rationally designed on the basis of the knowledge of relationships between structure modifications and pharmacological properties. The step-by-step approach to the development of new analogues led to the discoveries of several promising antifolate drugs such as trimetrexate and raltitrexed, which can overcome the acquired and natural resistance to methotrexate, a classical antifolate, and clinical trials of these newer classes of antifolate compounds are currently underway.

Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme.

Science.gov (United States)

Jun, H J; Acquaviva, J; Chi, D; Lessard, J; Zhu, H; Woolfenden, S; Bronson, R T; Pfannl, R; White, F; Housman, D E; Iyer, L; Whittaker, C A; Boskovitz, A; Raval, A; Charest, A

2012-06-21

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type epidermal growth factor receptor (EGFR) and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that an important component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients.

Transformation of sweet orange [Citrus sinensis (L.) Osbeck] with pthA-nls for acquiring resistance to citrus canker disease.

Science.gov (United States)

Yang, Li; Hu, Chunhua; Li, Na; Zhang, Jiayin; Yan, Jiawen; Deng, Ziniu

2011-01-01

The COOH terminal of pthA encoding three nuclear localizing signals (NLS) was amplified by polymerase chain reaction (PCR) from the plasmid of Xanthomonas axonopodis pv. citri, the pathogen of citrus canker disease. Then the sense and antisense strands of the nls were cloned into pBI121 vector. pthA-nls driven by the CaMV35 s promoter was transferred into sweet orange via Agrobacterium -mediated transformation. Successful integration was confirmed by PCR and Southern blotting, and 12 sense-nls (nls (+)) and 9 antisense-nls (nls (-)) transgenic clones were obtained. The expression of nls fragment was analyzed by RT-PCR, Real time q-PCR and Western blotting, in which the specific NLS protein was detected only in nls (+) transgenic clones. In an in vitro assay, when pin-puncture inoculation was performed with 2.5 × 10(7) cfu/ml of bacterial solution, the nls (+) transgenic clones showed no typical lesion development, while typical symptoms were observed in the wild types and the nls (-) transgenic clones. In vivo assay results indicated that the nls (+) transgenic clones showed less disease incidence, in comparison with the wild types and the nls (-) transgenic clones, when pin-puncture inoculation was performed with 10(4)-10(5) cfu/ml. The minimum disease incidence was 23.3% for 'Sucarri' sweet orange and 33.3% for 'Bingtang' sweet orange. When 10(4)-10(7) cfu/ml of pathogen was spray inoculated, the nls (+) transgenic clones did not show any symptom, and even the concentration raised to 10(9) cfu/ml, the disease incidence was 20-80%, while the wild types and the nls (-) transgenic clones had 100% disease development with whatever concentration of inoculum. Two transgenic clones were confirmed to be resistant to citrus canker disease in the repeated inoculation. The results suggested that the transformation of nls sense strands may offer an effective way to acquire resistance to citrus canker disease.

Community-acquired pneumonia due to pandemic A(H1N12009 influenzavirus and methicillin resistant Staphylococcus aureus co-infection.

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Ronan J Murray

Full Text Available BACKGROUND: Bacterial pneumonia is a well described complication of influenza. In recent years, community-onset methicillin-resistant Staphylococcus aureus (cMRSA infection has emerged as a contributor to morbidity and mortality in patients with influenza. Since the emergence and rapid dissemination of pandemic A(H1N12009 influenzavirus in April 2009, initial descriptions of the clinical features of patients hospitalized with pneumonia have contained few details of patients with bacterial co-infection. METHODOLOGY/PRINCIPAL FINDINGS: Patients with community-acquired pneumonia (CAP caused by co-infection with pandemic A(H1N12009 influenzavirus and cMRSA were prospectively identified at two tertiary hospitals in one Australian city during July to September 2009, the period of intense influenza activity in our region. Detailed characterization of the cMRSA isolates was performed. 252 patients with pandemic A(H1N12009 influenzavirus infection were admitted at the two sites during the period of study. Three cases of CAP due to pandemic A(H1N12009/cMRSA co-infection were identified. The clinical features of these patients were typical of those with S. aureus co-infection or sequential infection following influenza. The 3 patients received appropriate empiric therapy for influenza, but inappropriate empiric therapy for cMRSA infection; all 3 survived. In addition, 2 fatal cases of CAP caused by pandemic A(H1N12009/cMRSA co-infection were identified on post-mortem examination. The cMRSA infections were caused by three different cMRSA clones, only one of which contained genes for Panton-Valentine Leukocidin (PVL. CONCLUSIONS/SIGNIFICANCE: Clinicians managing patients with pandemic A(H1N12009 influenzavirus infection should be alert to the possibility of co-infection or sequential infection with virulent, antimicrobial-resistant bacterial pathogens such as cMRSA. PVL toxin is not necessary for the development of cMRSA pneumonia in the setting of pandemic

ORIGINAL ARTICLE MULTIPLE ANTIBIOTIC RESISTANCE (MAR ...

African Journals Online (AJOL)

boaz

ABSRACT. Background/Objectives: Pseudomonas and Klebsiella infections are important nosocomial infections because of the attendant significant morbidity, mortality and socio-economic impact. These infections are difficult to treat due to the innate and acquired resistance mediated by the organisms' genome and other ...

Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification.

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Silvia La Monica

Full Text Available Despite the initial response, all patients with epidermal growth factor receptor (EGFR-mutant non-small cell lung cancer (NSCLC eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs. The EGFR-T790M secondary mutation is responsible for half of acquired resistance cases, while MET amplification has been associated with acquired resistance in about 5-15% of NSCLCs. Clinical findings indicate the retained addiction of resistant tumors on EGFR signaling. Therefore, we evaluated the molecular mechanisms supporting the therapeutic potential of gefitinib maintenance in the HCC827 GR5 NSCLC cell line harbouring MET amplification as acquired resistance mechanism. We demonstrated that resistant cells can proliferate and survive regardless of the presence of gefitinib, whereas the absence of the drug significantly enhanced cell migration and invasion. Moreover, the continuous exposure to gefitinib prevented the epithelial-mesenchymal transition (EMT with increased E-cadherin expression and down-regulation of vimentin and N-cadherin. Importantly, the inhibition of cellular migration was correlated with the suppression of EGFR-dependent Src, STAT5 and p38 signaling as assessed by a specific kinase array, western blot analysis and silencing functional studies. On the contrary, the lack of effect of gefitinib on EGFR phosphorylation in the H1975 cells (EGFR-T790M correlated with the absence of effects on cell migration and invasion. In conclusion, our findings suggest that certain EGFR-mutated patients may still benefit from a second-line therapy including gefitinib based on the specific mechanism underlying tumor cell resistance.

Comparison of multi-drug resistant environmental methicillin-resistant Staphylococcus aureus [MRSA] isolated from recreational beaches and high touch surfaces in built environments

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Marilyn C Roberts

2013-04-01

Full Text Available Over the last decade community-acquired methicillin-resistant Staphylococcus aureus [MRSA] has emerged as a major cause of disease in the general population with no health care exposure or known classical risk factors for MRSA infections. The potential community reservoirs have not been well defined though certain strains such as ST398 and USA300 have been well studied in some settings. MRSA has been isolated from recreational beaches, high-touch surfaces in homes, universities and other community environmental surfaces. However, in most cases the strains were not characterized to determine if they are related to community-acquired or hospital-acquired clinical strains. We compared 55 environmental MRSA from 805 samples including sand, fresh and marine water samples from local marine and fresh water recreational beaches (n=296, high touch surfaces on the University of Washington campus (n=294, surfaces in UW undergraduate housing (n=85, and the local community (n=130. Eleven USA300, representing 20% of the isolates, were found on the UW campus surfaces, student housing surfaces and on the community surfaces but not in the recreational beach samples from the Northwest USA. Similarly, the predominant animal ST133 was found in the recreational beach samples but not in the high touch surface samples. All USA300 isolates were multi-drug resistant carrying 2-6 different antibiotic resistance genes coding for kanamycin, macrolides and/or macrolides-lincosamides-streptogramin B and tetracycline, with the majority [72%] carrying 4-6 different antibiotic resistance genes. A surprising 98% of the 55 MRSA isolates were resistant to other classes of antibiotics and most likely represent reservoirs for these genes in the environment.

Comparison of different treatments for isoniazid-resistant tuberculosis : an individual patient data meta-analysis

NARCIS (Netherlands)

Fregonese, Federica; Ahuja, Shama D; Akkerman, Onno W; Arakaki-Sanchez, Denise; Ayakaka, Irene; Baghaei, Parvaneh; Bang, Didi; Bastos, Mayara; Benedetti, Andrea; Bonnet, Maryline; Cattamanchi, Adithya; Cegielski, Peter; Chien, Jung-Yien; Cox, Helen; Dedicoat, Martin; Erkens, Connie; Escalante, Patricio; Falzon, Dennis; Garcia-Prats, Anthony J; Gegia, Medea; Gillespie, Stephen H; Glynn, Judith R; Goldberg, Stefan; Griffith, David; Jacobson, Karen R; Johnston, James C; Jones-López, Edward C; Khan, Awal; Koh, Won-Jung; Kritski, Afranio; Lan, Zhi Yi; Lee, Jae Ho; Li, Pei Zhi; Maciel, Ethel L; Galliez, Rafael Mello; Merle, Corinne S C; Munang, Melinda; Narendran, Gopalan; Nguyen, Viet Nhung; Nunn, Andrew; Ohkado, Akihiro; Park, Jong Sun; Phillips, Patrick P J; Ponnuraja, Chinnaiyan; Reves, Randall; Romanowski, Kamila; Seung, Kwonjune; Schaaf, H Simon; Skrahina, Alena; Soolingen, Dick van; Tabarsi, Payam; Trajman, Anete; Trieu, Lisa; Banurekha, Velayutham V; Viiklepp, Piret; Wang, Jann-Yuan; Yoshiyama, Takashi; Menzies, Dick

BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success,

Molecular chess? Hallmarks of anti-cancer drug resistance.

Science.gov (United States)

Cree, Ian A; Charlton, Peter

2017-01-05

The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. Resistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients. The oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to 'molecular chess'. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

Magnetic Oculomotor Prosthetics for Acquired Nystagmus.

Science.gov (United States)

Nachev, Parashkev; Rose, Geoff E; Verity, David H; Manohar, Sanjay G; MacKenzie, Kelly; Adams, Gill; Theodorou, Maria; Pankhurst, Quentin A; Kennard, Christopher

2017-10-01

Acquired nystagmus, a highly symptomatic consequence of damage to the substrates of oculomotor control, often is resistant to pharmacotherapy. Although heterogeneous in its neural cause, its expression is unified at the effector-the eye muscles themselves-where physical damping of the oscillation offers an alternative approach. Because direct surgical fixation would immobilize the globe, action at a distance is required to damp the oscillation at the point of fixation, allowing unhindered gaze shifts at other times. Implementing this idea magnetically, herein we describe the successful implantation of a novel magnetic oculomotor prosthesis in a patient. Case report of a pilot, experimental intervention. A 49-year-old man with longstanding, medication-resistant, upbeat nystagmus resulting from a paraneoplastic syndrome caused by stage 2A, grade I, nodular sclerosing Hodgkin's lymphoma. We designed a 2-part, titanium-encased, rare-earth magnet oculomotor prosthesis, powered to damp nystagmus without interfering with the larger forces involved in saccades. Its damping effects were confirmed when applied externally. We proceeded to implant the device in the patient, comparing visual functions and high-resolution oculography before and after implantation and monitoring the patient for more than 4 years after surgery. We recorded Snellen visual acuity before and after intervention, as well as the amplitude, drift velocity, frequency, and intensity of the nystagmus in each eye. The patient reported a clinically significant improvement of 1 line of Snellen acuity (from 6/9 bilaterally to 6/6 on the left and 6/5-2 on the right), reflecting an objectively measured reduction in the amplitude, drift velocity, frequency, and intensity of the nystagmus. These improvements were maintained throughout a follow-up of 4 years and enabled him to return to paid employment. This work opens a new field of implantable therapeutic devices-oculomotor prosthetics-designed to modify eye

Antimicrobial resistance in Libya: 1970–2011

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Khalifa Sifaw Ghenghesh

2013-03-01

Full Text Available Resistance to antimicrobial agents is a major health problem that affects the whole world. Providing information on the past state of antimicrobial resistance in Libya may assist the health authorities in addressing the problem more effectively in the future. Information was obtained mainly from Highwire Press (including PubMed search for the period 1970–2011 using the terms ‘antibiotic resistance in Libya’, ‘antimicrobial resistance in Libya’, ‘tuberculosis in Libya’, and ‘primary and acquired resistance in Libya’ in title and abstract. From 1970 to 2011 little data was available on antimicrobial resistance in Libya due to lack of surveillance and few published studies. Available data shows high resistance rates for Salmonella species in the late 1970s and has remained high to the present day. High prevalence rates (54–68% of methicillin-resistant Staphylococcus aureus (MRSA were reported in the last decade among S. aureus from patients with burns and surgical wound infections. No reports were found of vancomycin-resistant S. aureus (VRSA or vancomycin-intermediate-resistant S. aureus (VISA using standard methods from Libya up to the end of 2011. Reported rates of primary (i.e. new cases and acquired (i.e. retreatment cases multidrug-resistant tuberculosis (MDR-TB from the eastern region of Libya in 1971 were 16.6 and 33.3% and in 1976 were 8.6 and 14.7%, in western regions in 1984–1986 were 11 and 21.5% and in the whole country in 2011 were estimated at 3.4 and 29%, respectively. The problem of antibiotic resistance is very serious in Libya. The health authorities in particular and society in general should address this problem urgently. Establishing monitoring systems based on the routine testing of antimicrobial sensitivity and education of healthcare workers, pharmacists, and the community on the health risks associated with the problem and benefits of prudent use of antimicrobials are some steps that can be taken to

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells.

Science.gov (United States)

Wang, Yue; Niu, Xiu Long; Guo, Xiao Qin; Yang, Jing; Li, Ling; Qu, Ye; Xiu Hu, Cun; Mao, Li Qun; Wang, Dan

2015-06-01

About 40-60% of ovarian cancer (OVCA) cases express ERα, but only a small proportion of patients respond clinically to anti-estrogen treatment with estrogen receptor (ER) antagonist tamoxifen (TAM). The mechanism of TAM resistance in the course of OVCA progression remains unclear. However, IL6 plays a critical role in the development and progression of OVCA. Our recent results indicated that IL6 secreted by OVCA cells may promote the resistance of these cells to TAM via ER isoforms and steroid hormone receptor coactivator-1. Here we demonstrate that both exogenous (a relatively short period of treatment with recombinant IL6) and endogenous IL6 (generated as a result of transfection with a plasmid encoding sense IL6) increases expression of pERα-Ser118 and pERα-Ser167 in non-IL6-expressing A2780 cells, while deleting endogenous IL6 expression in IL6-overexpressing CAOV-3 cells (by transfection with a plasmid encoding antisense IL6) reduces expression of pERα-Ser118 and pERα-Ser167, indicating that IL6-induced TAM resistance may also be associated with increased expression of pERα-Ser118 and pERα-Ser167 in OVCA cells. Results of further investigation indicate that IL6 phosphorylates ERα at Ser118 and Ser167 by triggering activation of MEK/ERK and phosphotidylinositol 3 kinase/Akt signaling, respectively, to activate the ER pathway and thereby induce OVCA cells resistance to TAM. These results indicate that IL6 secreted by OVCA cells may also contribute to the refractoriness of these cells to TAM via the crosstalk between ER and IL6-mediated intracellular signal transduction cascades. Overexpression of IL6 not only plays an important role in OVCA progression but also promotes TAM resistance. Our results indicate that TAM-IL6-targeted adjunctive therapy may lead to a more effective intervention than TAM alone. © 2015 Society for Endocrinology.

Increased Prevalence of Activated Protein C Resistance During ...

African Journals Online (AJOL)

Background: Acquired resistance to protein C in pregnancy has been established as one of the factors associated with ..... diabetes, sickle cell disease, smoking, anti-phospholipid syndrome inherited thrombophilia, and previous history of.

Antimicrobial consumption, costs and resistance patterns: a two year prospective study in a Romanian intensive care unit.

Science.gov (United States)

Axente, Carmen; Licker, Monica; Moldovan, Roxana; Hogea, Elena; Muntean, Delia; Horhat, Florin; Bedreag, Ovidiu; Sandesc, Dorel; Papurica, Marius; Dugaesescu, Dorina; Voicu, Mirela; Baditoiu, Luminita

2017-05-22

Due to the vulnerable nature of its patients, the wide use of invasive devices and broad-spectrum antimicrobials used, the intensive care unit (ICU) is often called the epicentre of infections. In the present study, we quantified the burden of hospital acquired pathology in a Romanian university hospital ICU, represented by antimicrobial agents consumption, costs and local resistance patterns, in order to identify multimodal interventional strategies. Between 1 st January 2012 and 31 st December 2013, a prospective study was conducted in the largest ICU of Western Romania. The study group was divided into four sub-samples: patients who only received prophylactic antibiotherapy, those with community-acquired infections, patients who developed hospital acquired infections and patients with community acquired infections complicated by hospital-acquired infections. The statistical analysis was performed using the EpiInfo version 3.5.4 and SPSS version 20. A total of 1596 subjects were enrolled in the study and the recorded consumption of antimicrobial agents was 1172.40 DDD/ 1000 patient-days. The presence of hospital acquired infections doubled the length of stay (6.70 days for patients with community-acquired infections versus 16.06/14.08 days for those with hospital-acquired infections), the number of antimicrobial treatment days (5.47 in sub-sample II versus 11.18/12.13 in sub-samples III/IV) and they increased by 4 times compared to uninfected patients. The perioperative prophylactic antibiotic treatment had an average length duration of 2.78 while the empirical antimicrobial therapy was 3.96 days in sample II and 4.75/4.85 days for the patients with hospital-acquired infections. The incidence density of resistant strains was 8.27/1000 patient-days for methicilin resistant Staphylococcus aureus, 7.88 for extended spectrum β-lactamase producing Klebsiella pneumoniae and 4.68/1000 patient-days for multidrug resistant Acinetobacter baumannii. Some of the most

Electrical Signaling, Photosynthesis and Systemic Acquired Acclimation

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Magdalena Szechyńska-Hebda

2017-09-01

Full Text Available Electrical signaling in higher plants is required for the appropriate intracellular and intercellular communication, stress responses, growth and development. In this review, we have focus on recent findings regarding the electrical signaling, as a major regulator of the systemic acquired acclimation (SAA and the systemic acquired resistance (SAR. The electric signaling on its own cannot confer the required specificity of information to trigger SAA and SAR, therefore, we have also discussed a number of other mechanisms and signaling systems that can operate in combination with electric signaling. We have emphasized the interrelation between ionic mechanism of electrical activity and regulation of photosynthesis, which is intrinsic to a proper induction of SAA and SAR. In a special way, we have summarized the role of non-photochemical quenching and its regulator PsbS. Further, redox status of the cell, calcium and hydraulic waves, hormonal circuits and stomatal aperture regulation have been considered as components of the signaling. Finally, a model of light-dependent mechanisms of electrical signaling propagation has been presented together with the systemic regulation of light-responsive genes encoding both, ion channels and proteins involved in regulation of their activity. Due to space limitations, we have not addressed many other important aspects of hormonal and ROS signaling, which were presented in a number of recent excellent reviews.

Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.

NARCIS (Netherlands)

Fregonese, Federica; Ahuja, Shama D; Akkerman, Onno W; Arakaki-Sanchez, Denise; Ayakaka, Irene; Baghaei, Parvaneh; Bang, Didi; Bastos, Mayara; Benedetti, Andrea; Bonnet, Maryline; Cattamanchi, Adithya; Cegielski, Peter; Chien, Jung-Yien; Cox, Helen; Dedicoat, Martin; Erkens, Connie; Escalante, Patricio; Falzon, Dennis; Garcia-Prats, Anthony J; Gegia, Medea; Gillespie, Stephen H; Glynn, Judith R; Goldberg, Stefan; Griffith, David; Jacobson, Karen R; Johnston, James C; Jones-López, Edward C; Khan, Awal; Koh, Won-Jung; Kritski, Afranio; Lan, Zhi Yi; Lee, Jae Ho; Li, Pei Zhi; Maciel, Ethel L; Galliez, Rafael Mello; Merle, Corinne S C; Munang, Melinda; Narendran, Gopalan; Nguyen, Viet Nhung; Nunn, Andrew; Ohkado, Akihiro; Park, Jong Sun; Phillips, Patrick P J; Ponnuraja, Chinnaiyan; Reves, Randall; Romanowski, Kamila; Seung, Kwonjune; Schaaf, H Simon; Skrahina, Alena; Soolingen, Dick van; Tabarsi, Payam; Trajman, Anete; Trieu, Lisa; Banurekha, Velayutham V; Viiklepp, Piret; Wang, Jann-Yuan; Yoshiyama, Takashi; Menzies, Dick

Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and

Multidrug-resistant Salmonella enterica serovar Typhimurium isolates are resistant to antibiotics that influence their swimming and swarming motility

Science.gov (United States)

Motile bacteria utilize one or more strategies for movement, such as darting, gliding, sliding, swarming, swimming, and twitching. The ability to move is considered a virulence factor in many pathogenic bacteria, including Salmonella. Multidrug-resistant (MDR) Salmonella encodes acquired factors t...

COMBINED INVITRO MODULATION OF ADRIAMYCIN RESISTANCE

NARCIS (Netherlands)

MEIJER, C; MULDER, NH; TIMMERBOSSCHA, H; PETERS, WHM; DEVRIES, EGE

1991-01-01

In a P-glycoprotein-negative cell line, GLC4-Adr90, a 75-fold acquired Adriamycin (Adr) resistance coincided with a reduced cellular Adr level, an increased detoxifying capacity (glutathione (GSH) and glutathione S-transferase (GST) elevated), and a reduced topoisomerase-II (topo-II) activity

Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer.

Science.gov (United States)

Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

2016-07-04

The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.

Incidence of multidrug-resistant, extensively drug-resistant and pan-drug-resistant bacteria in children hospitalized at Dr. Hasan Sadikin general hospital Bandung Indonesia

Science.gov (United States)

Adrizain, R.; Suryaningrat, F.; Alam, A.; Setiabudi, D.

2018-03-01

Antibiotic resistance has become a global issue, with 700,000 deaths attributable to multidrug-resistance (MDR) occurring each year. Centers for Disease Control and Prevention (CDC) show rapidly increasing rates of infection due to antibiotic-resistant bacteria. The aim of the study isto describe the incidence of MDR, extensively drug-resistant (XDR) and pan drug-resistant (PDR) in Enterococcus spp., Staphylococcus aureus, K. pneumonia, Acinetobacter baumanii, P. aeruginosin, and Enterobacter spp. (ESKAPE) pathogens in children admitted to Dr. Hasan Sadikin Hospital. All pediatric patients having blood culture drawn from January 2015 to December 2016 were retrospectively studied. Data include the number of drawn blood culture, number of positive results, type of bacteria, sensitivity pattern. International standard definitions for acquired resistance by ECDC and CDC was used as definitions for MDR, XDR and PDR bacteria. From January 2015 to December 2016, 299 from 2.542 (11.7%) blood culture was positive, with Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., respectively 5, 6, 24, 5, 20 with total 60 (20%). The MDR and XDR pathogen found were 47 and 13 patients, respectively.

Molecular characterization of acquired enrofloxacin resistance in Mycoplasma synoviae field isolates.

Science.gov (United States)

Lysnyansky, I; Gerchman, I; Mikula, I; Gobbo, F; Catania, S; Levisohn, S

2013-07-01

The in vitro activity of enrofloxacin against 73 Mycoplasma synoviae field strains isolated in Israel and Europe was determined by broth microdilution. Decreased susceptibility to enrofloxacin was identified in 59% of strains, with the MICs ranging from 1 to >16 μg/ml. The estimated MIC50 and MIC90 values for enrofloxacin were 2 and 8 μg/ml, respectively. Moreover, this study showed that 92% of recent Israeli field isolates (2009 to 2011) of M. synoviae have MICs of ≥ 2 μg/ml to enrofloxacin. Comparison of the quinolone resistance-determining regions (QRDRs) in M. synoviae isolates revealed a clear correlation between the presence of one of the amino acid substitutions Asp79-Asn, Thr80-Ala/Ile, Ser81-Pro, and Asp84-Asn/Tyr/His of the ParC QRDR and decreased susceptibility to enrofloxacin (MIC, ≥ 1 μg/ml). Amino acid substitutions at positions GyrA 87, GyrB 401/402, and ParE 420/454 were also identified, but there was no clear-cut correlation with susceptibility to enrofloxacin. Comparison of vlhA molecular profiles revealed the presence of 9 different genotypes in the Israeli M. synoviae field isolates and 10 genotypes in the European isolates; only one vlhA genotype (type 4) was identified in both cohorts. Based on results of vlhA molecular typing, several mechanisms for emergence and dissemination of Israeli enrofloxacin-resistant M. synoviae isolates are suggested.

Impact of carbapenem resistance on the outcome of patients' hospital-acquired bacteraemia caused by Klebsiella pneumoniae.

Science.gov (United States)

Hussein, K; Raz-Pasteur, A; Finkelstein, R; Neuberger, A; Shachor-Meyouhas, Y; Oren, I; Kassis, I

2013-04-01

Carbapenem-resistant Enterobacteriaceae, especially Klebsiella spp., have become a major health problem recently worldwide. Since 2006 the incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections has increased substantially in Israel. Bloodstream infections (BSIs) caused by these strains have been associated with high rates of treatment failure and mortality. This study was designed to identify risk factors for carbapenem resistance among patients with healthcare-related (HCR) K. pneumoniae bacteraemia and predictors of mortality associated with HCR-CRKP bacteraemia compared with carbapenem-susceptible K. pneumoniae (CSKP). In this retrospective case-control study, all cases of K. pneumoniae bacteraemia during 2006-2008 were identified. Resistance patterns, underlying morbidities, risk factors for drug resistance and mortality rates were compared for patients with CRKP and CSKP bacteraemia. Two hundred and fourteen patients with CSKP bacteraemia were compared with 103 patients with CRKP bacteraemia. Severe, chronic comorbidities and prior antibiotic use were more frequent among patients with CRKP bacteraemia. On multivariate analysis prior use of macrolides and antibiotic exposure for ≥14 days remained the only independent factors associated with CRKP bacteraemia. Mortality rates of CRKP patients were significantly higher than those of CSKP patients. On multivariate analyses: bedridden status, chronic liver disease, Charlson comorbidity index ≥5, mechanical ventilation, and haemodialysis remained independently associated with mortality among patients with K. pneumoniae bacteraemia. Carbapenem resistance was not a risk factor for mortality. Previous antibiotic exposure is a risk factor for CRKP-BSI. Mortality among patients with K. pneumoniae bacteraemia is associated with serious comorbidities, but not with carbapenem resistance. Copyright © 2012 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Clinical Predictors of Hospital-acquired Pneumonia Associated with Acute Ischemic

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Alexis Suárez Quesada

2015-06-01

Full Text Available Background: hospital-acquired pneumonia is a constant challenge given the current microbiological spectrum, antimicrobial resistance together with its high mortality, morbidity and hospital costs. Objective: to identify the clinical predictors of pneumonia associated with acute ischemic stroke. Methods: a prospective cohort study was conducted in 201 patients diagnosed with acute ischemic stroke consecutively admitted to the stroke unit of the General Carlos Manuel de Céspedes Teaching Hospital during the first seven days after the onset, from January 2012 through December 2013. The independent predictors of hospital-acquired pneumonia were obtained using multivariable logistic regression. Results: fifty six point seven percent were male. The mean age was 64.17 ± 14.33 years. Cases of hospital-acquired pneumonia associated with stroke accounted for 19, 9 %. Subjects who developed pneumonia were older (68.55 ± 13.51 vs. 63.08 ± 14.36 years, had a lower score in the Glasgow Coma Scale (8.00 ± 2.60 vs. 14.00 ± 2.82, and an increased number of leukocytes at admission (10.888 ± 3.487 vs. 9.233 ± 2.539 × 109/L. The following independent factors were identified: Glasgow Coma Scale ≤ 11 (OR: 26.099; 95 % CI 7.164-85.075, history of chronic obstructive pulmonary disease (OR: 8.896; 95 % CI 1.203-65.779, dysphagia (OR: 7.652; 95 % CI 2.369- 24.720, history of heart failure (OR: 4.583; 95 % CI 1.240- 16.932 and dysarthria/severe motor aphasia (OR: 4.222; 95 % CI 1.374- 12.975. Conclusions: the resulting logistic regression model is valid for predicting post-stroke pneumonia based on data routinely acquired.

Antimicrobial resistance in zoonotic nontyphoidal Salmonella: an alarming trend?

Science.gov (United States)

Michael, G B; Schwarz, S

2016-12-01

Zoonotic bacteria of the genus Salmonella have acquired various antimicrobial resistance properties over the years. The corresponding resistance genes are commonly located on plasmids, transposons, gene cassettes, or variants of the Salmonella Genomic Islands SGI1 and SGI2. Human infections by nontyphoidal Salmonella isolates mainly result from ingestion of contaminated food. The two predominantly found Salmonella enterica subsp. enterica serovars in the USA and in Europe are S. Enteritidis and S. Typhimurium. Many other nontyphoidal Salmonella serovars have been implicated in foodborne Salmonella outbreaks. Summary reports of the antimicrobial susceptibility patterns of nontyphoidal Salmonella isolates over time suggest a moderate to low level of antimicrobial resistance and multidrug-resistance. However, serovar-specific analyses showed in part a steady state, a continuous decline, or a recent increase in resistance to certain antimicrobial agents. Resistance to critically important antimicrobial agents, e.g. third-generation cephalosporins and (fluoro)quinolones is part of many monitoring programmes and the corresponding results confirm that extended-spectrum β-lactamases are still rarely found in nontyphoidal Salmonella serovars, whereas resistance to (fluoro)quinolones is prevalent at variable frequencies among different serovars from humans and animals in different countries. Although it is likely that nontyphoidal Salmonella isolates from animals represent a reservoir for resistance determinants, it is mostly unknown where and when Salmonella isolates acquired resistance properties and which exchange processes have happened since then. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

HYPERTHERMIC POTENTIATION OF CISPLATIN TOXICITY IN A HUMAN SMALL-CELL LUNG-CARCINOMA CELL-LINE AND A CISPLATIN-RESISTANT SUBLINE

NARCIS (Netherlands)

HETTINGA, JVE; LEMSTRA, W; MEIJER, C; MULDER, NH; KONINGS, AWT; DEVRIES, EGE; KAMPINGA, HH

1994-01-01

A human small cell lung carcinoma cell line (GLC4) and its subline with in vitro acquired cisplatin (cDDP) resistance (GLC4-cDDP) were used to study the applicability of hyperthermia to interfere with acquired cDDP resistance. GLC4 and GLC4-cDDP did not differ in heat sensitivity (clonogenic

A genomic approach to identify regulatory nodes in the transcriptional network of systemic acquired resistance in plants.

Directory of Open Access Journals (Sweden)

Dong Wang

2006-11-01

Full Text Available Many biological processes are controlled by intricate networks of transcriptional regulators. With the development of microarray technology, transcriptional changes can be examined at the whole-genome level. However, such analysis often lacks information on the hierarchical relationship between components of a given system. Systemic acquired resistance (SAR is an inducible plant defense response involving a cascade of transcriptional events induced by salicylic acid through the transcription cofactor NPR1. To identify additional regulatory nodes in the SAR network, we performed microarray analysis on Arabidopsis plants expressing the NPR1-GR (glucocorticoid receptor fusion protein. Since nuclear translocation of NPR1-GR requires dexamethasone, we were able to control NPR1-dependent transcription and identify direct transcriptional targets of NPR1. We show that NPR1 directly upregulates the expression of eight WRKY transcription factor genes. This large family of 74 transcription factors has been implicated in various defense responses, but no specific WRKY factor has been placed in the SAR network. Identification of NPR1-regulated WRKY factors allowed us to perform in-depth genetic analysis on a small number of WRKY factors and test well-defined phenotypes of single and double mutants associated with NPR1. Among these WRKY factors we found both positive and negative regulators of SAR. This genomics-directed approach unambiguously positioned five WRKY factors in the complex transcriptional regulatory network of SAR. Our work not only discovered new transcription regulatory components in the signaling network of SAR but also demonstrated that functional studies of large gene families have to take into consideration sequence similarity as well as the expression patterns of the candidates.

Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options

Science.gov (United States)

Lee, Chang-Ro; Lee, Jung Hun; Park, Moonhee; Park, Kwang Seung; Bae, Il Kwon; Kim, Young Bae; Cha, Chang-Jun; Jeong, Byeong Chul; Lee, Sang Hee

2017-01-01

Acinetobacter baumannii is undoubtedly one of the most successful pathogens responsible for hospital-acquired nosocomial infections in the modern healthcare system. Due to the prevalence of infections and outbreaks caused by multi-drug resistant A. baumannii, few antibiotics are effective for treating infections caused by this pathogen. To overcome this problem, knowledge of the pathogenesis and antibiotic resistance mechanisms of A. baumannii is important. In this review, we summarize current studies on the virulence factors that contribute to A. baumannii pathogenesis, including porins, capsular polysaccharides, lipopolysaccharides, phospholipases, outer membrane vesicles, metal acquisition systems, and protein secretion systems. Mechanisms of antibiotic resistance of this organism, including acquirement of β-lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites, are also discussed. Lastly, novel prospective treatment options for infections caused by multi-drug resistant A. baumannii are summarized. PMID:28348979

Antimicrobial susceptibility, risk factors and prevalence of bla cefotaximase, temoneira, and sulfhydryl variable genes among Escherichia coli in community-acquired pediatric urinary tract infection.

Science.gov (United States)

Nisha, Kallyadan V; Veena, Shetty A; Rathika, Shenoy D; Vijaya, Shenoy M; Avinash, Shetty K

2017-01-01

The emergence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli has become an important challenge among pediatric patients with community-acquired urinary tract infection (UTI). The aim of this study was to assess the antimicrobial susceptibility patterns, associated risk factors and to survey the frequency of bla cefotaximase (CTX-M), bla temoneira (TEM), and bla sulfhydryl variable (SHV) genotypes in ESBL-producing E. coli isolated from children with community-acquired UTI. This was a prospective study conducted from November 2012 to March 2016 in a tertiary care center. E. coli isolated in urine cultures from children aged ≤18 years was identified and confirmed for ESBL production. ESBL-positive strains were screened for ESBL encoding genes. Chi-square test and Fisher's exact test were used to compare the difference in antibiotic susceptibility with respect to ESBL positive and negative, and binary logistic regression was used to identify the risk factors associated with ESBL production. Among 523 E. coli isolates, 196 (37.5%) were ESBL positive, >90% were resistant to cephalosporins, and 56% were resistant to fluoroquinolones. Least resistance was observed for imipenem, netilmicin, and nitrofurantoin (2%, 8.6%, 15.3%). Association between ESBL production and drug resistance was significant for ceftazidime ( P antibiotics were the common risk factors. ESBL-producing E. coli from community-acquired pediatric UTI carries more than one type of beta-lactamase coding genes correlating their increased antibiotic resistance. Aggressive infection control policy, routine screening for detecting ESBL isolates in clinical samples, and antimicrobial stewardship are the keys to prevent their dissemination in community settings.

Antibiotic resistance patterns and beta-lactamase identification in ...

African Journals Online (AJOL)

Children acquire bacteria from their mother during birth,[3,4] and ... Our results revealed high resistance rates to co-trimoxazole (54.0%), penicillin .... the inclusion of a beta-lactamase inhibitor, clavulanic acid. .... Folate pathway inhibitor/.

Recessive Resistance to Plant Viruses: Potential Resistance Genes Beyond Translation Initiation Factors

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Masayoshi Hashimoto

2016-10-01

Full Text Available The ability of plant viruses to propagate their genomes in host cells depends on many host factors. In the absence of an agrochemical that specifically targets plant viral infection cycles, one of the most effective methods for controlling viral diseases in plants is taking advantage of the host plant’s resistance machinery. Recessive resistance is conferred by a recessive gene mutation that encodes a host factor critical for viral infection. It is a branch of the resistance machinery and, as an inherited characteristic, is very durable. Moreover, recessive resistance may be acquired by a deficiency in a negative regulator of plant defense responses, possibly due to the autoactivation of defense signaling. Eukaryotic translation initiation factor (eIF 4E and eIF4G and their isoforms are the most widely exploited recessive resistance genes in several crop species, and they are effective against a subset of viral species. However, the establishment of efficient, recessive resistance-type antiviral control strategies against a wider range of plant viral diseases requires genetic resources other than eIF4Es. In this review, we focus on recent advances related to antiviral recessive resistance genes evaluated in model plants and several crop species. We also address the roles of next-generation sequencing and genome editing technologies in improving plant genetic resources for recessive resistance-based antiviral breeding in various crop species.

Infecciones adquiridas en la comunidad por Staphylococcus aureus resistente a meticilina en un hospital de agudos Community-acquired methicillin-resistant Staphylococcus aureus infections in a hospital for acute diseases

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S. Palombarani

2007-09-01

Full Text Available Staphylococcus aureus resistente a meticilina (SAMR es uno de los principales agentes asociados a infecciones intrahospitalarias; sin embargo, en los últimos años ha surgido como un patógeno emergente de la comunidad, causando infecciones graves, principalmente en jóvenes. Se describen 33 casos de infecciones por SAMR de origen comunitario, diagnosticadas entre mayo de 2005 y junio de 2006 en el HIGA "Eva Perón". Se estudiaron retrospectivamente los aislamientos; se confirmó la resistencia a meticilina mediante la detección del gen mecA, se investigó la presencia de genes que codifican dos factores de virulencia (leucocidina de Panton-Valentine -LPV- y g-hemolisina y el tipo de casete mec mediante PCR. Todos los pacientes se encontraban sanos previamente. Cuatro pacientes menores de 12 años presentaron bacteriemia, uno con neumonía grave y los 3 restantes con infección osteoarticular; todos los pacientes mayores de 12 años presentaron infecciones de piel y partes blandas sin compromiso sistémico. Se constató la presencia de casete mec tipo IV en todos los aislamientos; la resistencia a meticilina no se acompañó de resistencia a otros antimicrobianos; los aislamientos fueron portadores de genes que codifican para LPV y para g-hemolisina. Es importante considerar la presencia de estas cepas de origen comunitario a fin de elaborar estrategias para su correcto tratamiento.Methicillin- resistant Staphylococcus aureus (MRSA is one of the most prevalent pathogens associated with nosocomial infections. However, most recently, MRSA has arisen as an emerging community pathogen, causing serious infections, mainly among young patients. We herein describe 33 cases of infections caused by community-acquired MRSA (CMRSA, diagnosed between May 2005 and June 2006, at "Eva Perón" Hospital. The isolations were retrospectively studied. Methicillin resistance was confirmed by means of the detection of the mecA gene, and the genes for two virulence

Coordinated Expression of Borrelia burgdorferi Complement Regulator-Acquiring Surface Proteins during the Lyme Disease Spirochete's Mammal-Tick Infection Cycle▿

OpenAIRE

Bykowski, Tomasz; Woodman, Michael E.; Cooley, Anne E.; Brissette, Catherine A.; Brade, Volker; Wallich, Reinhard; Kraiczy, Peter; Stevenson, Brian

2007-01-01

The Lyme disease spirochete, Borrelia burgdorferi, is largely resistant to being killed by its hosts’ alternative complement activation pathway. One possible resistance mechanism of these bacteria is to coat their surfaces with host complement regulators, such as factor H. Five different B. burgdorferi outer surface proteins having affinities for factor H have been identified: complement regulator-acquiring surface protein 1 (BbCRASP-1), encoded by cspA; BbCRASP-2, encoded by cspZ; and three ...

A Mechanism of Unidirectional Transformation, Leading to Antibiotic Resistance, Occurs within Nasopharyngeal Pneumococcal Biofilm Consortia.

Science.gov (United States)

Lattar, Santiago M; Wu, Xueqing; Brophy, Jennifer; Sakai, Fuminori; Klugman, Keith P; Vidal, Jorge E

2018-05-15

Streptococcus pneumoniae acquires genes for resistance to antibiotics such as streptomycin (Str) or trimethoprim (Tmp) by recombination via transformation of DNA released by other pneumococci and closely related species. Using naturally transformable pneumococci, including strain D39 serotype 2 (S2) and TIGR4 (S4), we studied whether pneumococcal nasopharyngeal transformation was symmetrical, asymmetrical, or unidirectional. Incubation of S2 Tet and S4 Str in a bioreactor simulating the human nasopharynx led to the generation of Spn Tet/Str recombinants. Double-resistant pneumococci emerged soon after 4 h postinoculation at a recombination frequency (rF) of 2.5 × 10 -4 while peaking after 8 h at a rF of 1.1 × 10 -3 Acquisition of antibiotic resistance genes by transformation was confirmed by treatment with DNase I. A high-throughput serotyping method demonstrated that all double-resistant pneumococci belonged to one serotype lineage (S2 Tet/Str ) and therefore that unidirectional transformation had occurred. Neither heterolysis nor availability of DNA for transformation was a factor for unidirectional transformation given that the density of each strain and extracellular DNA (eDNA) released from both strains were similar. Unidirectional transformation occurred regardless of the antibiotic-resistant gene carried by donors or acquired by recipients and regardless of whether competence-stimulating peptide-receptor cross talk was allowed. Moreover, unidirectional transformation occurred when two donor strains (e.g., S4 Str and S19F Tmp ) were incubated together, leading to S19F Str/Tmp but at a rF 3 orders of magnitude lower (4.9 × 10 -6 ). We finally demonstrated that the mechanism leading to unidirectional transformation was due to inhibition of transformation of the donor by the recipient. IMPORTANCE Pneumococcal transformation in the human nasopharynx may lead to the acquisition of antibiotic resistance genes or genes encoding new capsular variants

Distinct apoptotic blocks mediate resistance to panHER inhibitors in HER2+ breast cancer cells.

Science.gov (United States)

Karakas, Bahriye; Ozmay, Yeliz; Basaga, Huveyda; Gul, Ozgur; Kutuk, Ozgur

2018-05-04

Despite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells. Cells were also cross-resistant to dacomitinib. BH3 profiles of HER2+ breast cancer cells efficiently predicted antiapoptotic protein dependence and development of resistance to panHER inhibitors. Reactivation of ERK1/2 was primarily responsible for acquired resistance in SKBR3 and ZR-75-30 cells. Adding specific ERK1/2 inhibitor SCH772984 to neratinib or dacomitinib led to increased apoptotic response in neratinib-resistant SKBR3 and ZR-75-30 cells, but we did not detect a similar response in neratinib-resistant BT474 cells. Accordingly, suppression of BCL-2/BCL-XL by ABT-737 was required in addition to ERK1/2 inhibition for neratinib- or dacomitinib-induced apoptosis in neratinib-resistant BT474 cells. Our results showed that different mitochondrial apoptotic blocks mediated acquired panHER inhibitor resistance in HER2+ breast cancer cell lines as well as highlighted the potential of BH3 profiling assay in prediction of panHER inhibitor resistance in breast cancer cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Community-acquired bacterial meningitis

NARCIS (Netherlands)

van de Beek, Diederik; Brouwer, Matthijs; Hasbun, Rodrigo; Koedel, Uwe; Whitney, Cynthia G.; Wijdicks, Eelco

2016-01-01

Meningitis is an inflammation of the meninges and subarachnoid space that can also involve the brain cortex and parenchyma. It can be acquired spontaneously in the community - community-acquired bacterial meningitis - or in the hospital as a complication of invasive procedures or head trauma

Acquired Methemoglobinaemia

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Adil Al-Lawati

2012-05-01

Full Text Available Acquired methemoglobinaemia is a relatively rare condition and, therefore infrequently encountered in acute medical practice. Suspicion of the condition may be triggered when the measured PaO2 is ‘out of keeping’ with the oxygen saturations that are discovered with pulse oximetry. We describe two separate cases of acquired methemoglobinaemia secondary to the recreational use of alkyl nitrites (’poppers’. The patients presented at separate times to two different teaching hospitals in London, UK. The similarity of these cases has led the authors to conclude that a raised awareness of this potentially fatal condition, and its association with a widely-available recreational drug, is necessary to ensure a correct and timely diagnosis.

Molecular basis of antifungal drug resistance in yeasts

DEFF Research Database (Denmark)

Morio, Florent; Jensen, Rasmus Hare; Le Pape, Patrice

2017-01-01

Besides inherent differences in in vitro susceptibilities, clinically-relevant yeast species may acquire resistance upon exposure to most antifungal drugs used in the clinic. In recent years, major fundamental research studies have been conducted to improve our understanding of the molecular basis...... of antifungal resistance. This topic is of major interest as antifungal resistance in yeast is clearly evolving and is correlated with clinical failure. This minireview is an overview of the most recent findings about key molecular mechanisms evolving in human pathogenic yeasts, particularly Candida spp......., in the context of antifungal drug resistance. Also included are the methods currently available for in vitro antifungal susceptibility testing and for molecular detection of mutations associated with resistance. Finally, the genetic drivers of antifungal resistance are discussed in light of the spectra...

Bacterial resistance to antimicrobial agents in Latin America. The giant is awakening.

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Guzmán-Blanco, M; Casellas, J M; Sader, H S

2000-03-01

Resistant bacteria are emerging in Latin America as a real threat to the favorable outcome of infections in community- and hospital-acquired infections. Despite present extensive surveillance, healthcare workers who most need the information may be unaware of this growing problem. Outbreaks of meningococci with diminished susceptibility to penicillin have been reported in the region; a constant increase of resistance to penicillin in pneumococci and poor activity of commonly used oral antibiotics for the treatment of community-acquired urinary tract infections have made the treatment of these infections more difficult. Reports from tertiary hospitals are similar to many other areas of the world, with increasing frequency of Klebsiella pneumoniae-carrying extended-spectrum beta-lactamase, multiresistant strains of Pseudomonas aeruginosa and Acinetobacter baumanni in ICU settings, and reports of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. A surveillance network readily accessible to those who prescribe antibiotics in Latin America is highly desirable.

Laboratory-acquired brucellosis

DEFF Research Database (Denmark)

Fabiansen, C.; Knudsen, J.D.; Lebech, A.M.

2008-01-01

Brucellosis is a rare disease in Denmark. We describe one case of laboratory-acquired brucellosis from an index patient to a laboratory technician following exposure to an infected blood culture in a clinical microbiology laboratory Udgivelsesdato: 2008/6/9......Brucellosis is a rare disease in Denmark. We describe one case of laboratory-acquired brucellosis from an index patient to a laboratory technician following exposure to an infected blood culture in a clinical microbiology laboratory Udgivelsesdato: 2008/6/9...

FabH Mutations Confer Resistance to FabF-Directed Antibiotics in Staphylococcus aureus

OpenAIRE

Parsons, Joshua B.; Yao, Jiangwei; Frank, Matthew W.; Rock, Charles O.

2014-01-01

Delineating the mechanisms for genetically acquired antibiotic resistance is a robust approach to target validation and anticipates the evolution of clinical drug resistance. This study defines a spectrum of mutations in fabH that render Staphylococcus aureus resistant to multiple natural products known to inhibit the elongation condensing enzyme (FabF) of bacterial type II fatty acid synthesis. Twenty independently isolated clones resistant to platensimycin, platencin, or thiolactomycin were...

Genetic control of acquired resistance to gastrointestinal nematode parasites in sheep

International Nuclear Information System (INIS)

Windon, R.G.; Wagland, B.M.; Dineen, J.K.

1988-01-01

A radiation attenuated larval vaccine has been used to evaluate the role of genetic components of the immune response in the control of Trichostrongylus colubriformis in sheep. Through selection based on age dependent responsiveness, lines of sheep have been established in which lambs are either high or low responders to vaccination and challenge infection. The estimated and realized heritabilities for the selected trait are 0.35-0.41. Significant interline differences were demonstrated and, within the lines, ewe lambs were consistently more responsive than rams or wethers. The effect of selection was not antigenically specific, since high responsiveness to T. colubriformis was associated with increased responsiveness to other related (T. rugatus) and unrelated parasites (Ostertagia circumcincta and Haemonchus contortus). In addition, high responders had a more vigorous reaction against naturally acquired infections than low responders. The general immunological competence was also increased in high responders; this was shown by the levels of serum complement fixing antibody to larval antigens after vaccination and challenge, in vitro blastogenic responses stimulated by larval antigens and the phagocytic function of peripheral leucocytes. No production penalty (weight gain and wool growth) was associated with heightened responsiveness. (author). 10 refs, 1 fig

Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer.

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Pawar, Aishwarya; Gollavilli, Paradesi Naidu; Wang, Shaomeng; Asangani, Irfan A

2018-02-27

BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Treatment Options for Carbapenem-Resistant and Extensively Drug-Resistant Acinetobacter baumannii Infections

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Viehman, J. Alexander; Nguyen, Minh-Hong; Doi, Yohei

2014-01-01

Acinetobacter baumannii is a leading cause of healthcare-associated infections worldwide. Due to various intrinsic and acquired mechanisms of resistance, most β-lactam agents are not effective against many strains, and carbapenems have played an important role in therapy. Recent trends show many infections are caused by carbapenem-resistant, or even extensively drug-resistant (XDR) strains, for which effective therapy is not well established. Evidence to date suggests that colistin constitutes the backbone of therapy, but the unique pharmacokinetic properties of colistin have led many to suggest the use of combination antimicrobial therapy. However, the combination of agents and dosing regimens that delivers the best clinical efficacy while minimizing toxicity is yet to be defined. Carbapenems, sulbactam, rifampin and tigecycline have been the most studied in the context of combination therapy. Most data regarding therapy for invasive, resistant A. baumannii infections come from uncontrolled case series and retrospective analyses, though some clinical trials have been completed and others are underway. Early institution of appropriate antimicrobial therapy is shown to consistently improve survival of patients with carbapenem-resistant and XDR A. baumannii infection, but the choice of empiric therapy in these infections remains an open question. This review summarizes the most current knowledge regarding the epidemiology, mechanisms of resistance, and treatment considerations of carbapenem-resistant and XDR A. baumannii. PMID:25091170

First report in South America of companion animal colonization by the USA1100 clone of community-acquired meticillin-resistant Staphylococcus aureus (ST30) and by the European clone of methicillin-resistant Staphylococcus pseudintermedius (ST71).

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Quitoco, Isidório Mebinda Zuco; Ramundo, Mariana Severo; Silva-Carvalho, Maria Cícera; Souza, Raquel Rodrigues; Beltrame, Cristiana Ossaille; de Oliveira, Táya Figueiredo; Araújo, Rodrigo; Del Peloso, Pedro Fernandez; Coelho, Leonardo Rocchetto; Figueiredo, Agnes Marie Sá

2013-08-27

Methicillin-resistant staphylococci can colonize and cause diseases in companion animals. Unfortunately, few molecular studies have been carried out in Brazil and other countries with the aim of characterizing these isolates. Consequently, little is known about the potential role of companion animals in transmitting these resistant bacteria to humans. In this work we searched for mecA gene among Staphylococcus isolates obtained from nasal microbiota of 130 healthy dogs and cats attended in a veterinary clinic located in the west region of Rio de Janeiro. The isolates recovered were identified to the species level and characterized using molecular tools. A community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) isolate related to USA1100 (Southwest Pacific clone) and susceptible to all non-β-lactams was detected in a cat (1.7%, 1/60). Another coagulase-positive isolate harboring mecA was recovered from a dog (1.4%, 1/70) and identified as Staphylococcus pseudintermedius (MRSP) related to the European clone (ST71). The two isolates of Staphylococcus conhii subsp. urealyticus (1.4%, 1/70 dogs and 1.7%, 1/60 cats), similarly to the MRSP isolate, also presented high-level multiresistance. The majority of the methicillin-resistant coagulase-negative staphylococci recovered were Staphylococcus saprophyticus (5.7%, 4/70 dogs and 6.7%, 4/60 cats) and all clustered into the same PFGE type. This work demonstrates that mecA-harboring Staphylococcus isolates are common members of the nasal microbiota of the healthy companion animals studied (9.2%, 12/130 animals), including some high-level multiresistant isolates of S. pseudintermedius and S. conhii subsp. urealyticus. The detection, for the first time in South America, of USA1100-related CA-MRSA and of ST71 MRSP (European clone), colonizing companion animals, is of concern. Both S. pseudintermedius and S. aureus are important agents of infections for animals. The USA1100 CA-MRSA is a causative of severe and

Molecular dissection of the response of the rice Systemic Acquired Resistance Deficient 1 (SARD1) gene to different types of ionizing radiation.

Science.gov (United States)

Jung, In Jung; Hwang, Jung Eun; Han, Sung Min; Kim, Dong Sub; Ahn, Joon-Woo; Choi, Hong-Il; Kwon, Soon-Jae; Kang, Si-Yong; Kim, Jin-Baek

2017-07-01

Exposure to ionizing radiation induces plant defenses by regulating the expression of response genes. The systemic acquired resistance deficient 1 (SARD1) is a key gene in plant defense response. In this study, the function of Oryza sativa SARD1 (OsSARD1) was investigated after exposure of seeds/plants to ionizing radiation, jasmonic acid (JA) or salicylic acid (SA). Rice seeds exposed to two types of ionizing radiations (gamma ray [GR] and ion beam [IB]) were analyzed by quantitative reverse transcription PCR (qRT-PCR) to identify the genes that are altered in response to ionizing radiation. Then, OsSARD1-overexpressing homozygous Arabidopsis plants were generated to assess the effects of OsSARD1 in the response to irradiation. The phenotypes of these transgenic plants, as well as control plants, were monitored after GR irradiation at doses of 200 and 300 Gray (Gy). The OsSARD1 transcript was strongly downregulated after exposure to GR and IB irradiation. Previous phylogenetic analysis showed that the Arabidopsis SARD1 (AtSARD1) protein is closely related to Arabidopsis calmodulin-binding protein 60g (AtCBP60g), which is known to be required for activation of SA biosynthesis. In this study, phylogenetic analysis showed that OsSARD1 was grouped with AtSARD1. The OsSARD1 gene was induced after exposure to SA and JA. The biological phenotype of OsSARD1-overexpressing Arabidopsis plants was examined. OsSARD1-overexpressing plants displayed resistance to GR; in comparison with wild-type plants, the height and weight of OsSARD1-overexpressing plants were significantly greater after GR irradiation. In addition, OsSARD1 protein was abundantly accumulated in the nucleus. The results indicate that OsSARD1 plays an important role in the regulation of the defense responses to GR and IB irradiation and exhibits phytohormone induced expression.

Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells

DEFF Research Database (Denmark)

Morales Torres, Christina; García, Maria J; Ribas, Maria

2009-01-01

Gene amplification is one of the most frequent manifestations of genomic instability in human tumors and plays an important role in tumor progression and acquisition of drug resistance. To better understand the factors involved in acquired resistance to cytotoxic drugs via gene amplification, we ...

Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4.

Science.gov (United States)

Breslin, Susan; Lowry, Michelle C; O'Driscoll, Lorraine

2017-02-28

Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance. Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to neratinib was assessed. Cellular phenotype changes were evaluated using migration, invasion and anoikis assays. Immunoblotting for HER family members and drug efflux pumps, as well as enzyme activity assays were performed. Neratinib resistance conferred cross-resistance to trastuzumab, lapatinib and afatinib. Furthermore, the efficacy of neratinib was reduced in trastuzumab- and lapatinib-resistant cells. Neratinib-resistant cells were more aggressive than their drug-sensitive counterparts, with increased CYP3A4 activity identified as a novel mechanism of neratinib resistance. The potential of increased CYP3A4 activity as a biomarker and/or target to add value to neratinib warrants investigation.

Anti - microbial resistance stratified by risk factor among Escherichia coli strains isolated from the urinary tract at a rural clinic in Central India

Directory of Open Access Journals (Sweden)

Chatterjee B

2009-01-01

Full Text Available Background: The failure of empirical therapy is frequently observed, even in community-acquired urinary tract infections. We, therefore, conducted a prospective, clinic-based study in 2004-2005 to document anti-microbial resistance rates and correlate them with possible risk factors to assist empirical decision-making. Materials and Methods: Symptomatic patients with pyuria underwent urine culture. Isolates were identified using standard methods and anti-microbial resistance was determined by disk-diffusion. Ultrasonography was used to detect complicating factors. Patients were stratified by the presence of complicating factors and history of invasive procedures for comparison of resistance rates. Statistical Method Used: Chi-square or Fisher exact tests, as appropriate. Results: There were 156 E. coli isolates, of which 105 were community-acquired. Twenty-three community-acquired isolates were from patients with complicating factors while 82 were from patients without any. Fifty-one isolates were from patients who had recently undergone invasive procedures on the urinary tract. Thirty-two community-acquired isolates from reproductive-age women without apparent complicating factors had resistance rates of 50% or above against tetracyclines, Co-trimoxazole, aminopenicillins, Nalidixic acid, Ciprofloxacin and 1 st generation cephalosporins. Resistance rates were significantly higher among isolates from patients subjected to invasive procedures, except against Co-trimoxazole, tetracyclines and Amikacin. Conclusion: High rates of anti-microbial resistance in community-acquired uropathogens have made antimicrobial sensitivity testing necessary even in a rural, primary-care setting.

Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer.

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Tanino, Ryosuke; Tsubata, Yukari; Harashima, Nanae; Harada, Mamoru; Isobe, Takeshi

2018-03-30

Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 ( SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1

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Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling; Wurtz, Anna; Walther, Zenta; Cai, Guoping; Zhao, Zhongming; Jia, Peilin; de Stanchina, Elisa; Shapiro, Erik M.; Gale, Molly; Yin, Ruonan; Horn, Leora; Carbone, David P.; Stephens, Philip J; Miller, Vincent; Gettinger, Scott; Pao, William; Politi, Katerina

2014-01-01

SUMMARY Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. Addition of rapamycin reversed resistance in vivo. Analysis of afatinib+cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib+cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs. PMID:24813888

Absence of bacterial resistance following repeat exposure to photodynamic therapy

Science.gov (United States)

Pedigo, Lisa A.; Gibbs, Aaron J.; Scott, Robert J.; Street, Cale N.

2009-06-01

The prevalence of antibiotic resistant bacteria necessitates exploration of alternative approaches to treat hospital and community acquired infections. The aim of this study was to determine whether bacterial pathogens develop resistance to antimicrobial photodynamic therapy (aPDT) during repeated sub-lethal challenge. Antibiotic sensitive and resistant strains of S. aureus and antibiotic sensitive E. coli were subjected to repeat PDT treatments using a methylene blue photosensitizer formulation and 670 nm illumination from a non-thermal diode laser. Parameters were adjusted such that kills were antibiotic resistance strains. Furthermore, repeated sub-lethal exposure does not induce resistance to subsequent PDT treatments. The absence of resistance formation represents a significant advantage of PDT over traditional antibiotics.

Evolutionary Origin of Antibiotic Resistance, A Historical Perspective

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Yamile Adriana Celis Bustos

2017-07-01

Full Text Available Antimicrobial resistance is a natural aspect of bacterial evolution that can result from mutations or acquisition of foreign genes. Various views on the origin of this resistance explain the ability of these organisms to acquire new features. Lamarck andDarwin’s theories of evolution have led to experiments designed to explore the origin of bacterial variation and the emergence of new features. These experiments show that antimicrobial resistance is related to mutations in chromosomal genes and/or transfer of extrachromosomal genetic elements that can be expressed based on the antibiotic pressure exerted. The main experiments and findings that seek to explain the phenomenon of antibiotic resistance are reviewed here in.

Dioxin exerts anti-estrogenic actions in a novel dioxin-responsive telomerase-immortalized epithelial cell line of the porcine oviduct (TERT-OPEC).

Science.gov (United States)

Hombach-Klonisch, Sabine; Pocar, Paola; Kauffold, Johannes; Klonisch, Thomas

2006-04-01

Oviduct epithelial cells are important for the nourishment and survival of ovulated oocytes and early embryos, and they respond to the steroid hormones estrogen and progesterone. Endocrine-disrupting polyhalogenated aromatic hydrocarbons (PHAH) are environmental toxins that act in part through the ligand-activated transcription factor arylhydrocarbon receptor (AhR; dioxin receptor), and exposure to PHAH has been shown to decrease fertility. To investigate effects of PHAHs on the oviduct epithelium as a potential target tissue of dioxin-type endocrine disruptors, we have established a novel telomerase-immortalized oviduct porcine epithelial cell line (TERT-OPEC). TERT-OPEC exhibited active telomerase and the immunoreactive epithelial marker cytokeratin but lacked the stromal marker vimentin. TERT-OPEC contained functional estrogen receptor (ER)-alpha and AhR, as determined by the detection of ER-alpha- and AhR-specific target molecules. Treatment of TERT-OPEC with the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a significant increase in the production of the cytochrome P-450 microsomal enzyme CYP1A1. Activated AhR caused a downregulation of ER nuclear protein fraction and significantly decreased ER-signaling in TERT-OPEC as determined by ERE-luciferase transient transfection assays. In summary, the TCDD-induced and AhR-mediated anti-estrogenic responses by TERT-OPEC suggest that PHAH affect the predominantly estrogen-dependent differentiation of the oviduct epithelium within the fallopian tube. This action then alters the local endocrine milieu, potentially resulting in a largely unexplored cause of impaired embryonic development and female infertility.

[Community-acquired bacteremia in adult patients attending the emergency service of a teaching hospital].

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Artico, Muriel J; Rocchi, Marta; Gasparotto, Ana; Ocaña Carrizo, Valeria; Navarro, Mercedes; Mollo, Valeria; Avilés, Natalia; Romero, Vanessa; Carrillo, Sonia; Monterisi, Aída

2012-01-01

Bacteremia is an important cause of morbimortality. This study describes the episodes of community-acquired bacteremia in adult patients registered at our hospital. Between January 2005, and December 2009, 271 episodes were studied. The diagnostic yield of blood cultures was 13.5 %. A total of 52 % of patients were male and 48 % female. The mean age was 60. The most frequent comorbidities were: diabetes (21 %), neoplasia (18 %), cardiopathy (11 %), and HIV infection (8 %). The focus was- respiratory (21 %), urinary (15 %), cutaneous (9 %), and others (13 %). Gram-positive bacteria prevailed (51.4%). The most frequent microorganisms were Escherichia coli (25 %), Streptococcus pneumoniae (22.9 %), and Staphylococcus aureus (12.3 %). Bacteremia was polymicrobial in 7 % of the cases. Thirty three percent of E. coli isolates were resistant to ciprofloxacin and 6 % to ceftazidime. Fourteen percent of S. aureus strains were resistant to oxacillin whereas only 7 % of S. pneumoniae expressed high resistance to penicillin with MICs = 2 ug/ml, according to meningitis breakpoints.

Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

Directory of Open Access Journals (Sweden)

Valentina Pirazzoli

2014-05-01

Full Text Available Patients with EGFR-mutant lung adenocarcinomas (LUADs who initially respond to first-generation tyrosine kinase inhibitors (TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

A model of antibiotic-resistant bacterial epidemics in hospitals

OpenAIRE

Webb, Glenn F.; D'Agata, Erika M. C.; Magal, Pierre; Ruan, Shigui

2005-01-01

The emergence of drug-resistant strains of bacteria is an increasing threat to society, especially in hospital settings. Many antibiotics that were formerly effective in combating bacterial infections in hospital patients are no longer effective because of the evolution of resistant strains, which compromises medical care worldwide. In this article, we formulate a two-level population model to quantify key elements in nosocomial (hospital-acquired) infections. At the bacteria level, patients ...

Quinolone resistance: much more than predicted

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Alvaro eHernandez

2011-02-01

Full Text Available Since quinolones are synthetic antibiotics, it was predicted that mutations in target genes would be the only mechanism through which resistance could be acquired, because there will not be quinolone resistance genes in nature. Contrary to this prediction, a variety of elements ranging from efflux pumps, target-protecting proteins and even quinolone-modifying enzymes have been shown to contribute to quinolone resistance. The finding of some of these elements in plasmids indicates that quinolone resistance can be transferable. As a result, there has been a developing interest on the reservoirs for quinolone resistance genes and on the potential risks associated with the use of these antibiotics in non-clinical environments. As a matter of fact, plasmid-encoded, quinolone-resistance qnr genes originated in the chromosome of aquatic bacteria, thus the use of quinolones in fish farming might constitute a risk for the emergence of resistance. Failure to predict the development of quinolone resistance reinforces the need of taking into consideration the wide plasticity of biological systems for future predictions. This plasticity allows pathogens to deal with toxic compounds, including those with a synthetic origin as quinolones.

Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer

International Nuclear Information System (INIS)

Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

2016-01-01

The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns. The online version of this article (doi:10.1186/s12885-016-2452-5) contains supplementary material, which is available to authorized users

Antimicrobial Resistance of Hypervirulent Klebsiella pneumoniae: Epidemiology, Hypervirulence-Associated Determinants, and Resistance Mechanisms

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Chang-Ro Lee

2017-11-01

Full Text Available Klebsiella pneumoniae is one of the most clinically relevant species in immunocompromised individuals responsible for community-acquired and nosocomial infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Since the mid-1980s, hypervirulent K. pneumoniae, generally associated with the hypermucoviscosity phenotype, has emerged as a clinically significant pathogen responsible for serious disseminated infections, such as pyogenic liver abscesses, osteomyelitis, and endophthalmitis, in a generally younger and healthier population. Hypervirulent K. pneumoniae infections were primarily found in East Asia and now are increasingly being reported worldwide. Although most hypervirulent K. pneumoniae isolates are antibiotic-susceptible, some isolates with combined virulence and resistance, such as the carbapenem-resistant hypervirulent K. pneumoniae isolates, are increasingly being detected. The combination of multidrug resistance and enhanced virulence has the potential to cause the next clinical crisis. To better understand the basic biology of hypervirulent K. pneumoniae, this review will provide a summarization and discussion focused on epidemiology, hypervirulence-associated factors, and antibiotic resistance mechanisms of such hypervirulent strains. Epidemiological analysis of recent clinical isolates in China warns the global dissemination of hypervirulent K. pneumoniae strains with extensive antibiotic resistance in the near future. Therefore, an immediate response to recognize the global dissemination of this hypervirulent strain with resistance determinants is an urgent priority.

Antibiotic resistance increases with local temperature

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MacFadden, Derek R.; McGough, Sarah F.; Fisman, David; Santillana, Mauricio; Brownstein, John S.

2018-06-01

Bacteria that cause infections in humans can develop or acquire resistance to antibiotics commonly used against them1,2. Antimicrobial resistance (in bacteria and other microbes) causes significant morbidity worldwide, and some estimates indicate the attributable mortality could reach up to 10 million by 20502-4. Antibiotic resistance in bacteria is believed to develop largely under the selective pressure of antibiotic use; however, other factors may contribute to population level increases in antibiotic resistance1,2. We explored the role of climate (temperature) and additional factors on the distribution of antibiotic resistance across the United States, and here we show that increasing local temperature as well as population density are associated with increasing antibiotic resistance (percent resistant) in common pathogens. We found that an increase in temperature of 10 °C across regions was associated with an increases in antibiotic resistance of 4.2%, 2.2%, and 2.7% for the common pathogens Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. The associations between temperature and antibiotic resistance in this ecological study are consistent across most classes of antibiotics and pathogens and may be strengthening over time. These findings suggest that current forecasts of the burden of antibiotic resistance could be significant underestimates in the face of a growing population and climate change4.

Bacterial cheating limits antibiotic resistance

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Xiao Chao, Hui; Yurtsev, Eugene; Datta, Manoshi; Artemova, Tanya; Gore, Jeff

2012-02-01

The widespread use of antibiotics has led to the evolution of resistance in bacteria. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removing the antibiotic. The cooperative nature of this growth suggests that a cheater strain---which does not contribute to breaking down the antibiotic---may be able to take advantage of cells cooperatively inactivating the antibiotic. Here we find experimentally that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We observe stable coexistence between the two strains and find that a simple model successfully explains the behavior as a function of antibiotic concentration and cell density. We anticipate that our results will provide insight into the evolutionary origin of phenotypic diversity and cooperative behaviors.

The end of the line? A case of drug resistance to third-line ...

African Journals Online (AJOL)

Here, we describe the first reported case of acquired resistance to the integrase strand transfer inhibitors in South Africa. This case illustrates the dilemma of treatment in the context of inadequate adherence and poor psychosocial support and highlights the potential risk of transmission of multidrug-resistant virus.

Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis.

Science.gov (United States)

Tacconelli, Evelina; Carrara, Elena; Savoldi, Alessia; Harbarth, Stephan; Mendelson, Marc; Monnet, Dominique L; Pulcini, Céline; Kahlmeter, Gunnar; Kluytmans, Jan; Carmeli, Yehuda; Ouellette, Marc; Outterson, Kevin; Patel, Jean; Cavaleri, Marco; Cox, Edward M; Houchens, Chris R; Grayson, M Lindsay; Hansen, Paul; Singh, Nalini; Theuretzbacher, Ursula; Magrini, Nicola

2018-03-01

The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier. Future development strategies should focus on

New insights into Vinca alkaloids resistance mechanism and circumvention in lung cancer.

Science.gov (United States)

Zhang, Ying; Yang, Shao-Hui; Guo, Xiu-Li

2017-12-01

Nowadays, lung cancer, as a health problem in worldwide, has high mortality both in men and women. Despite advances in diagnosis and surgical techniques of lung cancer in recent decades, chemotherapy is still a fundamentally and extensively useful strategy. Vinca alkaloids are a class of important and widely used drugs in the treatment of lung cancer, targeting on the Vinca binding site at the exterior of microtubule plus ends. Either intrinsic or acquired resistance to chemotherapy of Vinca alkaloids has been a major obstacle to the treatment of lung cancer, which arose great interests in studies of understanding and overcoming resistance. In this review, we focused on the application and resistance mechanisms of the Vinca alkaloids such as vinblastine, vincristine, vinorelbine and vinflunine in lung cancer. We reviewed characteristic resistance mechanisms in lung cancer including over-expression of ATP-binding cassette (ABC) transporters P-glycoprotein and structural, functional or expression alterations of β-tubulin (βII, βIII, βIV) which may devote to the development of acquired resistance to the Vinca alkaloids; multidrug-resistance proteins (MRP1, MRP2, MRP3) and RLIP76 protein have also been identified that probably play a significant role in intrinsic resistance. Lung resistance-related protein (LRP) is contributed to lung cancer therapy resistance, but is not deal with the Vinca alkaloids resistance in lung cancer. Understanding the principle of the Vinca alkaloids in clinical application and mechanisms of drug resistance will support individualized lung cancer therapy and improve future therapies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

"Population structure of drug-susceptible, -resistant and ESBL-producing Escherichia coli from community-acquired urinary tract infections"

DEFF Research Database (Denmark)

Hertz, Frederik Boetius; Nielsen, Jesper Boye; Schønning, Kristian

2016-01-01

BACKGROUND: Escherichia coli is the most common cause of urinary tract infection (UTI). The pathogenic isolates are becoming increasingly resistant to antibiotics; with a worldwide dissemination of resistant sequence types (ST). We characterized three different uropathogenic E. coli populations...

A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer. | Office of Cancer Genomics

Science.gov (United States)

Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide.

Computed tomography findings of community-acquired Stenotrophomonas Maltophilia pneumonia in an immunocompetent patient: A case report

Energy Technology Data Exchange (ETDEWEB)

Cha, Yoon Ki; Kim, Jeung Sook; Park, Seong Yeon; Oh, Jin Young; Kwon, Jae Hyun [Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang (Korea, Republic of)

2016-11-15

Stenotrophomonas maltophilia (S. maltophilia) is a rare, but globally emerging gram-negative multiple-drug-resistant organism usually found in a nosocomial setting in immunocompromised patients. To our best knowledge, computed tomography (CT) features of community-acquired S. maltophilia pneumonia have not been previously reported in an immunocompetent patient. Herein, we presented the CT findings of a previous healthy 56-year-old male with S. maltophilia pneumonia.

VAV3 mediates resistance to breast cancer endocrine therapy

NARCIS (Netherlands)

H. Aguilar (Helena); A. Urruticoechea (Ander); P. Halonen (Pasi); K. Kiyotani (Kazuma); T. Mushiroda (Taisei); X. Barril (Xavier); J. Serra-Musach (Jordi); A.B.M.M.K. Islam (Abul); L. Caizzi (Livia); L. Di Croce (Luciano); E. Nevedomskaya (Ekaterina); W. Zwart (Wilbert); J. Bostner (Josefine); E. Karlsson (Elin); G. Pérez Tenorio (Gizeh); T. Fornander (Tommy); D.C. Sgroi (Dennis); R. Garcia-Mata (Rafael); M.P.H.M. Jansen (Maurice); N. García (Nadia); N. Bonifaci (Núria); F. Climent (Fina); E. Soler (Eric); A. Rodríguez-Vida (Alejo); M. Gil (Miguel); J. Brunet (Joan); G. Martrat (Griselda); L. Gómez-Baldó (Laia); A.I. Extremera (Ana); J. Figueras; J. Balart (Josep); R. Clarke (Robert); K.L. Burnstein (Kerry); K.E. Carlson (Kathryn); J.A. Katzenellenbogen (John); M. Vizoso (Miguel); M. Esteller (Manel); A. Villanueva (Alberto); A.B. Rodríguez-Peña (Ana); X.R. Bustelo (Xosé); Y. Nakamura (Yusuke); H. Zembutsu (Hitoshi); O. Stål (Olle); R.L. Beijersbergen (Roderick); M.A. Pujana (Miguel)

2014-01-01

textabstractIntroduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through

Imaging voids beneath bridge bent using electrical resistivity tomography.

Science.gov (United States)

2014-02-01

Five electrical resistivity tomography (ERT) profiles and borehole control were acquired beneath two bridges on the bank of the : Gasconade River in order to determine extension of the underground water-filled openings in rock encountered during a dr...

SENSITIVITY TO ANTIBACTERIAL DRUGS IN AGENTS OF COMMUNITY-ACQUIRED INFECTIONS

Directory of Open Access Journals (Sweden)

Osolodchenko T.,

2015-04-01

Full Text Available Introduction The widespread and uncontrolled use of antibiotics leads to selection of resistant strains and rise to atypical forms of most infectious agents. Constantly progressive resistance of microorganisms is currently the most important negative phenomenon of antibiotic therapy. The aim of the work was to optimize antibiotic therapy in community-acquired infections. The objective of study was to determine the range and degree of resistance in clinical isolates of microorganisms of different taxonomic groups, obtained from patients in outpatient care. Material and methods 213 clinical isolates of microorganisms obtained from patients in outpatient care were studied: 34,7 % strains were obtained from patients with inflammatory processes in upper respiratory tract, 11,7 % – with ear inflammation, 36,6 % – with inflammatory diseases of urinary and genital tracts, 11,3 % – with of skin and soft tissues inflammation, 4,2 % – eye inflammation and 1,4 % – with postoperative infectious complications. The collection of clinical material was performed accordingly before the start of antibacterial therapy. Microorganisms’ isolation and identification were carried out with the help of microbiological methods according to the regulatory documents. The study of resistance of bacterial strains to the antibacterial drugs was performed with the help of disc diffusion method on the Muller-Hinton nutritional medium and of fungal strains – on Saburo medium with the use of standard commercial discs. Results and discussion The array and level of resistance to antibacterial drugs in clinical isolates of microorganisms of different taxonomic groups obtained from patients in outpatient care was established. The research has established that 43,3 % Staphylococcus spp. isolates possessed polyantibiotic resistance and 3,8 % – extensive resistance, only sensitivity to aminoglycosides and glycopeptides was preserved. The majority of beta

Low Prevalence of Carbapenem-Resistant Bacteria in River Water: Resistance Is Mostly Related to Intrinsic Mechanisms.

Science.gov (United States)

Tacão, Marta; Correia, António; Henriques, Isabel S

2015-10-01

Carbapenems are last-resort antibiotics to handle serious infections caused by multiresistant bacteria. The incidence of resistance to these antibiotics has been increasing and new resistance mechanisms have emerged. The dissemination of carbapenem resistance in the environment has been overlooked. The main goal of this research was to assess the prevalence and diversity of carbapenem-resistant bacteria in riverine ecosystems. The presence of frequently reported carbapenemase-encoding genes was inspected. The proportion of imipenem-resistant bacteria was on average 2.24 CFU/ml. Imipenem-resistant strains (n=110) were identified as Pseudomonas spp., Stenotrophomonas maltophilia, Aeromonas spp., Chromobacterium haemolyticum, Shewanella xiamenensis, and members of Enterobacteriaceae. Carbapenem-resistant bacteria were highly resistant to other beta-lactams such as quinolones, aminoglycosides, chloramphenicol, tetracyclines, and sulfamethoxazole/trimethoprim. Carbapenem resistance was mostly associated with intrinsically resistant bacteria. As intrinsic resistance mechanisms, we have identified the blaCphA gene in 77.3% of Aeromonas spp., blaL1 in all S. maltophilia, and blaOXA-48-like in all S. xiamenensis. As acquired resistance mechanisms, we have detected the blaVIM-2 gene in six Pseudomonas spp. (5.45%). Integrons with gene cassettes encoding resistance to aminoglycosides (aacA and aacC genes), trimethoprim (dfrB1b), and carbapenems (blaVIM-2) were found in Pseudomonas spp. Results suggest that carbapenem resistance dissemination in riverine ecosystems is still at an early stage. Nevertheless, monitoring these aquatic compartments for the presence of resistance genes and its host organisms is essential to outline strategies to minimize resistance dissemination.

Guideline recommendations and antimicrobial resistance: the need for a change.

Science.gov (United States)

Elias, Christelle; Moja, Lorenzo; Mertz, Dominik; Loeb, Mark; Forte, Gilles; Magrini, Nicola

2017-07-26

Antimicrobial resistance has become a global burden for which inappropriate antimicrobial use is an important contributing factor. Any decisions on the selection of antibiotics use should consider their effects on antimicrobial resistance. The objective of this study was to assess the extent to which antibiotic prescribing guidelines have considered resistance patterns when making recommendations for five highly prevalent infectious syndromes. We used Medline searches complemented with extensive use of Web engine to identify guidelines on empirical treatment of community-acquired pneumonia, urinary tract infections, acute otitis media, rhinosinusitis and pharyngitis. We collected data on microbiology and resistance patterns and identified discrete pattern categories. We assessed the extent to which recommendations considered resistance, in addition to efficacy and safety, when recommending antibiotics. We identified 135 guidelines, which reported a total of 251 recommendations. Most (103/135, 79%) were from developed countries. Community-acquired pneumonia was the syndrome mostly represented (51, 39%). In only 16 (6.4%) recommendations, selection of empirical antibiotic was discussed in relation to resistance and specific microbiological data. In a further 69 (27.5%) recommendations, references were made in relation to resistance, but the attempt was inconsistent. Across syndromes, 12 patterns of resistance with implications on recommendations were observed. 50% to 75% of recommendations did not attempt to set recommendation in the context of these patterns. There is consistent evidence that guidelines on empirical antibiotic use did not routinely consider resistance in their recommendations. Decision-makers should analyse and report the extent of local resistance patterns to allow better decision-making. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless

Antibacterial Activity of Electrochemically Synthesized Colloidal Silver Nanoparticles Against Hospital-Acquired Infections

Science.gov (United States)

Thuc, Dao Tri; Huy, Tran Quang; Hoang, Luc Huy; Hoang, Tran Huy; Le, Anh-Tuan; Anh, Dang Duc

2017-06-01

This study evaluated the antibacterial activity of electrochemically synthesized colloidal silver nanoparticles (AgNPs) against hospital-acquired infections. Colloidal AgNPs were synthesized via a single process using bulk silver bars, bi-distilled water, trisodium citrate, and direct current voltage at room temperature. Colloidal AgNPs were characterized by transmission electron microscopy, field-emission scanning electron microscopy, and energy-dispersive x-ray analyses. The antibacterial activity of colloidal AgNPs against four bacterial strains isolated from clinical samples, including methicillin-resistant Staphylococcus aureus, Escherichia coli O157:H7, multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Klebsiella pneumonia, was evaluated by disc diffusion, minimum inhibitory concentration (MIC), and ultrathin sectioning electron microscopy. The results showed that the prepared AgNPs were 19.7 ± 4.3 nm in size, quasi-spherical, and of high purity. Zones of inhibition approximately 6-10 mm in diameter were found, corresponding to AgNPs concentrations of 50 μg/mL to 100 μg/mL. The MIC results revealed that the antibacterial activity of the prepared AgNPs was strongly dependent on the concentration and strain of the tested bacteria.

mtct regimen choice, drug resistance and the treatment of hiv

African Journals Online (AJOL)

risk of transmission is highest during labour and delivery, ... will have a major impact on controlling perinatally acquired HIV infection. ... could result in the development of drug resistance with potential .... dosing, pharmacokinetics and safety.

Threat of multidrug resistant Staphylococcus aureus in Western Nepal

DEFF Research Database (Denmark)

Bhatta, Dharm R.; Cavaco, Lina; Nath, Gopal

2015-01-01

antibiotic susceptibility testing in developing countries like Nepal. Hospital acquired infections including prevalence of MRSA can be minimized by appropriate hygienic measures in patient care and management and by antibiotic stewardship. Screening of erythromycin resistant isolates would minimize clinical...

Efflux-mediated antimicrobial resistance.

Science.gov (United States)

Poole, Keith

2005-07-01

Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious disease. And while true biocide resistance is as yet unrealized, in vitro and in vivo episodes of reduced biocide susceptibility are common and the history of antibiotic resistance should not be ignored in the development and use of biocidal agents. Efflux mechanisms of resistance, both drug specific and multidrug, are important determinants of intrinsic and/or acquired resistance to these antimicrobials, with some accommodating both antibiotics and biocides. This latter raises the spectre (as yet generally unrealized) of biocide selection of multiple antibiotic-resistant organisms. Multidrug efflux mechanisms are broadly conserved in bacteria, are almost invariably chromosome-encoded and their expression in many instances results from mutations in regulatory genes. In contrast, drug-specific efflux mechanisms are generally encoded by plasmids and/or other mobile genetic elements (transposons, integrons) that carry additional resistance genes, and so their ready acquisition is compounded by their association with multidrug resistance. While there is some support for the latter efflux systems arising from efflux determinants of self-protection in antibiotic-producing Streptomyces spp. and, thus, intended as drug exporters, increasingly, chromosomal multidrug efflux determinants, at least in Gram-negative bacteria, appear not to be intended as drug exporters but as exporters with, perhaps, a variety of other roles in bacterial cells. Still, given the clinical significance of multidrug (and drug-specific) exporters, efflux must be considered in formulating strategies/approaches to treating drug-resistant infections, both in the development of new agents, for example, less impacted by efflux and in targeting efflux directly with efflux inhibitors.

Metformin-letrozole in comparison with Metformin-clomiphene citrate in clomiphene-resistance PCOS patients undergoing IUI

Directory of Open Access Journals (Sweden)

Mohammad Hossein Fallahzadeh

2011-01-01

Full Text Available Background: Polycystic ovary syndrome (PCOS is associated with approximately 75% of women who suffer from infertility due to anovulation. Additionally, around 20– 25% of anovulatory women with PCOS do not respond at all to clomiphene citrate and are considered to be “clomiphene– resistant”. Aromatase inhibitors have been suggested as an alternative treatment to clomiphene as the discrepancy between ovulation and pregnancy rates with clomiphene citrate has been attributed to its anti-estrogenic action and estrogen receptor depletion. Objective: The aim of this study is to compare results of Metformin-letrozole with Metformin-clomiphene citrate in clomiphene resistance PCOS patients undergoing IUI.Materials and Methods: In this single blind randomized trial, ovarian cycles were studied in 100 clomiphene- resistant patients with PCOS. The inclusion criteria were patients who received 150mg clomiphene citrate daily for 3 cycles and failed to become pregnant. The patients were matched for their age, body mass index (BMI, and infertility period. They were randomly allocated to a metformin-letrozole group (n=50 and a metformin-clomiphene citrate group (n=50. Chemical and clinical pregnancies were assessed after IUI. Abortion rates were determined in both groups. Results: Regarding pregnancy rate, there was no significant difference between the two groups. One miscarriage (2% occurred in the metformin-clomiphene citrate group, whereas none was seen in the metformin-letrozole group. Conclusion: There is no significant difference in pregnancy rate between clomiphene citrate and letrozole groups although it has been 2% in the former and 5% in the latter.

A retrospective analysis of antimicrobial resistance in bacterial pathogens in an equine hospital (2012-2015).

Science.gov (United States)

van Spijk, J N; Schmitt, S; Fürst, A E; Schoster, A

2016-06-01

Antimicrobial resistance has become an important concern in veterinary medicine. The aim of this study was to describe the rate of antimicrobial resistance in common equine pathogens and to determine the occurrence of multidrug-resistant isolates. A retrospective analysis of all susceptibility testing results from bacterial pathogens cultured from horses at the University of Zurich Equine Hospital (2012-2015) was performed. Strains exhibiting resistance to 3 or more antimicrobial categories were defined as multidrug-resistant. Susceptibility results from 303 bacterial pathogens were analyzed, most commonly Escherichia coli (60/303, 20%) and Staphylococcus aureus (40/303, 13%). High rates of acquired resistance against commonly used antimicrobials were found in most of the frequently isolated equine pathogens. The highest rate of multidrug resistance was found in isolates of Acinetobacter baumannii (23/24, 96%), followed by Enterobacter cloacae complex (24/28, 86%) and Escherichia coli (48/60, 80%). Overall, 60% of Escherichia coli isolates were phenotypically ESBL-producing and 68% of Staphylococcus spp. were phenotypically methicillin-resistant. High rates of acquired antimicrobial resistance towards commonly used antibiotics are concerning and underline the importance of individual bacteriological and antimicrobial susceptibility testing to guide antimicrobial therapy. Minimizing and optimizing antimicrobial therapy in horses is needed.

Meticillin-resistant Staphylococcus aureus (MRSA)

DEFF Research Database (Denmark)

Stefani, Stefania; Chung, Doo Ryeon; Lindsay, Jodi A

2012-01-01

decisions with regard to harmonisation of typing methods. A stratified, three-level organisation of testing laboratories was proposed: local; regional; and national. The functions of, and testing methodology used by, each laboratory were defined. The group consensus was to recommend spa and staphylococcal......This article reviews recent findings on the global epidemiology of healthcare-acquired/associated (HA), community-acquired/associated (CA) and livestock-associated (LA) meticillin-resistant Staphylococcus aureus (MRSA) and aims to reach a consensus regarding the harmonisation of typing methods...... cassette chromosome mec (SCCmec) typing as the preferred methods. Both are informative in defining particular strain characteristics and utilise standardised nomenclatures, making them applicable globally. Effective communication between each of the different levels and between national centres was viewed...

Epidemiological Study of Hospital-Acquired Bacterial Conjunctivitis in a Level III Neonatal Unit

Directory of Open Access Journals (Sweden)

Catarina Dias

2013-01-01

Full Text Available Background. Conjunctivitis is one of the most frequently occurring hospital-acquired infections among neonates, although it is less studied than potentially life-threatening infections, such as sepsis and pneumonia. Objectives. The aims of our work were to identify epidemiologic characteristics, pathogens, and susceptibility patterns of bacterial hospital-acquired conjunctivitis (HAC in a level III neonatal unit. Materials and Methods. Data were collected retrospectively from patient charts and laboratory databases. Hospital-acquired conjunctivitis was defined in accordance with the Centers for Disease Control/National Healthcare Safety Network (CDC/NHSN diagnostic criteria. Results. One or more episodes of HAC were diagnosed in 4,0% ( of 1492 neonates admitted during the study period. Most of the episodes involved premature (75,4% and low birth weight (75,4% neonates. Infection rates were higher among patients undergoing noninvasive mechanical ventilation (46,7%, parenteral nutrition (13,6%, and phototherapy (6,8%. Predominant pathogens included Serratia marcescens (27,9%, Escherichia coli (23%, and Pseudomonas aeruginosa (18%. Susceptibility patterns revealed bacterial resistances to several antibiotic classes. Gentamicin remains the adequate choice for empirical treatment of HAC in our NICU. Conclusion. It is important to know the local patterns of the disease in order to adjust prevention strategies. Our work contributes to the epidemiological characterization of a sometimes overlooked disease.

Identification and functional characterisation of Complement Regulator Acquiring Surface Protein-1 of serum resistant Borrelia garinii OspA serotype 4

Directory of Open Access Journals (Sweden)

Zipfel Peter F

2010-02-01

Full Text Available Abstract Background B. burgdorferi sensu lato (sl is the etiological agent of Lyme borreliosis in humans. Spirochetes have adapted themselves to the human immune system in many distinct ways. One important immune escape mechanism for evading complement activation is the binding of complement regulators Factor H (CFH or Factor H-like protein1 (FHL-1 to Complement Regulator-Acquiring Surface Proteins (CRASPs. Results We demonstrate that B. garinii OspA serotype 4 (ST4 PBi resist complement-mediated killing by binding of FHL-1. To identify the primary ligands of FHL-1 four CspA orthologs from B. garinii ST4 PBi were cloned and tested for binding to human CFH and FHL-1. Orthologs BGA66 and BGA71 were found to be able to bind both complement regulators but with different intensities. In addition, all CspA orthologs were tested for binding to mammalian and avian CFH. Distinct orthologs were able to bind to CFH of different animal origins. Conclusions B. garinii ST4 PBi is able to evade complement killing and it can bind FHL-1 to membrane expressed proteins. Recombinant proteins BGA66 can bind FHL-1 and human CFH, while BGA71 can bind only FHL-1. All recombinant CspA orthologs from B. garinii ST4 PBi can bind CFH from different animal origins. This partly explains the wide variety of animals that can be infected by B. garinii.

AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells

International Nuclear Information System (INIS)

Zhao Wenhui; Zhang Qingyuan; Kang Xinmei; Jin Shi; Lou Changjie

2009-01-01

Acquired resistance to tamoxifen has become a serious obstacle in breast cancer treatment. The underlying mechanism responsible for this condition has not been completely elucidated. In this study, a tamoxifen-resistant (Tam-R) MCF-7 breast cancer cell line was developed to mimic the occurrence of acquired tamoxifen resistance as seen in clinical practice. Increased expression levels of HER1, HER2 and the estrogen receptor (ER)-AIB1 complex were found in tamoxifen-resistant cells. EGF stimulation and gefitinib inhibition experiments further demonstrated that HER1/HER2 signaling and AIB1 were involved in the proliferation of cells that had acquired Tam resistance. However, when AIB1 was silenced with AIB1-siRNA in Tam-R cells, the cell growth stimulated by the HER1/HER2 signaling pathway was significantly reduced, and the cells were again found to be inhibited by tamoxifen. These results suggest that the AIB1 protein could be a limiting factor in the HER1/HER2-mediated hormone-independent growth of Tam-R cells. Thus, AIB1 may be a new therapeutic target, and the removal of AIB1 may decrease the crosstalk between ER and the HER1/HER2 pathway, resulting in the restoration of tamoxifen sensitivity in tamoxifen-resistant cells.

Cellular resistance in radio- and chemotherapy: biological basis and strategies for circumvention

International Nuclear Information System (INIS)

Twentyman, P.R.

1991-01-01

In this review the author points out that resistance to cytotoxic drugs is a complex, multifactorial phenomenon involving a range of mechanisms. There is accumulating evidence that these are of relevance to both inherent and acquired resistance in the clinic. Demonstration that mechanisms of drug and radiation resistance are closely linked provides a basis for the related patterns of responsiveness observed in clinical practice. Strategies for circumvention of resistance mechanisms will depend for success upon finding ways of improving therapeutic ratio. Optimal clinical trial of resistance circumvention strategies will require the use of quantitative markers of resistance mechanisms in tumour and normal tissues. (author)

Antimicrobial-Resistant Enterococci in Animals and Meat: A Human Health Hazard?

DEFF Research Database (Denmark)

Hammerum, A.M.; Lester, C.H.; Heuer, Ole Eske

2010-01-01

clones predominate in certain animal species. This may suggest that antimicrobial-resistant E. faecium from animals could be regarded less hazardous to humans; however, due to their excellent ability to acquire and transfer resistance genes, E. faecium of animal origin may act as donors of antimicrobial...... resistance genes for other more virulent enterococci. For E. faecalis, the situation appears different, as similar clones of, for example, vancomycin-and gentamicin-resistant E. faecalis have been obtained from animals and from human patients. Continuous surveillance of antimicrobial resistance...... of avoparcin, gentamicin, and virginiamycin for growth promotion and therapy in food animals has lead to the emergence of vancomycin-and gentamicin-resistant enterococci and quinupristin/dalfopristin-resistant E. faecium in animals and meat. This implies a potential risk for transfer of resistance genes...

Copper Resistance of the Emerging Pathogen Acinetobacter baumannii

Science.gov (United States)

Williams, Caitlin L.; Neu, Heather M.; Gilbreath, Jeremy J.; Michel, Sarah L. J.; Zurawski, Daniel V.

2016-01-01

ABSTRACT Acinetobacter baumannii is an important emerging pathogen that is capable of causing many types of severe infection, especially in immunocompromised hosts. Since A. baumannii can rapidly acquire antibiotic resistance genes, many infections are on the verge of being untreatable, and novel therapies are desperately needed. To investigate the potential utility of copper-based antibacterial strategies against Acinetobacter infections, we characterized copper resistance in a panel of recent clinical A. baumannii isolates. Exposure to increasing concentrations of copper in liquid culture and on solid surfaces resulted in dose-dependent and strain-dependent effects; levels of copper resistance varied broadly across isolates, possibly resulting from identified genotypic variation among strains. Examination of the growth-phase-dependent effect of copper on A. baumannii revealed that resistance to copper increased dramatically in stationary phase. Moreover, A. baumannii biofilms were more resistant to copper than planktonic cells but were still susceptible to copper toxicity. Exposure of bacteria to subinhibitory concentrations of copper allowed them to better adapt to and grow in high concentrations of copper; this copper tolerance response is likely achieved via increased expression of copper resistance mechanisms. Indeed, genomic analysis revealed numerous putative copper resistance proteins that share amino acid homology to known proteins in Escherichia coli and Pseudomonas aeruginosa. Transcriptional analysis revealed significant upregulation of these putative copper resistance genes following brief copper exposure. Future characterization of copper resistance mechanisms may aid in the search for novel antibiotics against Acinetobacter and other highly antibiotic-resistant pathogens. IMPORTANCE Acinetobacter baumannii causes many types of severe nosocomial infections; unfortunately, some isolates have acquired resistance to almost every available antibiotic

Copper Resistance of the Emerging Pathogen Acinetobacter baumannii.

Science.gov (United States)

Williams, Caitlin L; Neu, Heather M; Gilbreath, Jeremy J; Michel, Sarah L J; Zurawski, Daniel V; Merrell, D Scott

2016-10-15

Acinetobacter baumannii is an important emerging pathogen that is capable of causing many types of severe infection, especially in immunocompromised hosts. Since A. baumannii can rapidly acquire antibiotic resistance genes, many infections are on the verge of being untreatable, and novel therapies are desperately needed. To investigate the potential utility of copper-based antibacterial strategies against Acinetobacter infections, we characterized copper resistance in a panel of recent clinical A. baumannii isolates. Exposure to increasing concentrations of copper in liquid culture and on solid surfaces resulted in dose-dependent and strain-dependent effects; levels of copper resistance varied broadly across isolates, possibly resulting from identified genotypic variation among strains. Examination of the growth-phase-dependent effect of copper on A. baumannii revealed that resistance to copper increased dramatically in stationary phase. Moreover, A. baumannii biofilms were more resistant to copper than planktonic cells but were still susceptible to copper toxicity. Exposure of bacteria to subinhibitory concentrations of copper allowed them to better adapt to and grow in high concentrations of copper; this copper tolerance response is likely achieved via increased expression of copper resistance mechanisms. Indeed, genomic analysis revealed numerous putative copper resistance proteins that share amino acid homology to known proteins in Escherichia coli and Pseudomonas aeruginosa Transcriptional analysis revealed significant upregulation of these putative copper resistance genes following brief copper exposure. Future characterization of copper resistance mechanisms may aid in the search for novel antibiotics against Acinetobacter and other highly antibiotic-resistant pathogens. Acinetobacter baumannii causes many types of severe nosocomial infections; unfortunately, some isolates have acquired resistance to almost every available antibiotic, and treatment options

Mechanism of Nisin, Pediocin 34, and Enterocin FH99 Resistance in Listeria monocytogenes.

Science.gov (United States)

Kaur, Gurpreet; Singh, Tejinder Pal; Malik, Ravinder Kumar; Bhardwaj, Arun

2012-03-01

Nisin-, pediocin 34-, and enterocin FH99-resistant variants of Listeria monocytogenes ATCC 53135 were developed. In an attempt to clarify the possible mechanisms underlying bacteriocin resistance in L. monocytogenes ATCC 53135, sensitivity of the resistant strains of L. monocytogenes ATCC 53135 to nisin, pediocin 34, and enterocin FH99 in the absence and presence of different divalent cations was assessed, and the results showed that the addition of divalent cations significantly reduced the inhibitory activity of nisin, pediocin 34, and enterocin FH99 against resistant variants of L. monocytogenes ATCC 53135. The addition of EDTA, however, restored this activity suggesting that the divalent cations seem to affect the initial electrostatic interaction between the positively charged bacteriocin and the negatively charged phospholipids of the membrane. Nisin-, pediocin 34-, and enterocin-resistant variants of L. monocytogenes ATCC 53135 were more resistant to lysozyme as compared to the wild-type strain both in the presence as well as absence of nisin, pediocin 34, and enterocin FH99. Ultra structural profiles of bacteriocin-sensitive L. monocytogenes and its bacteriocin-resistant counterparts revealed that the cells of wild-type strain of L. monocytogenes were maximally in pairs or short chains, whereas, its nisin-, pediocin 34-, and enterocin FH99-resistant variants tend to form aggregates. Results indicated that without a cell wall, the acquired nisin, pediocin 34, and enterocin FH99 resistance of the variants was lost. Although the bacteriocin-resistant variants appeared to lose their acquired resistance toward nisin, pediocin 34, and enterocin FH99, the protoplasts of the resistant variants appeared to be more resistant to bacteriocins than the protoplasts of their wild-type counterparts.

Drug Resistance to EGFR Inhibitors in Lung Cancer | Office of Cancer Genomics

Science.gov (United States)

The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. The mechanisms causing primary, acquired and persistent drug resistance to TKIs vary.

Community-acquired pneumonia.

Science.gov (United States)

Falguera, M; Ramírez, M F

2015-11-01

This article not only reviews the essential aspects of community-acquired pneumonia for daily clinical practice, but also highlights the controversial issues and provides the newest available information. Community-acquired pneumonia is considered in a broad sense, without excluding certain variants that, in recent years, a number of authors have managed to delineate, such as healthcare-associated pneumonia. The latter form is nothing more than the same disease that affects more frail patients, with a greater number of risk factors, both sharing an overall common approach. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Risk factors and mortality from hospital acquired pneumonia in the Stroke Intensive Care Unit

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Liudmila Carnesoltas Suarez

2013-02-01

Full Text Available Introduction. Stroke is the third leading cause of death. Hospital acquired pneumonia is an ongoing challenge due to the current microbiological spectrum, antimicrobial resistance, high mortality and associated costs. Objetive. To describe risk factors and their relationship to hospital stay and mortality of patients admitted to the Stroke ICU with hospital acquired pneumonia from 2007 to 2009. Methods. Prospective descriptive study. Variables: age, sex, risk factors, time of onset, stay and discharge status. We used chi square (X2 of homogeneity to determine the possible association between variables and the Fisher test probabilities. Results. 61 patients developed hospital acquired pneumonia (34.07%. We found a predominance of 60-80 year-old males. Among the risk factors we found major neurological damage in 21 (34.4%, smoking in 15 (24.5%, heart failure in 11 (18.0%, diabetes mellitus in 6 (9.8%, COPD in 4 (6.5%. Mechanical ventilation was used in 14 (38.4%, endotracheal intubation in 16 (29.2%, prolonged bedridden condition in 11 (18% and nasogastric tube placement in 7 (11.5%. The infection appeared between the third and sixth day in 57.4%; hospital stay was prolonged in 54% and 25 patients died (40.92%. Conclusions. Hospital acquired pneumonia was more common patients with mechanical ventilation, which prolonged stay and increased mortality. The microbiological environment was dominated by Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumanni.

Role of free radicals in an adriamycin-resistant human small cell lung cancer cell line

NARCIS (Netherlands)

Meijer, C.; Mulder, N H; Timmer-Bosscha, H; Zijlstra, J G; de Vries, E G

1987-01-01

In two Adriamycin (Adr) resistant sublines (GLC4-Adr1 and GLC4-Adr2) of a human small cell lung carcinoma cell line, GLC4, cross-resistance for radiation was found. GLC4-Adr1 has an acquired Adr resistance factor of 44 after culturing without Adr for 20 days and GLC4-Adr2, the same subline cultured

Methicilin-resistant Staphylococcus aureus (MRSA) at Jos University ...

African Journals Online (AJOL)

A prospective surveillance of Methicillin resistant staphylococcus aureus (MRSA) was carried out at Jos University Teaching Hospital, Nigeria, over a one year period. This study highlights the continuos importance of MRSA in causing both hospital and to a less extent community acquired infections. Out of the 180 ...

Pan Drug-Resistant Environmental Isolate of Acinetobacter baumannii from Croatia.

Science.gov (United States)

Goic-Barisic, Ivana; Seruga Music, Martina; Kovacic, Ana; Tonkic, Marija; Hrenovic, Jasna

2017-06-01

Acinetobacter baumannii is an emerging nosocomial pathogen with also emerging resistance to different antibiotics. Multidrug and pan drug-resistant clinical isolates were reported worldwide. Here we report the first evidence of pan drug-resistant environmental isolate of A. baumannii. The isolate was recovered from the effluent of secondary treated municipal wastewater of the City of Zagreb, Croatia. The isolate was resistant to penicillins/β-lactamase inhibitors, carbapenems, fluoroquinolones, aminoglycosides, folate pathway inhibitors, and polymyxins, except intermediately susceptible to minocycline and tigecycline. Intrinsic chromosomally located bla OXA-51-like gene and acquired plasmid-located bla OXA-23-like gene were related to clinical isolates. Pan drug-resistant A. baumannii can occur in natural environments outside of the hospital. Secondary treated municipal wastewater represents a potential epidemiological reservoir of pan drug-resistant A. baumannii and carbapenem resistance gene.

Systemic acquired resistance in soybean is regulated by two proteins, Orthologous to Arabidopsis NPR1

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Sandhu Devinder

2009-08-01

Full Text Available Abstract Background Systemic acquired resistance (SAR is induced in non-inoculated leaves following infection with certain pathogenic strains. SAR is effective against many pathogens. Salicylic acid (SA is a signaling molecule of the SAR pathway. The development of SAR is associated with the induction of pathogenesis related (PR genes. Arabidopsis non-expressor of PR1 (NPR1 is a regulatory gene of the SA signal pathway 123. SAR in soybean was first reported following infection with Colletotrichum trancatum that causes anthracnose disease. We investigated if SAR in soybean is regulated by a pathway, similar to the one characterized in Arabidopsis. Results Pathogenesis-related gene GmPR1 is induced following treatment of soybean plants with the SAR inducer, 2,6-dichloroisonicotinic acid (INA or infection with the oomycete pathogen, Phytophthora sojae. In P. sojae-infected plants, SAR was induced against the bacterial pathogen, Pseudomonas syringae pv. glycinea. Soybean GmNPR1-1 and GmNPR1-2 genes showed high identities to Arabidopsis NPR1. They showed similar expression patterns among the organs, studied in this investigation. GmNPR1-1 and GmNPR1-2 are the only soybean homologues of NPR1and are located in homoeologous regions. In GmNPR1-1 and GmNPR1-2 transformed Arabidopsis npr1-1 mutant plants, SAR markers: (i PR-1 was induced following INA treatment and (ii BGL2 following infection with Pseudomonas syringae pv. tomato (Pst, and SAR was induced following Pst infection. Of the five cysteine residues, Cys82, Cys150, Cys155, Cys160, and Cys216 involved in oligomer-monomer transition in NPR1, Cys216 in GmNPR1-1 and GmNPR1-2 proteins was substituted to Ser and Leu, respectively. Conclusion Complementation analyses in Arabidopsis npr1-1 mutants revealed that homoeologous GmNPR1-1 and GmNPR1-2 genes are orthologous to Arabidopsis NPR1. Therefore, SAR pathway in soybean is most likely regulated by GmNPR1 genes. Substitution of Cys216 residue, essential

Systemic acquired resistance in soybean is regulated by two proteins, Orthologous to Arabidopsis NPR1.

Science.gov (United States)

Sandhu, Devinder; Tasma, I Made; Frasch, Ryan; Bhattacharyya, Madan K

2009-08-05

Systemic acquired resistance (SAR) is induced in non-inoculated leaves following infection with certain pathogenic strains. SAR is effective against many pathogens. Salicylic acid (SA) is a signaling molecule of the SAR pathway. The development of SAR is associated with the induction of pathogenesis related (PR) genes. Arabidopsis non-expressor of PR1 (NPR1) is a regulatory gene of the SA signal pathway 123. SAR in soybean was first reported following infection with Colletotrichum trancatum that causes anthracnose disease. We investigated if SAR in soybean is regulated by a pathway, similar to the one characterized in Arabidopsis. Pathogenesis-related gene GmPR1 is induced following treatment of soybean plants with the SAR inducer, 2,6-dichloroisonicotinic acid (INA) or infection with the oomycete pathogen, Phytophthora sojae. In P. sojae-infected plants, SAR was induced against the bacterial pathogen, Pseudomonas syringae pv. glycinea. Soybean GmNPR1-1 and GmNPR1-2 genes showed high identities to Arabidopsis NPR1. They showed similar expression patterns among the organs, studied in this investigation. GmNPR1-1 and GmNPR1-2 are the only soybean homologues of NPR1and are located in homoeologous regions. In GmNPR1-1 and GmNPR1-2 transformed Arabidopsis npr1-1 mutant plants, SAR markers: (i) PR-1 was induced following INA treatment and (ii) BGL2 following infection with Pseudomonas syringae pv. tomato (Pst), and SAR was induced following Pst infection. Of the five cysteine residues, Cys82, Cys150, Cys155, Cys160, and Cys216 involved in oligomer-monomer transition in NPR1, Cys216 in GmNPR1-1 and GmNPR1-2 proteins was substituted to Ser and Leu, respectively. Complementation analyses in Arabidopsis npr1-1 mutants revealed that homoeologous GmNPR1-1 and GmNPR1-2 genes are orthologous to Arabidopsis NPR1. Therefore, SAR pathway in soybean is most likely regulated by GmNPR1 genes. Substitution of Cys216 residue, essential for oligomer-monomer transition of Arabidopsis NPR1

Bacterial Cheating Limits the Evolution of Antibiotic Resistance

Science.gov (United States)

Yurtsev, Eugene; Xiao Chao, Hui; Datta, Manoshi; Artemova, Tatiana; Gore, Jeff

2012-02-01

The emergence of antibiotic resistance in bacteria is a significant health concern. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removal of the antibiotic. The presence of a cooperative mechanism of resistance suggests that a cheater strain - which does not contribute to breaking down the antibiotic - may be able to take advantage of resistant cells. We find experimentally that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We use a simple model in conjunction with difference equations to explain the observed population dynamics as a function of cell density and antibiotic concentration. Our experimental difference equations resemble the logistic map, raising the possibility of oscillations or even chaotic dynamics.

Induction of mutations for nematode resistance in tomato

International Nuclear Information System (INIS)

Alameddine, A.

1976-01-01

The objective of this work is to develop resistance to root-knot nematodes in tomato by induction, selection and utilization of the newly created resistant strains. Seeds of two varieties of tomato Lycopersicon esculentum L., namely Amcopack and Supermarmande, were subjected to various doses of gamma rays ranging from 10 Krads to 40 Krads in an effort to gain resistance to Meloidogyne incognita Chitwood, the prevalent species of nematodes in Lebanon. The variety Supermarmande seemed not to be affected by irradiation while Amcopack gained some resistance with a corresponding increase in the dose of radiation. The data suggest that in a variety like Amcopack, irradiation may stimulate resistance while in others like Supermarmande, susceptibility is not reduced with a corresponding increase of dosage. Those alterations in reaction within varieties may be due to genetic differences which allow some varieties to acquire resistance to nematodes when exposed to certain dosages, while others to suffer seriously due to sensitivity. (author)

Zinc and copper in animal feed – development of resistance and co-resistance to antimicrobial agents in bacteria of animal origin

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Siamak Yazdankhah

2014-09-01

Full Text Available Farmed animals such as pig and poultry receive additional Zn and Cu in their diets due to supplementing elements in compound feed as well as medical remedies. Enteral bacteria in farmed animals are shown to develop resistance to trace elements such as Zn and Cu. Resistance to Zn is often linked with resistance to methicillin in staphylococci, and Zn supplementation to animal feed may increase the proportion of multiresistant E. coli in the gut. Resistance to Cu in bacteria, in particular enterococci, is often associated with resistance to antimicrobial drugs like macrolides and glycopeptides (e.g. vancomycin. Such resistant bacteria may be transferred from the food-producing animals to humans (farmers, veterinarians, and consumers. Data on dose-response relation for Zn/Cu exposure and resistance are lacking; however, it seems more likely that a resistance-driven effect occurs at high trace element exposure than at more basal exposure levels. There is also lack of data which could demonstrate whether Zn/Cu-resistant bacteria may acquire antibiotic resistance genes/become antibiotics resistant, or if antibiotics-resistant bacteria are more capable to become Zn/Cu resistant than antibiotics-susceptible bacteria. Further research is needed to elucidate the link between Zn/Cu and antibiotic resistance in bacteria.

[Increasing incidence of community-acquired pneumonia caused by atypical microorganisms].

Science.gov (United States)

Tazón-Varela, M A; Alonso-Valle, H; Muñoz-Cacho, P; Gallo-Terán, J; Piris-García, X; Pérez-Mier, L A

2017-09-01

Knowing the most common microorganisms in our environment can help us to make proper empirical treatment decisions. The aim is to identify those microorganisms causing community-acquired pneumonia. An observational, descriptive and prospective study was conducted, including patients over 14 years with a clinical and radiographic diagnosis of community-acquired pneumonia during a 383 consecutive day period. A record was made of sociodemographic variables, personal history, prognostic severity scales, progress, and pathogenic agents. The aetiological diagnosis was made using blood cultures, detection of Streptococcus pneumoniae and Legionella pneumophila urinary antigens, sputum culture, influenza virus and Streptococcus pyogenes detection. Categorical variables are presented as absolute values and percentages, and continuous variables as their means and standard deviations. Of the 287 patients included in the study (42% women, mean age 66±22 years), 10.45% died and 70% required hospital admission. An aetiological diagnosis was achieved in 43 patients (14.98%), with 16 microorganisms found in 59 positive samples. The most frequently isolated pathogen was Streptococcus pneumonia (24/59, 41%), followed by gram-negative enteric bacilli, Klebsiella pneumonia, Escherichia coli, Serratia marcescens and Enterobacter cloacae isolated in 20% of the samples (12/59), influenza virus (5/59, 9%), methicillin-resistant Staphylococcus aureus (3/59, 5%), Pseudomonas aeruginosa (2/59, 3%), Moraxella catarrhalis (2/59, 3%), Legionella pneumophila (2/59, 3%), and Haemophilus influenza (2/59, 3%). Polymicrobial infections accounted for 14% (8/59). A high percentage of atypical microorganisms causing community-acquired pneumonia were found. Copyright © 2016 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

Testing the "toxin hypothesis of allergy": Mast cells, IgE, and innate and acquired immune responses to venoms*

Science.gov (United States)

Tsai, Mindy; Starkl, Philipp; Marichal, Thomas; Galli, Stephen J.

2015-01-01

Summary Work in mice indicates that innate functions of mast cells, particularly degradation of venom toxins by mast cell-derived proteases, can enhance resistance to certain arthropod or reptile venoms. Recent reports indicate that acquired Th2 immune responses associated with the production of IgE antibodies, induced by Russell’s viper venom or honeybee venom, or by a component of honeybee venom, bee venom phospholipase 2 (bvPLA2), can increase the resistance of mice to challenge with potentially lethal doses of either of the venoms or bvPLA2. These findings support the conclusion that, in contrast to the detrimental effects associated with allergic Th2 immune responses, mast cells and IgE-dependent immune responses to venoms can contribute to innate and adaptive resistance to venom-induced pathology and mortality. PMID:26210895

Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test

NARCIS (Netherlands)

Curvers, J; Thomassen, MCLGD; Rimmer, J; Hamulyak, K; van der Meer, J; Tans, G; Preston, FE; Rosing, J

Background. Several hereditary and acquired risk factors for venous thromboembolism (VTE) are associated with impaired down-regulation of thrombin formation via the protein C pathway. To identify individuals at risk, functional tests are needed that estimate the risk to develop venous thrombosis.

Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity.

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Kirsi H Pietiläinen

2008-03-01

Full Text Available The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.We used a special study design of "clonal controls," rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white, with a mean +/- standard deviation (SD age 25.8 +/- 1.4 y and a body mass index (BMI difference 5.2 +/- 1.8 kg/m(2. Sequence analyses of mitochondrial DNA (mtDNA in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA catabolism (p < 0.0001. In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025. Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

DEFF Research Database (Denmark)

Vestergaard, Martin; Leng, Bingfeng; Haaber, Jakob

2016-01-01

The emergence of antimicrobial resistance severely threatens our ability to treat bacterial infections. While acquired resistance has received considerable attention, relatively little is known of intrinsic resistance that allows bacteria to naturally withstand antimicrobials. Gene products...... that confer intrinsic resistance to antimicrobial agents may be explored for alternative antimicrobial therapies, by potentiating the efficacy of existing antimicrobials. In this study, we identified the intrinsic resistome to a broad spectrum of antimicrobials in the human pathogen, Staphylococcus aureus. We...... with the atpA mutant compared to wild type cells with gentamicin at a clinically relevant concentration. Our results demonstrate that many gene products contribute to the intrinsic antimicrobial resistance of S. aureus. Knowledge of these intrinsic resistance determinants provides alternative targets...

Effect of bactericidal activity of three disinfectants on methicillin-resistant Staphylococcus aureus (MRSA

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Cesar Augusto Marchionatti Avancini

2017-05-01

Full Text Available Background and Objectives: Methicillin-resistant Staphylococcus aureus (MRSA can cause hospital-acquired infections (HA-MRSA, community- acquired ones (CA-MRSA, and infections transmitted by pets and animals raised for food production (livestock-acquired or LA-MRSA. The conduct to control the transmission of these diseases requires a careful action against the causative agents on surfaces in the environment and the choice of disinfectants and antiseptics is crucial. The objective of the present study was to evaluate the effect of the bactericidal activity of sodium hypochlorite (SH, iodophor (I and a quaternary ammonium compound (QAC, cetyl-trimethyl-ammonium chloride, commonly used in hospital and animal production settings, on 21 MRSA isolates and a control bacterium, and test the hypothesis of cross resistance of antibiotics and disinfectants. Methods: The bactericidal activity of four successive dilutions of the disinfectants was evaluated through the suspension test, using an initial inoculum population density of 107 CFU/mL, after contact times of 5, 15 and 30 minutes. Results: Five minutes of contact of SH 25 ppm, I 12.5 ppm and QAC 125 ppm sufficed to inactivate the reference bacterium S. aureus ATCC 6538 and all MRSA. Conclusions: Once the factors that influence the efficiency of disinfectants are controlled, sodium hypochlorite, iodophor and the quaternary ammonium compound are suitable for controlling MRSA in the sources of infection. No resistance relationship was observed in the methicillin-resistant isolates with these substances.

Individualizing Risk of Multidrug-Resistant Pathogens in Community-Onset Pneumonia

OpenAIRE

Falcone, Marco; Russo, Alessandro; Giannella, Maddalena; Cangemi, Roberto; Scarpellini, Maria Gabriella; Bertazzoni, Giuliano; Alarc?n, Jos? Mart?nez; Taliani, Gloria; Palange, Paolo; Farcomeni, Alessio; Vestri, Annarita; Bouza, Emilio; Violi, Francesco; Venditti, Mario

2015-01-01

Introduction The diffusion of multidrug-resistant (MDR) bacteria has created the need to identify risk factors for acquiring resistant pathogens in patients living in the community. Objective To analyze clinical features of patients with community-onset pneumonia due to MDR pathogens, to evaluate performance of existing scoring tools and to develop a bedside risk score for an early identification of these patients in the Emergency Department. Patients and Methods This was an open, observation...

Risk of resistance related to antibiotic use before admission in patients with community-acquired bacteraemia

DEFF Research Database (Denmark)

Pedersen, Gitte; Schønheyder, Henrik Carl; Steffensen, Flemming Hald

1999-01-01

%), Streptococcus pneumoniae (23%) Staphylococcus aureus (10%). Of the 575 isolates of E. coli, 425 (74%), 432 (75%) and 518 (90%) were susceptible to ampicillin, sulphonamides and trimethoprim, respectively. Previous antibiotic prescriptions were strongly associated with resistance to ampicillin, sulphonamides...... and trimethoprim in E. coli. The association was less pronounced for S. aureus and enteric rods other than E. coli. Antibiotic prescriptions within the last 3 months predicted antibiotic resistance, and this should be taken into account when selecting empirical antibiotic therapy of severe community...... admission and to 37% during the 6 months. The most frequently prescribed antibiotics within 30 days were ampicillin (28%), penicillin G (27%), sulphonamides and/or trimethoprim (16%) and macrolides (14%). The most frequent blood isolates were Escherichia coli (33%), other Enterobacteriaceae 8...

Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

DEFF Research Database (Denmark)

Zub, Kamila Anna; Sousa, Mirta Mittelstedt Leal de; Sarno, Antonio

2015-01-01

of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further...... and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels...

Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

Science.gov (United States)

García-Becerra, Rocío; Santos, Nancy; Díaz, Lorenza; Camacho, Javier

2013-01-01

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. PMID:23344024

Spontaneous bacteriocin resistance in Listeria monocytogenes as a susceptibility screen for identifying different mechanisms of resistance and modes of action by bacteriocins of lactic acid bacteria.

Science.gov (United States)

Macwana, Sunita; Muriana, Peter M

2012-01-01

A practical system was devised for grouping bacteriocins of lactic acid bacteria (LAB) based on mode of action as determined by changes in inhibitory activity to spontaneously-acquired bacteriocin resistance (Bac(R)). Wild type Listeria monocytogenes 39-2 was sensitive to five bacteriocins produced by 3 genera of LAB: pediocin PA-1 and pediocin Bac3 (Pediococcus), lacticin FS97 and lacticin FS56 (Lactococcus), and curvaticin FS47 (Lactobacillus). A spontaneous Bac(R) derivative of L. monocytogenes 39-2 obtained by selective recovery against lacticin FS56 provided complete resistance to the bacteriocin made by Lactococcus lactis FS56. The lacticin FS56-resistant strain of L. monocyotgenes 39-2 was also cross-resistant to curvaticin FS47 and pediocin PA-1, but not to lacticin FS97 or pediocin Bac3. The same pattern of cross-resistance was also observed with Bac(R) isolates obtained with L. monocytogenes Scott A-2. A spontaneous mutation that renders a strain cross-resistant to different bacteriocins indicates that they share a common mechanism of resistance due to similar modes of action of the bacteriocins. Spontaneous resistance was acquired to other bacteriocins (in aggregate) by following the same procedure against which the Bac(R) strain was still sensitive. In subsequent challenge assays, mixtures of bacteriocins of different modes of action provided greater inhibition than mixtures of bacteriocins of the same mode of action (as determined by our screening method). This study identifies a methodical approach to classify bacteriocins into functional groups based on mechanism of resistance (i.e., mode of action) that could be used for identifying the best mixture of bacteriocins for use as biopreservatives. Copyright © 2011 Elsevier B.V. All rights reserved.

Detection of CTX-M-15 beta-lactamases in Enterobacteriaceae causing hospital- and community-acquired urinary tract infections as early as 2004, in Dar es Salaam, Tanzania.

Science.gov (United States)

Manyahi, Joel; Moyo, Sabrina J; Tellevik, Marit Gjerde; Ndugulile, Faustine; Urassa, Willy; Blomberg, Bjørn; Langeland, Nina

2017-04-17

The spread of Extended Spectrum β-lactamases (ESBLs) among Enterobacteriaceae and other Gram-Negative pathogens in the community and hospitals represents a major challenge to combat infections. We conducted a study to assess the prevalence and genetic makeup of ESBL-type resistance in bacterial isolates causing community- and hospital-acquired urinary tract infections. A total of 172 isolates of Enterobacteriaceae were collected in Dar es Salaam, Tanzania, from patients who met criteria of community and hospital-acquired urinary tract infections. We used E-test ESBL strips to test for ESBL-phenotype and PCR and sequencing for detection of ESBL genes. Overall 23.8% (41/172) of all isolates were ESBL-producers. ESBL-producers were more frequently isolated from hospital-acquired infections (32%, 27/84 than from community-acquired infections (16%, 14/88, p Enterobacteriaceae causing both hospital- and community-acquired infections in Tanzania.

Aggressive chemotherapy and the selection of drug resistant pathogens.

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Silvie Huijben

2013-09-01

Full Text Available Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold, without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible.

Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

International Nuclear Information System (INIS)

Brown, Iain; Shalli, Kawan; McDonald, Sarah L; Moir, Susan E; Hutcheon, Andrew W; Heys, Steven D; Schofield, Andrew C

2004-01-01

Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects. We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively. Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively). This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies

Framework of Comprehensive Proliferation Resistance Evaluation Methodology

International Nuclear Information System (INIS)

Kim, Min Su; Jo, Seong Youn; Kim, Min Soo; Kim, Jae San; Lee, Hyun Kyung

2007-01-01

Civilian nuclear programs can be used as a pretext to acquire technologies, materials, equipment for military weapon programs. Consequently, international society has a strong incentive to develop a nuclear system more proliferation resistant to assure that the civilian nuclear energy system is an unattractive and least desirable route for diversion of weapon usable material. The First step developing a more proliferation resistant nuclear energy system is to develop a systematic and standardized evaluation methodology to ensure that any future nuclear energy system satisfies the proliferation resistance goals. Many attempts to develop systematic evaluation methodology have been proposed and many systems for assessing proliferation resistance have been previously studied. However, a comprehensive proliferation resistance evaluation can not be achieved by simply applying one method since complicated proliferation resistance characteristics, including inherent features and extrinsic features, should be completely evaluated. Therefore, it is necessary to develop one incorporated evaluation methodology to make up for weak points of each evaluation method. The objective of this study is to provide a framework of comprehensive proliferation resistance evaluation methodology by incorporating two generally used evaluation methods, attribute and scenario analysis

Why sensitive bacteria are resistant to hospital infection control [version 2; referees: 2 approved

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Esther van Kleef

2017-11-01

Full Text Available Background: Large reductions in the incidence of antibiotic-resistant strains of Staphylococcus aureus and Clostridium difficile have been observed in response to multifaceted hospital-based interventions. Reductions in antibiotic-sensitive strains have been smaller or non-existent. It has been argued that since infection control measures, such as hand hygiene, should affect resistant and sensitive strains equally, observed changes must have largely resulted from other factors, including changes in antibiotic use. We used a mathematical model to test the validity of this reasoning. Methods: We developed a mechanistic model of resistant and sensitive strains in a hospital and its catchment area. We assumed the resistant strain had a competitive advantage in the hospital and the sensitive strain an advantage in the community. We simulated a hospital hand hygiene intervention that directly affected resistant and sensitive strains equally. The annual incidence rate ratio (IRR associated with the intervention was calculated for hospital- and community-acquired infections of both strains. Results: For the resistant strain, there were large reductions in hospital-acquired infections (0.1 ≤ IRR ≤ 0.6 and smaller reductions in community-acquired infections (0.2 ≤ IRR ≤  0.9. These reductions increased in line with increasing importance of nosocomial transmission of the strain. For the sensitive strain, reductions in hospital acquisitions were much smaller (0.6 ≤ IRR ≤ 0.9, while communityacquisitions could increase or decrease (0.9 ≤ IRR ≤ 1.2. The greater the importance of the community environment for the transmission of the sensitive strain, the smaller the reductions. Conclusions: Counter-intuitively, infection control interventions, including hand hygiene, can have strikingly discordant effects on resistant and sensitive strains even though they target them equally, following differences in their adaptation to hospital and

Orthology Analysis and In Vivo Complementation Studies to Elucidate the Role of DIR1 during Systemic Acquired Resistance in Arabidopsis thaliana and Cucumis sativus

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Marisa Isaacs

2016-05-01

Full Text Available AtDIR1 (Defective in Induced Resistance1 is an acidic lipid transfer protein essential for systemic acquired resistance (SAR in Arabidopsis thaliana. Upon SAR induction, DIR1 moves from locally infected to distant uninfected leaves to activate defense priming; however, a molecular function for DIR1 has not been elucidated. Bioinformatic analysis and in silico homology modeling identified putative AtDIR1 orthologs in crop species, revealing conserved protein motifs within and outside of DIR1’s central hydrophobic cavity. In vitro assays to compare the capacity of recombinant AtDIR1 and targeted AtDIR1-variant proteins to bind the lipophilic probe TNS (6,P-toluidinylnaphthalene-2-sulfonate provided evidence that conserved leucine 43 and aspartic acid 39 contribute to the size of the DIR1 hydrophobic cavity and possibly hydrophobic ligand binding. An Arabidopsis–cucumber SAR model was developed to investigate the conservation of DIR1 function in cucumber (Cucumis sativus, and we demonstrated that phloem exudates from SAR-induced cucumber rescued the SAR defect in the Arabidopsis dir1-1 mutant. Additionally, an AtDIR1 antibody detected a protein of the same size as AtDIR1 in SAR-induced cucumber phloem exudates, providing evidence that DIR1 function during SAR is conserved in Arabidopsis and cucumber. In vitro TNS displacement assays demonstrated that recombinant AtDIR1 did not bind the SAR signals azelaic acid (AzA, glycerol-3-phosphate or pipecolic acid. However, recombinant CsDIR1 and CsDIR2 interacted weakly with AzA and pipecolic acid. Bioinformatic and functional analyses using the Arabidopsis–cucumber SAR model provide evidence that DIR1 orthologs exist in tobacco, tomato, cucumber, and soybean, and that DIR1-mediated SAR signaling is conserved in Arabidopsis and cucumber.

[State-of-the-art status on airborne antibiotic resistant bacteria and antibiotic resistance genes].

Science.gov (United States)

Li, J; Yao, M S

2018-04-06

The world is facing more deaths due to increasing antibiotic-resistant bacterial infections and the shortage of new highly effective antibiotics, however the air media as its important transmission route has not been adequately studied. Based on the latest literature acquired in this work, we have discussed the state-of-the-art research progress of the concentration, distribution and spread of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in different environmental air media, and also analyzed some future prevention and control measures. The large use of antibiotics in the medical settings and animal husbandry places has resulted in higher abundances of ARB and ARGs in the relevant and surrounding atmosphere than in urban and general indoor air environments. ARGs can be spread by adhering to airborne particles, and researchers have also found that air media contain more abundant ARGs than other environmental media such as soil, water and sediment. It was suggested in this review that strengthening the monitoring, study on spreading factors and biological toxicity, and also research and development on pathogen accurate diagnosis and new green antibiotic are expected to help effectively monitor, prevent and control of the impacts of airborne resistant bacteria and resistance genes on both human and ecologies.

Mutational profiling of non-small-cell lung cancer patients resistant to first-generation EGFR tyrosine kinase inhibitors using next generation sequencing

Science.gov (United States)

Jin, Ying; Shao, Yang; Shi, Xun; Lou, Guangyuan; Zhang, Yiping; Wu, Xue; Tong, Xiaoling; Yu, Xinmin

2016-01-01

Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is secondary EGFR-T790M mutation. Other mechanisms, such as HER2 and MET amplifications, and PIK3CA mutations, were also reported. However, the mechanisms in the remaining patients are still unknown. In this study, we performed mutational profiling in a cohort of 83 NSCLC patients with TKI-sensitizing EGFR mutations at diagnosis and acquired resistance to three different first-generation EGFR TKIs using targeted next generation sequencing (NGS) of 416 cancer-related genes. In total, we identified 322 genetic alterations with a median of 3 mutations per patient. 61% of patients still exhibit TKI-sensitizing EGFR mutations, and 36% of patients acquired EGFR-T790M. Besides other known resistance mechanisms, we identified TET2 mutations in 12% of patients. Interestingly, we also observed SOX2 amplification in EGFR-T790M negative patients, which are restricted to Icotinib treatment resistance, a drug widely used in Chinese NSCLC patients. Our study uncovered mutational profiles of NSCLC patients with first-generation EGFR TKIs resistance with potential therapeutic implications. PMID:27528220

Resistance Pattern and Detection of Metallo-beta-lactamase Genes ...

African Journals Online (AJOL)

2018-02-23

Feb 23, 2018 ... Background: Acquired metallo-β-lactamases (MBLs) pose serious problem both in terms of ... P. aeruginosa from clinical samples submitted to the Medical Microbiology ... pan-drug-resistant .... Phenotypically confirmed MBL producers were stored ... 103 (51.5%); ear swab 32 (16%); urine 27 (13.5%); and.

Identification and validation of cetuximab resistance associated long noncoding RNA biomarkers in metastatic colorectal cancer.

Science.gov (United States)

Peng, Ke; Liu, Ruiqi; Yu, Yiyi; Liang, Li; Yu, Shan; Xu, Xiaojing; Liu, Tianshu

2018-01-01

Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy. To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2.0 arrays. Then we performed lncRNA expression profiling in a cetuximab treated mCRC cohort from Gene Expression Ominus (GEO). The potential lncRNAs were further validated in acquired cetuximab resistant cell lines and clinical samples of our hospital. The functions and associated pathways of the prognostic lncRNA were predicted by GO and KEGG analyses. 249 lncRNA-specific probe sets (corresponding to 212 lncRNAs) were represented in Affymetrix HG-U133A 2.0 arrays. We found that 9 lncRNAs were differentially expressed between disease control group (DCG) and non-responders, and 5 of these 9 lncRNAs were significantly related with the progression-free survival (PFS) of the patients. Among those 5 lncRNAs, POU5F1P4 was also down-regulated in acquired cetuximab resistant cells, as well as in cetuximab resistant patients. Downregulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. Our findings indicate the potential roles of lncRNAs in cetuximab resistance, and may provide the useful information for discovery of new biomarkers and therapeutic targets. Copyright © 2017 Elsevier Masson SAS. All rights reserved.