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Sample records for regulates drug resistance

  1. Drug Resistance

    Science.gov (United States)

    ... Drug-resistance testing is also recommended for all pregnant women with HIV before starting HIV medicines and also in some pregnant women already taking HIV medicines. Pregnant women will work with their health ...

  2. The Pathway Analysis of Micrornas Regulated Drug-Resistant Responses in HeLa Cells.

    Science.gov (United States)

    Yang, Yubo; Dai, Cuihong; Cai, Zhipeng; Hou, Aiju; Cheng, Dayou; Wu, Guanying; Li, Jing; Cui, Jie; Xu, Dechang

    2016-03-01

    Chemotherapy is the main strategy in the treatment of cancer; however, the development of drug-resistance is the obstacle in long-term treatment of cervical cancer. Cisplatin is one of the most common drugs used in cancer therapy. Recently, accumulating evidence suggests that miRNAs are involved in various bioactivities in oncogenesis. It is not unexpected that miRNAs play a key role in acquiring of drug-resistance in the progression of tumor. In this study, we induced and maintained four levels of cisplatin-resistant HeLa cell lines (HeLa/CR1, HeLa/CR2, HeLa/CR3, and HeLa/CR4). According to the previous studies and existing evidence, we selected five miRNAs (miR-183, miR-182, miR-30a, miR-15b, and miR-16) and their potential target mRNAs as our research targets. The real-time RT-PCR was adopted to detect the relative expression of miRNAs and their mRNAs. The results show that miR-182 and miR-15b were up-regulated in resistant cell lines, while miR-30a was significantly down-regulated. At the same time, their targets are related to drug resistance. Compared to their parent HeLa cell line, the expression of selected miRNAs in resistant cell lines altered. The alteration suggests that HeLa cell drug resistance is associated with distinct miRNAs, which indicates that miRNAs may be one of the therapy targets in the treatment of cervical cancer by sensitizing cell to chemotherapy. We suggested a possible network diagram based on the existing theory and the preliminary results of candidate miRNAs and their targets in HeLa cells during development of drug resistance.

  3. Drug resistance

    NARCIS (Netherlands)

    Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.

    2012-01-01

    Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure

  4. Methylation of WTH3, a possible drug resistant gene, inhibits p53 regulated expression

    International Nuclear Information System (INIS)

    Tian, Kegui; Wang, Yuezeng; Huang, Yu; Sun, Boqiao; Li, Yuxin; Xu, Haopeng

    2008-01-01

    Previous results showed that over-expression of the WTH3 gene in MDR cells reduced MDR1 gene expression and converted their resistance to sensitivity to various anticancer drugs. In addition, the WTH3 gene promoter was hypermethylated in the MCF7/AdrR cell line and primary drug resistant breast cancer epithelial cells. WTH3 was also found to be directly targeted and up regulated by the p53 gene. Furthermore, over expression of the WTH3 gene promoted the apoptotic phenotype in various host cells. To further confirm WTH3's drug resistant related characteristics, we recently employed the small hairpin RNA (shRNA) strategy to knockdown its expression in HEK293 cells. In addition, since the WTH3 promoter's p53-binding site was located in a CpG island that was targeted by methylation, we were interested in testing the possible effect this epigenetic modification had on the p53 transcription factor relative to WTH3 expression. To do so, the in vitro methylation method was utilized to examine the p53 transgene's influence on either the methylated or non-methylated WTH3 promoter. The results generated from the gene knockdown strategy showed that reduction of WTH3 expression increased MDR1 expression and elevated resistance to Doxorubicin as compared to the original control cells. Data produced from the methylation studies demonstrated that DNA methylation adversely affected the positive impact of p53 on WTH3 promoter activity. Taken together, our studies provided further evidence that WTH3 played an important role in MDR development and revealed one of its transcription regulatory mechanisms, DNA methylation, which antagonized p53's positive impact on WTH3 expression

  5. 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...

  6. Sphingolipids: Key Regulators of Apoptosis and Pivotal Players in Cancer Drug Resistance

    Directory of Open Access Journals (Sweden)

    Paola Giussani

    2014-03-01

    Full Text Available Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used by cancer cells to evade apoptosis could be translated in an improvement of therapies. Among many tools acquired by cancer cells to this end, the de-regulated synthesis and metabolism of sphingolipids have been well documented. Sphingolipids are known to play many structural and signalling roles in cells, as they are involved in the control of growth, survival, adhesion, and motility. In particular, in order to increase survival, cancer cells: (a counteract the accumulation of ceramide that is endowed with pro-apoptotic potential and is induced by many drugs; (b increase the synthesis of sphingosine-1-phosphate and glucosylceramide that are pro-survivals signals; (c modify the synthesis and the metabolism of complex glycosphingolipids, particularly increasing the levels of modified species of gangliosides such as 9-O acetylated GD3 (αNeu5Ac(2-8αNeu5Ac(2-3βGal(1-4βGlc(1-1Cer or N-glycolyl GM3 (αNeu5Ac (2-3βGal(1-4βGlc(1-1Cer and de-N-acetyl GM3 (NeuNH(2βGal(1-4βGlc(1-1Cer endowed with anti-apoptotic roles and of globoside Gb3 related to a higher expression of the multidrug resistance gene MDR1. In light of this evidence, the employment of chemical or genetic approaches specifically targeting sphingolipid dysregulations appears a promising tool for the improvement of current chemotherapy efficacy.

  7. Antimicrobial (Drug) Resistance

    Science.gov (United States)

    ... with facebook share with twitter share with linkedin Antimicrobial (Drug) Resistance Go to Information for Researchers ► Credit: ... and infectious diseases. Why Is the Study of Antimicrobial (Drug) Resistance a Priority for NIAID? Over time, ...

  8. HSA-based multi-target combination therapy: regulating drugs' release from HSA and overcoming single drug resistance in a breast cancer model.

    Science.gov (United States)

    Gou, Yi; Zhang, Zhenlei; Li, Dongyang; Zhao, Lei; Cai, Meiling; Sun, Zhewen; Li, Yongping; Zhang, Yao; Khan, Hamid; Sun, Hongbing; Wang, Tao; Liang, Hong; Yang, Feng

    2018-11-01

    Multi-drug delivery systems, which may be promising solution to overcome obstacles, have limited the clinical success of multi-drug combination therapies to treat cancer. To this end, we used three different anticancer agents, Cu(BpT)Br, NAMI-A, and doxorubicin (DOX), to build human serum albumin (HSA)-based multi-drug delivery systems in a breast cancer model to investigate the therapeutic efficacy of overcoming single drug (DOX) resistance to cancer cells in vivo, and to regulate the drugs' release from HSA. The HSA complex structure revealed that NAMI-A and Cu(BpT)Br bind to the IB and IIA sub-domain of HSA by N-donor residue replacing a leaving group and coordinating to their metal centers, respectively. The MALDI-TOF mass spectra demonstrated that one DOX molecule is conjugated with lysine of HSA by a pH-sensitive linker. Furthermore, the release behavior of three agents form HSA can be regulated at different pH levels. Importantly, in vivo results revealed that the HSA-NAMI-A-Cu(BpT)Br-DOX complex not only increases the targeting ability compared with a combination of the three agents (the NAMI-A/Cu(BpT)Br/DOX mixture), but it also overcomes DOX resistance to drug-resistant breast cancer cell lines.

  9. Metastatic castration-resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation

    Directory of Open Access Journals (Sweden)

    R. A. Gafanov

    2018-01-01

    Full Text Available Prostate cancer (PC is one of the most common causes of death from malignant neoplasms in men in many countries around the world. Transmission of the signal in the androgenic axis of regulation is crucial for the development and progression of PC. Despite the constant dependence on androgen receptor signals in castration resistance, the use of new anti-androgenic drugs invariably leads to the stability  of the ongoing treatment. The interaction of androgen receptor and alternative (phosphoinositide-3-kinases, PI3K pathways in the regulation of cells can be one of the mechanisms of resistance to treatment. In this article, we describe current treatments for metastatic castration-resistant PC and the possible role of the PI3K pathway in the pathogenesis and progression of PC.

  10. Chloroquine uptake, altered partitioning and the basis of drug resistance: evidence for chloride-dependent ionic regulation.

    Science.gov (United States)

    Martiney, J A; Ferrer, A S; Cerami, A; Dzekunov, S; Roepe, P

    1999-01-01

    The biochemical mechanism of chloroquine resistance in Plasmodium falciparum remains unknown. We postulated that chloroquine-resistant strains could alter ion fluxes that then indirectly control drug accumulation within the parasite by affecting pH and/or membrane potential ('altered partitioning mechanism'). Two principal intracellular pH-regulating systems in many cell types are the amiloride-sensitive Na+/H+ exchanger (NHE), and the sodium-independent, stilbene-sensitive Cl-/HCO3- antiporter (AE). We report that under physiological conditions (balanced CO2 and HCO3-) chloroquine uptake and susceptibility are not altered by amiloride analogues. We also do not detect a significant difference in NHE activity between chloroquine-sensitive and chloroquine-resistant strains via single cell photometry methods. AE activity is dependent on the intracellular and extracellular concentrations of Cl- and HCO3- ions. Chloroquine-resistant strains differentially respond to experimental modifications in chloride-dependent homeostasis, including growth, cytoplasmic pH and pH regulation. Chloroquine susceptibility is altered by stilbene DIDS only on chloroquine-resistant strains. Our results suggest that a Cl(-)-dependent system (perhaps AE) has a significant effect on the uptake of chloroquine by the infected erythrocyte, and that alterations of this biophysical parameter may be part of the mechanism of chloroquine resistance in P. falciparum.

  11. Involvement of CUL4A in Regulation of Multidrug Resistance to P-gp Substrate Drugs in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yunshan Wang

    2013-12-01

    Full Text Available CUL4A encodes a core component of a cullin-based E3 ubiquitin ligase complex that regulates many critical processes such as cell cycle progression, DNA replication, DNA repair and chromatin remodeling by targeting a variety of proteins for ubiquitination and degradation. In the research described in this report we aimed to clarify whether CUL4A participates in multiple drug resistance (MDR in breast cancer cells. We first transfected vectors carrying CUL4A and specific shCUL4A into breast cancer cells and corresponding Adr cells respectively. Using reverse transcription polymerase chain reactions and western blots, we found that overexpression of CUL4A in MCF7 and MDA-MB-468 cells up-regulated MDR1/P-gp expression on both the transcription and protein levels, which conferred multidrug resistance to P-gp substrate drugs, as determined by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assays. On the other hand, silencing CUL4A in MCF7/Adr and MDA-MB-468/Adr cells led to the opposite effect. Moreover, ERK1/2 in CUL4A-overexpressing cells was highly activated and after treatment with PD98059, an ERK1/2-specific inhibitor, CUL4A-induced expression of MDR1/P-gp was decreased significantly. Lastly, immunohistochemistry in breast cancer tissues showed that P-gp expression had a positive correlation with the expression of CUL4A and ERK1/2. Thus, these results implied that CUL4A and ERK1/2 participated in multi-drug resistance in breast cancer through regulation of MDR1/P-gp expression.

  12. Antimicrobial (Drug) Resistance Prevention

    Science.gov (United States)

    ... June 6, 2018 HIV Vaccine Elicits Antibodies in Animals that Neutralize Dozens of HIV Strains , June 4, 2018 ... Antimicrobial (Drug) Resistance > Understanding share with facebook share with twitter share ...

  13. Kinetically Controlled Drug Resistance

    DEFF Research Database (Denmark)

    Sun, Xin E.; Hansen, Bjarne Gram; Hedstrom, Lizbeth

    2011-01-01

    The filamentous fungus Penicillium brevicompactum produces the immunosuppressive drug mycophenolic acid (MPA), which is a potent inhibitor of eukaryotic IMP dehydrogenases (IMPDHs). IMPDH catalyzes the conversion of IMP to XMP via a covalent enzyme intermediate, E-XMP*; MPA inhibits by trapping E...... of resistance is not apparent. Here, we show that, unlike MPA-sensitive IMPDHs, formation of E-XMP* is rate-limiting for both PbIMPDH-A and PbIMPDH-B. Therefore, MPA resistance derives from the failure to accumulate the drug-sensitive intermediate....

  14. Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay; Sørensen, Belinda Halling; Sauter, Daniel Rafael Peter

    2015-01-01

    to be an essential component of both VRAC and VSOAC. Reduced VRAC and VSOAC activities are seen in drug resistant cancer cells. ANO1 is a calcium-activated chloride channel expressed on the plasma membrane of e.g. secretory epithelia. ANO1 is amplified and highly expressed in a large number of carcinomas. The gene...... functions as well as their role in cancer and drug resistance....

  15. Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133-positive glioblastoma stem cells

    Directory of Open Access Journals (Sweden)

    Wen-Shin Song

    2016-10-01

    Conclusion: SOX2 plays a crucial role in regulating tumorigenicity in CD133+ GBM cells. Our results not only revealed the genetic plasticity contributing to drug resistance and stemness but also demonstrated the dominant role of SOX2 in maintenance of GBM CSCs, which may provide a novel therapeutic target to overcome the conundrum of poor survival of brain cancers.

  16. PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90.

    Directory of Open Access Journals (Sweden)

    Shantelle L LaFayette

    2010-08-01

    Full Text Available Fungal pathogens exploit diverse mechanisms to survive exposure to antifungal drugs. This poses concern given the limited number of clinically useful antifungals and the growing population of immunocompromised individuals vulnerable to life-threatening fungal infection. To identify molecules that abrogate resistance to the most widely deployed class of antifungals, the azoles, we conducted a screen of 1,280 pharmacologically active compounds. Three out of seven hits that abolished azole resistance of a resistant mutant of the model yeast Saccharomyces cerevisiae and a clinical isolate of the leading human fungal pathogen Candida albicans were inhibitors of protein kinase C (PKC, which regulates cell wall integrity during growth, morphogenesis, and response to cell wall stress. Pharmacological or genetic impairment of Pkc1 conferred hypersensitivity to multiple drugs that target synthesis of the key cell membrane sterol ergosterol, including azoles, allylamines, and morpholines. Pkc1 enabled survival of cell membrane stress at least in part via the mitogen activated protein kinase (MAPK cascade in both species, though through distinct downstream effectors. Strikingly, inhibition of Pkc1 phenocopied inhibition of the molecular chaperone Hsp90 or its client protein calcineurin. PKC signaling was required for calcineurin activation in response to drug exposure in S. cerevisiae. In contrast, Pkc1 and calcineurin independently regulate drug resistance via a common target in C. albicans. We identified an additional level of regulatory control in the C. albicans circuitry linking PKC signaling, Hsp90, and calcineurin as genetic reduction of Hsp90 led to depletion of the terminal MAPK, Mkc1. Deletion of C. albicans PKC1 rendered fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuated virulence in a murine model of systemic candidiasis. This work establishes a new role for PKC signaling in drug resistance, novel circuitry through which

  17. Connective tissue growth factor confers drug resistance in breast cancer through concomitant up-regulation of Bcl-xL and cIAP1.

    Science.gov (United States)

    Wang, Ming-Yang; Chen, Pai-Sheng; Prakash, Ekambaranellore; Hsu, Hsing-Chih; Huang, Hsin-Yi; Lin, Ming-Tsan; Chang, King-Jen; Kuo, Min-Liang

    2009-04-15

    Connective tissue growth factor (CTGF) expression is elevated in advanced breast cancer and promotes metastasis. Chemotherapy response is only transient in most metastatic diseases. In the present study, we examined whether CTGF expression could confer drug resistance in human breast cancer. In breast cancer patients who received neoadjuvant chemotherapy, CTGF expression was inversely associated with chemotherapy response. Overexpression of CTGF in MCF7 cells (MCF7/CTGF) enhanced clonogenic ability, cell viability, and resistance to apoptosis on exposure to doxorubicin and paclitaxel. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) mitigated this drug resistance capacity. CTGF overexpression resulted in resistance to doxorubicin- and paclitaxel-induced apoptosis by up-regulation of Bcl-xL and cellular inhibitor of apoptosis protein 1 (cIAP1). Knockdown of Bcl-xL or cIAP1 with specific small interfering RNAs abolished the CTGF-mediated resistance to apoptosis induced by the chemotherapeutic agents in MCF7/CTGF cells. Inhibition of extracellular signal-regulated kinase (ERK)-1/2 effectively reversed the resistance to apoptosis as well as the up-regulation of Bcl-xL and cIAP1 in MCF7/CTGF cells. A neutralizing antibody against integrin alpha(v)beta(3) significantly attenuated CTGF-mediated ERK1/2 activation and up-regulation of Bcl-xL and cIAP1, indicating that the integrin alpha(v)beta(3)/ERK1/2 signaling pathway is essential for CTGF functions. The Bcl-xL level also correlated with the CTGF level in breast cancer patients. We also found that a COOH-terminal domain peptide from CTGF could exert activities similar to full-length CTGF, in activation of ERK1/2, up-regulation of Bcl-xL/cIAP1, and resistance to apoptosis. We conclude that CTGF expression could confer resistance to chemotherapeutic agents through augmenting a survival pathway through ERK1/2-dependent Bcl-xL/cIAP1 up-regulation.

  18. SPIN1, negatively regulated by miR-148/152, enhances Adriamycin resistance via upregulating drug metabolizing enzymes and transporter in breast cancer.

    Science.gov (United States)

    Chen, Xu; Wang, Ya-Wen; Gao, Peng

    2018-05-09

    Spindlin1 (SPIN1), a protein highly expressed in several human cancers, has been correlated with tumorigenesis and development. Alterations of drug metabolizing enzymes and drug transporters are major determinants of chemoresistance in tumor cells. However, whether the metabolizing enzymes and transporters are under the control of SPIN1 in breast cancer chemoresistance has not yet been defined. SPIN1 expression in breast cancer cells and tissues was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Chemosensitivity assays in vitro and in vivo were performed to determine the effect of SPIN1 on Adriamycin resistance. Downstream effectors of SPIN1 were screened by microarray and confirmed by qRT-PCR and Western blot. Luciferase assay and Western blot were used to identify miRNAs regulating SPIN1. We showed that SPIN1 was significantly elevated in drug-resistant breast cancer cell lines and tissues, compared with the chemosensitive ones. SPIN1 enhanced Adriamycin resistance of breast cancer cells in vitro, and downregulation of SPIN1 by miRNA could decrease Adriamycin resistance in vivo. Mechanistically, drug metabolizing enzymes and transporter CYP2C8, UGT2B4, UGT2B17 and ABCB4 were proven to be downstream effectors of SPIN1. Notably, SPIN1 was identified as a direct target of the miR-148/152 family (miR-148a-3p, miR-148b-3p and miR-152-3p). As expected, miR-148a-3p, miR-148b-3p or miR-152-3p could increase Adriamycin sensitivity in breast cancer cells in vitro. Moreover, high expression of SPIN1 or low expression of the miR-148/152 family predicted poorer survival in breast cancer patients. Our results establish that SPIN1, negatively regulated by the miR-148/152 family, enhances Adriamycin resistance in breast cancer via upregulating the expression of drug metabolizing enzymes and drug transporter.

  19. Drug-resistant spinal tuberculosis

    Directory of Open Access Journals (Sweden)

    Anil K Jain

    2018-01-01

    Full Text Available Drug-resistant spinal tuberculosis (TB is an emerging health problem in both developing and developed countries. In this review article, we aim to define management protocols for suspicion, diagnosis, and treatment of such patients. Spinal TB is a deep-seated paucibacillary lesion, and the demonstration of acid-fast bacilli on Ziehl-Neelsen staining is possible only in 10%–30% of cases. Drug resistance is suspected in patients showing the failure of clinicoradiological improvement or appearance of a fresh lesion of osteoarticular TB while on anti tubercular therapy (ATT for a minimum period of 5 months. The conventional culture of Mycobacterium tuberculosis remains the gold standard for both bacteriological diagnosis and drug sensitivity testing (DST; however, the high turn around time of 2–6 weeks for detection with added 3 weeks for DST is a major limitation. To overcome this problem, rapid culture methods and molecular methods have been introduced. From a public health perspective, reducing the period between diagnosis and treatment initiation has direct benefits for both the patient and the community. For all patients of drug-resistant spinal TB, a complete Drug-O-Gram should be prepared which includes details of all drugs, their doses, and duration. Patients with confirmed multidrug-resistant TB strains should receive a regimen with at least five effective drugs, including pyrazinamide and one injectable. Patients with resistance to additional antitubercular drugs should receive individualized ATT as per their DST results.

  20. Computational Studies of Drug Resistance

    DEFF Research Database (Denmark)

    da Silva Martins, João Miguel

    Drug resistance has been an increasing problem in patient treatment and drug development. Starting in the last century and becoming a major worry in the medical and scienti c communities in the early part of the current millennium, major research must be performed to address the issues of viral...... is of the utmost importance in developing better and less resistance-inducing drugs. A drug's in uence can be characterized in many diff erent ways, however, and the approaches I take in this work re ect those same different in uences. This is what I try to achieve in this work, through seemingly unrelated...... approaches that come together in the study of drug's and their in uence on proteins and vice-versa. In part I, I aim to understand through combined theoretical ensemble analysis and free energy calculations the e ects mutations have over the binding anity and function of the M2 proton channel. This research...

  1. Drug-resistant tuberculosis

    African Journals Online (AJOL)

    statistics show that almost half a million new ... testing for second-line drugs, no international consensus has been reached about .... Given the high background rates of TB and MDR-TB in several countries, regimens are often constructed ...

  2. Extensively Drug-Resistant TB

    Centers for Disease Control (CDC) Podcasts

    2016-12-16

    Dr. Charlotte Kvasnovsky, a surgery resident and Ph.D. candidate in biostatistics, discusses various types of drug resistance in TB patients in South Africa.  Created: 12/16/2016 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/16/2016.

  3. Initial drug resistance in India

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Initial drug resistance in India. There is gradual increase in primary MDR all over India : Pondi= Pondicherry 1985; Bangalore =1986; Jaipur = 1991; Jaipur =2000. Overall the MDR is less than 3% (TRC studies).

  4. Drug-resistant tuberculosis: emerging treatment options

    Directory of Open Access Journals (Sweden)

    Adhvaryu MR

    2011-12-01

    Full Text Available Meghna Adhvaryu1, Bhasker Vakharia21Department of Biotechnology, SRK Institute of Computer Education and Applied Sciences, 2R&D, Bhuma Research in Ayurvedic and Herbal Medicine, Surat, Gujarat, IndiaAbstract: Multidrug-resistant tuberculosis has emerged worldwide, with an increasing incidence due to failure of implementation of apparently effective first-line antituberculous therapy as well as primary infection with drug-resistant strains. Failure of current therapy is attributed to a long duration of treatment leading to nonadherence and irregular therapy, lack of patient education about the disease, poverty, irregular supply by care providers, drug–drug interactions in patients coinfected with human immunodeficiency virus (HIV, inadequate regulations causing market overlap and irresponsible drug usage in the private sector, and lack of research, with no addition of new drugs in the last four decades. Present standards of care for the treatment of drug-susceptible tuberculosis, multidrug-resistant tuberculosis, tuberculosis-HIV coinfection, and latent tuberculosis infection are all unsatisfactory. Since 2000, the World Health Organization (WHO has focused on drug development for tuberculosis, as well as research in all relevant aspects to discover new regimens by 2015 and to eliminate tuberculosis as a public health concern by 2050. As a result, some 20 promising compounds from 14 groups of drugs have been discovered. Twelve candidates from eight classes are currently being evaluated in clinical trials. Ongoing research should prioritize identification of novel targets and newer application of existing drugs, discovery of multitargeted drugs from natural compounds, strengthening host factors by immunopotentiation with herbal immunomodulators, as well as protective vaccines before and after exposure, consideration of surgical measures when indicated, development of tools for rapid diagnosis, early identification of resistant strains, and

  5. DRUG RESISTANCE IN HELICOBACTER PYLORI

    Directory of Open Access Journals (Sweden)

    Júlia Silveira VIANNA

    Full Text Available ABSTRACT Background Helicobacter pylori has a worldwide distribution and is associated with the pathogenesis of various diseases of the digestive system. Treatment to eradicate this microorganism involves the use of a combination of antimicrobials, such as amoxicillin, metronidazole, clarithromycin, and levofloxacin, combined with proton pump inhibitors. Although the current therapy is effective, a high rate of treatment failure has been observed, mainly because of the acquisition of point mutations, one of the major resistance mechanisms developed by H. pylori. This phenomenon is related to frequent and/or inappropriate use of antibiotics. Conclusion This review reported an overview of the resistance to the main drugs used in the treatment of H. pylori, confirming the hypothesis that antibacterial resistance is a highly local phenomenon and genetic characteristics of a given population can influence which therapy is the most appropriate.

  6. Inflammation-regulating factors in ascites as predictive biomarkers of drug resistance and progression-free survival in serous epithelial ovarian cancers

    International Nuclear Information System (INIS)

    Lane, Denis; Matte, Isabelle; Garde-Granger, Perrine; Laplante, Claude; Carignan, Alex; Rancourt, Claudine; Piché, Alain

    2015-01-01

    Platinum-based combination therapy is the standard first-line treatment for women with advanced serous epithelial ovarian carcinoma (EOC). However, about 20 % will not respond and are considered clinically resistant. The availability of biomarkers to predict responses to the initial therapy would provide a practical approach to identify women who would benefit from a more appropriate first-line treatment. Ascites is an attractive inflammatory fluid for biomarker discovery as it is easy and minimally invasive to obtain. The aim of this study was to evaluate whether six selected inflammation-regulating factors in ascites could serve as diagnostic or drug resistance biomarkers in patients with advanced serous EOC. A total of 53 women with stage III/IV serous EOC and 10 women with benign conditions were enrolled in this study. Eleven of the 53 women with serous EOC were considered clinically resistant to treatment with progression-free survival < 6 months. Ascites were collected at the time of the debulking surgery and the levels of cytokines were measured by ELISA. The six selected cytokines were evaluated for their ability to discriminate serous EOC from benign controls, and to discriminate platinum resistant from platinum sensitive patients. Median ascites levels of IL-6, IL-10 and osteoprotegerin (OPG) were significantly higher in women with advanced serous EOC than in controls (P ≤ 0.012). There were no significant difference in the median ascites levels of leptin, soluble urokinase plasminogen activator receptor (suPAR) and CCL18 among serous EOC women and controls. In Receiver Operator curve (ROC) analysis, IL-6, IL-10 and OPG had a high area under the curve value of 0.905, 0.832 and 0.825 respectively for distinguishing EOC from benign controls. ROC analysis of individual cytokines revealed low discriminating potential to stratify patients according to their sensitivity to first-line treatment. The combination of biomarkers with the highest discriminating

  7. Multidrug resistant to extensively drug resistant tuberculosis: What is ...

    Indian Academy of Sciences (India)

    Prakash

    The modern, ... World Health Organization is based on a four-drug regimen ... Better management and control of tuberculosis specially drug resistant TB by experienced and qualified .... a comprehensive approach including the major DOTS.

  8. Tumor Heterogeneity and Drug Resistance

    International Nuclear Information System (INIS)

    Kucerova, L.; Skolekova, S.; Kozovska, Z.

    2015-01-01

    New generation of sequencing methodologies revealed unexpected complexity and genomic alterations linked with the tumor subtypes. This diversity exists across the tumor types, histologic tumor subtypes and subsets of the tumor cells within the same tumor. This phenomenon is termed tumor heterogeneity. Regardless of its origin and mechanisms of development it has a major impact in the clinical setting. Genetic, phenotypic and expression pattern diversity of tumors plays critical role in the selection of suitable treatment and also in the prognosis prediction. Intratumoral heterogeneity plays a key role in the intrinsic and acquired chemoresistance to cytotoxic and targeted therapies. In this review we focus on the mechanisms of intratumoral and inter tumoral heterogeneity and their relationship to the drug resistance. Understanding of the mechanisms and spatiotemporal dynamics of tumor heterogeneity development before and during the therapy is important for the ability to design individual treatment protocols suitable in the given molecular context. (author)

  9. Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Yu-Jen Chen

    Full Text Available Multi-drug resistance (MDR, an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC transporters and activated Sonic hedgehog (Shh signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX, we examined the effect and mechanism of norcantharidin (NCTD, a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S and DOX-resistant (MCF-7R cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells.

  10. Drug-resistant tuberculosis in Sindh

    International Nuclear Information System (INIS)

    Almani, S.A.; Memon, N.M.; Qureshi, A.F.

    2002-01-01

    Objective: To assess the prevalence of primary and secondary drug resistance amongst the clinical isolates of M.tuberculosis, to identify risk factors and how to overcome this problem. Design: A case series of 50 indoor patients with sputum smear-positive pulmonary tuberculosis. Place and duration of Study: Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, Sindh, (Pakistan) from January 1999 to December 2000. Patients and methods: Four first line anti-tuberculous drugs rifampicine, ethambutol and streptomycin were tested for sensitivity pattern. Results: Twelve (26.66%) were sensitive to all four drugs, 12(26.66%) were resistant to one drug, 14 (31.11%) were resistant to two drugs, 2 (4.44%) were resistant to three drugs, and 5(11.11%) were resistant to all four drugs. Resistance to isoniazid was the most common in 27 cases (60%) with primary resistance in 6(13.33%) and secondary resistance in 21(46.66%), followed by resistance to streptomycin in 17 cases (37.77%) with primary resistance in 5(11.11%) and secondary resistance in 12 (26.66%). Resistance to ethambutol in 10 cases (22.22%) and rifampicine in 11 (24.44%) and all cases were secondary. Similarly multi-drugs resistance (MRD) TB was found in 11(24.44%) isolates. Conclusion: This study showed high prevalence of drug resistance among clinical isolates of M. tuberculosis. Their is a need to establish centers at number of places with adequate facilities for susceptibility testing so that the resistant pattern could be ascertained and treatment regimens tailored accordingly. (author)

  11. Mechanisms of drug resistance in cancer cells

    International Nuclear Information System (INIS)

    Iqbal, M.P.

    2003-01-01

    Development of drug resist chemotherapy. For the past several years, investigators have been striving hard to unravel mechanisms of drug resistance in cancer cells. Using different experimental models of cancer, some of the major mechanisms of drug resistance identified in mammalian cells include: (a) Altered transport of the drug (decreased influx of the drug; increased efflux of the drug (role of P-glycoprotein; role of polyglutamation; role of multiple drug resistance associated protein)), (b) Increase in total amount of target enzyme/protein (gene amplification), (c) alteration in the target enzyme/protein (low affinity enzyme), (d) Elevation of cellular glutathione, (e) Inhibition of drug-induced apoptosis (mutation in p53 tumor suppressor gene; increased expression of bcl-xl gene). (author)

  12. Clinical Management of HIV Drug Resistance

    Science.gov (United States)

    Cortez, Karoll J.; Maldarelli, Frank

    2011-01-01

    Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy. PMID:21994737

  13. Preventing drug resistance in severe influenza

    Science.gov (United States)

    Dobrovolny, Hana; Deecke, Lucas

    2015-03-01

    Severe, long-lasting influenza infections are often caused by new strains of influenza. The long duration of these infections leads to an increased opportunity for the emergence of drug resistant mutants. This is particularly problematic for new strains of influenza since there is often no vaccine, so drug treatment is the first line of defense. One strategy for trying to minimize drug resistance is to apply periodic treatment. During treatment the wild-type virus decreases, but resistant virus might increase; when there is no treatment, wild-type virus will hopefully out-compete the resistant virus, driving down the number of resistant virus. We combine a mathematical model of severe influenza with a model of drug resistance to study emergence of drug resistance during a long-lasting infection. We apply periodic treatment with two types of antivirals: neuraminidase inhibitors, which block release of virions; and adamantanes, which block replication of virions. We compare the efficacy of the two drugs in reducing emergence of drug resistant mutants and examine the effect of treatment frequency on the emergence of drug resistant mutants.

  14. [Drug regulation: theory and practice].

    Science.gov (United States)

    Zara Yahni, C; Segú Tolsa, L; Font Pous, M; Rovira, J

    1998-01-01

    Regulation of drugs from the public administration is an activity which is produced in different countries independently from the sanitary model they own. In the field of public financing of drugs there have been several measures to improve the efficiency of their use. However, the analysis of the impact of these measures is complex and this may justify the shortage of objectivable results, especially at long term. The objective of this study is to perform a systematic review of such measures due to the need to have information about the different alternatives before making a decision. The introduction of an isolated measure is in many cases compensated by other changes in other regulating or aiding fields which suggests the creation of an integral strategy which affects different fields (supply/demand of drugs and prescribers). It seems necessary to suggest a social debate taking as a basis the scientific information available at the moment and promote the taking of decisions which lead to a rational use of the available pharmacological resources.

  15. Combined antiretroviral and anti- tuberculosis drug resistance ...

    African Journals Online (AJOL)

    these epidemics, many challenges remain.[3] Antiretroviral and anti-TB drug resistance pose considerable threats to the control of these epidemics.[4,5]. The breakdown in HIV/TB control within prisons is another emerging threat.[6,7] We describe one of the first reports of combined antiretroviral and anti-TB drug resistance ...

  16. Drug Resistance of Mycobacterium tuberculosis Complex among ...

    African Journals Online (AJOL)

    BACKGROUND: In Burkina Faso, there is no recent data about the level of drug resistance in Mycobacterium tuberculosis strains among newly diagnosed tuberculosis cases. OBJECTIVE: To provide an update of the primary drug resistance of mycobacterium tuberculosis among patients in Burkina faso. METHODS: ...

  17. Emergence of Extensively Drug Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    Extensively drug-resistant tuberculosis (XDR TB) outbreaks have been reported in South Africa, and strains have been identified on 6 continents. Dr. Peter Cegielski, team leader for drug-resistant TB with the Division of Tuberculosis Elimination at CDC, comments on a multinational team's report on this emerging global public health threat.

  18. [Change in drug resistance of Staphylococcus aureus].

    Science.gov (United States)

    Lin, Yan; Liu, Yan; Luo, Yan-Ping; Liu, Chang-Ting

    2013-11-01

    To analyze the change in drug resistance of Staphylococcus aureus (SAU) in the PLA general hospital from January 2008 to December 2012, and to provide solid evidence to support the rational use of antibiotics for clinical applications. The SAU strains isolated from clinical samples in the hospital were collected and subjected to the Kirby-Bauer disk diffusion test. The results were assessed based on the 2002 American National Committee for Clinical Laboratory Standards (NCCLS) guidelines. SAU strains were mainly isolated from sputum, urine, blood and wound excreta and distributed in penology, neurology wards, orthopedics and surgery ICU wards. Except for glycopeptide drugs, methicillin-resistant Staphylococcus aureus (MRSA) had a higher drug resistance rate than those of the other drugs and had significantly more resistance than methicillin-sensitive Staphylococcus aureus (MSSA) (P resistance, we discovered a gradual increase in drug resistance to fourteen test drugs during the last five years. Drug resistance rate of SAU stayed at a higher level over the last five years; moreover, the detection ratio of MRSA keeps rising year by year. It is crucial for physicians to use antibiotics rationally and monitor the change in drug resistance in a dynamic way.

  19. Antimicrobial Drugs in Fighting against Antimicrobial Resistance

    OpenAIRE

    Cheng, Guyue; Dai, Menghong; Ahmed, Saeed; Hao, Haihong; Wang, Xu; Yuan, Zonghui

    2016-01-01

    The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i....

  20. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  1. Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

    Institute of Scientific and Technical Information of China (English)

    REBECCA L DUNNE; LINDA A DUNN; PETER UPCROFT; PETER J O'DONOGHUE; JACQUELINE A UPCROFT

    2003-01-01

    Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved,effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and crossresistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

  2. Emergence of Extensively Drug Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    2007-03-01

    Extensively drug-resistant tuberculosis (XDR TB) outbreaks have been reported in South Africa, and strains have been identified on 6 continents. Dr. Peter Cegielski, team leader for drug-resistant TB with the Division of Tuberculosis Elimination at CDC, comments on a multinational team's report on this emerging global public health threat.  Created: 3/1/2007 by Emerging Infectious Diseases.   Date Released: 3/26/2007.

  3. HIV resistance testing and detected drug resistance in Europe

    DEFF Research Database (Denmark)

    Schultze, Anna; Phillips, Andrew N; Paredes, Roger

    2015-01-01

    to Southern Europe. CONCLUSIONS: Despite a concurrent decline in virological failure and testing, drug resistance was commonly detected. This suggests a selective approach to resistance testing. The regional differences identified indicate that policy aiming to minimize the emergence of resistance......OBJECTIVES: To describe regional differences and trends in resistance testing among individuals experiencing virological failure and the prevalence of detected resistance among those individuals who had a genotypic resistance test done following virological failure. DESIGN: Multinational cohort...... study. METHODS: Individuals in EuroSIDA with virological failure (>1 RNA measurement >500 on ART after >6 months on ART) after 1997 were included. Adjusted odds ratios (aORs) for resistance testing following virological failure and aORs for the detection of resistance among those who had a test were...

  4. Drug resistance in the mouse cancer clinic

    NARCIS (Netherlands)

    Rottenberg, Sven; Borst, Piet

    2012-01-01

    Drug resistance is one of the most pressing problems in treating cancer patients today. Local and regional disease can usually be adequately treated, but patients eventually die from distant metastases that have become resistant to all available chemotherapy. Although work on cultured tumor cell

  5. Malaria epidemic and drug resistance, Djibouti.

    Science.gov (United States)

    Rogier, Christophe; Pradines, Bruno; Bogreau, H; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile

    2005-02-01

    Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.

  6. Streptococcus pneumoniae Drugs Resistance in Acute Rhinosinusitis

    Directory of Open Access Journals (Sweden)

    Chong Jie Hao

    2016-03-01

    Full Text Available Background: Acute rhinosinusitis that usually caused by Streptococcus pneumoniae becomes the reason why patients seek for medical care. Drugs resistance in Streptococcus pneumoniae is increasing worldwide. This study was conducted to determine drugs resistance of Streptococcus pneumonia from acute rhinosinusitis in Dr. Hasan Sadikin General Hospital. Methods: A descriptive laboratory study was conducted in June–October 2014 at the Laboratory of Microbiology Faculty of Medicine Universitas Padjadjaran. The sample was taken using nasopharyngeal swabbing from 100 acute rhinosinusitis patients in Dr. Hasan Sadikin General Hospital and planted on tryptic soy agar containing 5% sheep blood and 5 μg/ml of gentamicin sulphate and then incubated in 5% CO2 incubator at 37°C for 24 hours. The identification of Streptococcus pneumonia was performed by optochin test. The susceptibility test against Streptococcus pneumoniae was done using disk diffusion method.The antibiotic disks were trimethoprim-sulfamethoxazole, oxacillin, levofloxacin, azithromycin, and doxycycline. Results: Out of 100 samples, 8 of them were tested positive for Streptococcus pneumoniae. Three of Streptococcus pneumoniae isolates died with unknown reason after it were stored at -80 .The drugs resistance test showed the resistance of Streptococcus pneumonia to oxacillin, azithromycin and trimethoprim were 6, whereas levofloxacin and doxycycline are 4. Conclusions: Streptococcus pneumonia drugs resistance in acute rhinosinusitis shows the resistance of Streptococcus pneumoniae to oxacillin, azithromycin and trimethoprim are 6, whereas the resistance to levofloxacin and doxycycline are 4.

  7. Antimicrobial Drug Resistance and Gonorrhea

    Centers for Disease Control (CDC) Podcasts

    2017-12-26

    Dr. Robert Kirkcaldy, a medical officer at CDC, discusses his article on antimicrobial resistance and gonorrhea.  Created: 12/26/2017 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/26/2017.

  8. Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

    International Nuclear Information System (INIS)

    Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

    2008-01-01

    Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of

  9. Radiosensitivity of drug-resistant human tumour xenografts

    International Nuclear Information System (INIS)

    Mattern, J.; Bak, M. Jr.; Volm, M.; Hoever, K.H.

    1989-01-01

    The radiosensitivity of three drug-resistant sublines of a human epidermoid lung carcinoma growing as xenografts in nude mice was investigated. Drug resistance to vincristine, actinomycin D and cisplatin was developed in vivo by repeated drug treatment. It was found that all three drug-resistant tumour lines were not cross-resistant to irradiation. (orig.) [de

  10. Overview of drug-resistant tuberculosis worldwide

    Directory of Open Access Journals (Sweden)

    Ali A Velayati

    2016-01-01

    Full Text Available Even in the 21st century, we are losing the battle against eradication of tuberculosis (TB. In 2015, 9.6 million people were estimated to have fallen ill with TB, of which 1.5 million people died. This is the real situation despite the well-structured treatment programs and availability of effective treatment options since the 1950s. The high mortality rate has been associated with other risk factors, such as the HIV epidemic, underlying diseases, and decline of socioeconomic standards. Furthermore, the problem of drug resistance that was recognized in the early days of the chemotherapeutic era raises serious concerns. Although resistance to a single agent is the most common type, resistance to multiple agents is less frequent but of greater concern. The World Health Organization estimated approximately 5% of all new TB cases involved multidrug-resistant (MDR-TB. The estimation for MDR-TB is 3.3% for new cases, and 20.5% for previously treated cases. Failure to identify and appropriately treat MDR-TB patients has led to more dangerous forms of resistant TB. Based on World Health Organization reports, 5% of global TB cases are now considered to be extensively drug resistant (XDR, defined as MDR with additional resistance to both fluoroquinolones and at least one second-line injectable drug. XDR-TB had been reported by 105 countries by 2015. An estimated 9.7% of people with MDR-TB have XDR-TB. More recently, another dangerous form of TB bacillus was identified, which was named totally drug resistant (TDR-TB or extremely drug resistant TB. These strains were resistant to all first- and second-line anti-TB drugs. Collectively, it is accepted that 2% of MDR-TB strains turn to be TDR-TB. This number, however, may not reflect the real situation, as many laboratories in endemic TB countries do not have proper facilities and updated protocols to detect the XDR or TDR-TB strains. Nevertheless, existing data emphasize the need for additional control

  11. Drug-induced regulation of target expression

    DEFF Research Database (Denmark)

    Iskar, Murat; Campillos, Monica; Kuhn, Michael

    2010-01-01

    Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug......-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments....... In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We...

  12. HIV Genetic Diversity and Drug Resistance

    Science.gov (United States)

    Santos, André F.; Soares, Marcelo A.

    2010-01-01

    Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants. PMID:21994646

  13. Mesenchymal change and drug resistance in neuroblastoma.

    Science.gov (United States)

    Naiditch, Jessica A; Jie, Chunfa; Lautz, Timothy B; Yu, Songtao; Clark, Sandra; Voronov, Dimitry; Chu, Fei; Madonna, Mary Beth

    2015-01-01

    Metastatic initiation has many phenotypic similarities to epithelial-to-mesenchymal transition, including loss of cell-cell adhesion, increased invasiveness, and increased cell mobility. We have previously demonstrated that drug resistance is associated with a metastatic phenotype in neuroblastoma (NB). The purpose of this project was to determine if the development of doxorubicin resistance is associated with characteristics of mesenchymal change in human NB cells. Total RNA was isolated from wild type (WT) and doxorubicin-resistant (DoxR) human NB cell lines (SK-N-SH and SK-N-BE(2)C) and analyzed using the Illumina Human HT-12 version 4 Expression BeadChip. Differentially expressed genes (DEGs) were identified. Volcano plots and heat maps were generated. Genes of interest with a fold change in expression >1.5 and an adjusted P change via multiple pathways in the transition to a drug-resistant state. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Economic implications of resistance to antimalarial drugs.

    Science.gov (United States)

    Phillips, M; Phillips-Howard, P A

    1996-09-01

    The widespread evolution of drug resistance in malarial parasites has seriously hampered efforts to control this debilitating disease. Chloroquine, the mainstay of malaria treatment for many decades, is now proving largely ineffective in many parts of the world, particularly against the most severe form of malaria--falciparum. Alternative drugs have been developed, but they are frequently less safe and are all between 50 and 700% more expensive than chloroquine. Choice of drug clearly has important budgetary implications and national malaria control programmes need to weigh up the costs and benefits in deciding whether to change to more effective but more expensive drugs. The growth in drug resistance also has implications for the choice of diagnostic tool. Clinical diagnosis of malaria is relatively cheap, but less specific than some technological approaches. As more expensive drugs are employed, the cost of wasted treatment on suspected cases who do not in fact have malaria rises and the more worthwhile it becomes to invest in more specific diagnostic techniques. This paper presents an economic framework for analysing the various malaria drug and diagnostic tool options available. It discusses the nature of the key factors that need to be considered when making choices of malaria treatment (including treatment costs, drug resistance, the costs of treatment failure and compliance) and diagnosis (including diagnosis cost and accuracy, and the often overlooked costs associated with delayed treatment), and uses some simple equations to illustrate the impact of these on the relative cost effectiveness of the alternatives being considered. On the basis of some simplifying assumptions and illustrative calculations, it appears that in many countries more effective drugs and more specific and rapid diagnostic approaches will be worth adopting even although they imply additional expense.

  15. Drug resistance patterns in pulmonary tuberculosis

    International Nuclear Information System (INIS)

    Khoharo, H.K.; Shaikh, I.A.

    2011-01-01

    Objective: To determine the resistance patterns of mycobacterium tuberculosis (MTB) isolates among category I and II patients of pulmonary tuberculosis. Methods: This cross sectional study was conducted at the Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, from November 2008 to September 2009. Patients were divided into category I and II. The sputa were collected, stained with Ziehl-Nielsen (Z-N) staining and ultimately inoculated on Lowenstein-Jensen (L-J) media for six weeks. Out of 890 pulmonary tuberculosis (PTB) patients, the growth was obtained in 285 cases. The Drug sensitivity testing (DST) for Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) Pyrazinamide (PZA) and Streptomycin (SM) were performed. The data was analyzed on SPSS 10.0. A p-value of <0.05 was taken as significant. Result: Out of 285 cases, 176 (61.75%) were male and 109 (38.24%) female. The mean age was 37 +- 19.90 years. The DST showed drug sensitive and drug resistant isolates in 80 (28.05%) and 205 (71.92%) cases respectively (p=0.001). The drug resistant tuberculosis (DR-TB) rates for individual drugs; INH, RIF, EMB, PZA and SM were 51,22%, 15.4%, 13.33%, 9%12, and 3.85% respectively (p=0.03). The MDR-TB isolates were detected in 120 (42.10%) cases, including 5 (5.88%) in category I and 115 (57.50%) in category II patients (p=0.0001). Conclusion: Drug resistant and multidrug resistant tuberculosis was observed mainly in category II patients. However, primary MDR was also observed in category I patients and reflects dissemination of MDR cases within the community. (author)

  16. Mechanisms of Candida biofilm drug resistance

    Science.gov (United States)

    Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R

    2013-01-01

    Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922

  17. Female sexuality, regulation and resistance.

    Science.gov (United States)

    Khanna, R; Price, J

    1994-06-01

    India was the context for this discussion of female sexuality, rigid social norms, women's strategies for resistance, the evolution of norms from colonial India, prostitution, myths, and self-help women's activities. Sexuality is a changing set of ideas, and women have contributed to the redefinition. The biological view without consideration of the sociocultural and historical influences proscribes what is deviant and may be used to reinforce patriarchy and colonialism. Management and control of sexuality has been influenced by class, religion, caste, and ethnicity. During the colonial period, women's sexuality and treatment was challenged by the missionaries. The abolishment of "sati" as a traditional practice was used by the British to expand their rule and control over a wider regional area. Attempts were also made to regulate prostitution as means of protecting the health of the British army. The law requiring registration, examination, and commitment for treatment of prostitutes was not adhered to by the women involved. The notion of mothers as irresponsible came into being about 1900, and encouraged abandonment of traditional child- rearing ways for the Western standard of health and hygiene, and lifestyle. In Bengal, motherhood and mother qoddesses became the symbol of the liberation movement. The maternal role could be strengthened through education. The notion of mother and nationhood was supported by the women's movement in Great Britain and the US through positive eugenics ideas of quality race, which supported the ruling elite of British and Indians. Thus, the high class women were to be protected from early marriage, and encouraged to produce children fit to govern; the poor were to be protected from prostitution and overpopulation. Post colonial ideas about sexuality reflected a number of influences both from within and outside India. Health was a focus, and program targets were those who were outside the norm: women with too many children

  18. characterization of drug resistant pseudomonas aeruginosa and ...

    African Journals Online (AJOL)

    Abstract: Lizards as well as some other reptiles have been known to carry pathogenic bacteria organisms as well as drug resistant pathogens. Despite the fact that they remain asymptomatic in many cases, they nevertheless play significant roles in the epidemiology of these pathogens through their dissemination to the ...

  19. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    Science.gov (United States)

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M; Mylonakis, Eleftherios

    2015-01-01

    Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

  20. Population mobility, globalization, and antimicrobial drug resistance.

    Science.gov (United States)

    MacPherson, Douglas W; Gushulak, Brian D; Baine, William B; Bala, Shukal; Gubbins, Paul O; Holtom, Paul; Segarra-Newnham, Marisel

    2009-11-01

    Population mobility is a main factor in globalization of public health threats and risks, specifically distribution of antimicrobial drug-resistant organisms. Drug resistance is a major risk in healthcare settings and is emerging as a problem in community-acquired infections. Traditional health policy approaches have focused on diseases of global public health significance such as tuberculosis, yellow fever, and cholera; however, new diseases and resistant organisms challenge existing approaches. Clinical implications and health policy challenges associated with movement of persons across barriers permeable to products, pathogens, and toxins (e.g., geopolitical borders, patient care environments) are complex. Outcomes are complicated by high numbers of persons who move across disparate and diverse settings of disease threat and risk. Existing policies and processes lack design and capacity to prevent or mitigate adverse health outcomes. We propose an approach to global public health risk management that integrates population factors with effective and timely application of policies and processes.

  1. Drug resistance in Mexico: results from the National Survey on Drug-Resistant Tuberculosis.

    Science.gov (United States)

    Bojorquez-Chapela, I; Bäcker, C E; Orejel, I; López, A; Díaz-Quiñonez, A; Hernández-Serrato, M I; Balandrano, S; Romero, M; Téllez-Rojo Solís, M M; Castellanos, M; Alpuche, C; Hernández-Ávila, M; López-Gatell, H

    2013-04-01

    To present estimations obtained from a population-level survey conducted in Mexico of prevalence rates of mono-, poly- and multidrug-resistant strains among newly diagnosed cases of pulmonary tuberculosis (TB), as well as the main factors associated with multidrug resistance (combined resistance to isoniazid and rifampicin). Study data came from the National Survey on TB Drug Resistance (ENTB-2008), a nationally representative survey conducted during 2008-2009 in nine states with a stratified cluster sampling design. Samples were obtained for all newly diagnosed cases of pulmonary TB in selected sites. Drug susceptibility testing (DST) was performed for anti-tuberculosis drugs. DST results were obtained for 75% of the cases. Of these, 82.2% (95%CI 79.5-84.7) were susceptible to all drugs. The prevalence of multidrug-resistant TB (MDR-TB) was estimated at 2.8% (95%CI 1.9-4.0). MDR-TB was associated with previous treatment (OR 3.3, 95%CI 1.1-9.4). The prevalence of drug resistance is relatively low in Mexico. ENTB-2008 can be used as a baseline for future follow-up of drug resistance.

  2. Emergence of fluoroquinolone resistance among drug resistant tuberculosis patients at a tertiary care facility in Karachi, Pakistan.

    Science.gov (United States)

    Zaidi, Syed Mohammad Asad; Haseeb, Abdul; Habib, Shifa Salman; Malik, Amyn; Khowaja, Saira; SaifUllah, Nausheen; Rizvi, Nadeem

    2017-07-25

    Pakistan is classified as one of the high multi-drug resistant tuberculosis (MDR-TB) burden countries. A poorly regulated private sector, over-prescription of antibiotics and self-medication has led to augmented rates of drug-resistance in the country. Pakistan's first national anti-tuberculosis drug resistance survey identified high prevalence of fluoroquinolone resistance among MDR-TB patients. Further institutional evidence of fluoroquinolone drug-resistance can support re-evaluation of treatment regimens as well as invigorate efforts to control antibiotic resistance in the country. In this study, data for drug-susceptibility testing (DST) was retrospectively analyzed for a total of 133 patients receiving MDR-TB treatment at the Chest Department of Jinnah Postgraduate Medical Center, Karachi, Pakistan. Frequency analyses for resistance patterns was carried out and association of fluoroquinolone (ofloxacin) resistance with demographics and past TB treatment category were assessed. Within first-line drugs, resistance to isoniazid was detected in 97.7% of cases, followed by rifampicin (96.9%), pyrazinamide (86.4%), ethambutol (69.2%) and streptomycin (64.6%). Within second-line drugs, ofloxacin resistance was detected in 34.6% of cases. Resistance to ethionamide and amikacin was 2.3% and 1.6%, respectively. Combined resistance of oflaxacin and isoniazid was detected in 33.9% of cases. Age, gender and past TB treatment category were not significantly associated with resistance to ofloxacin. Fluoroquinolone resistance was observed in an alarmingly high proportion of MDR-TB cases. Our results suggest caution in their use for empirical management of MDR-TB cases and recommended treatment regimens for MDR-TB may require re-evaluation. Greater engagement of private providers and stringent pharmacy regulations are urgently required.

  3. Supermolecular drug challenge to overcome drug resistance in cancer cells.

    Science.gov (United States)

    Onishi, Yasuhiko; Eshita, Yuki; Ji, Rui-Cheng; Kobayashi, Takashi; Onishi, Masayasu; Mizuno, Masaaki; Yoshida, Jun; Kubota, Naoji

    2018-06-04

    Overcoming multidrug resistance (MDR) of cancer cells can be accomplished using drug delivery systems in large-molecular-weight ATP-binding cassette transporters before entry into phagolysosomes and by particle-cell-surface interactions. However, these hypotheses do not address the intratumoral heterogeneity in cancer. Anti-MDR must be related to alterations of drug targets, expression of detoxification, as well as altered proliferation. In this study, it is shown that the excellent efficacy and sustainability of anti-MDR is due to a stable ES complex because of the allosteric facilities of artificial enzymes when they are used as supramolecular complexes. The allosteric effect of supermolecular drugs can be explained by the induced-fit model and can provide stable feedback control systems through the loop transfer function of the Hill equation. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Antituberculosis drug resistance patterns in adults with tuberculous meningitis

    DEFF Research Database (Denmark)

    Senbayrak, Seniha; Ozkutuk, Nuri; Erdem, Hakan

    2015-01-01

    BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to antituberculosis drugs is an increasingly common clinical problem. This study aimed to evaluate drug resistance profiles of TBM isolates in adult patients in nine European countries involving 32 centers...

  5. Telomerase and drug resistance in cancer

    OpenAIRE

    Lipinska, Natalia; Romaniuk, Aleksandra; Paszel-Jaworska, Anna; Toton, Ewa; Kopczynski, Przemyslaw; Rubis, Blazej

    2017-01-01

    It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs (e.g., doxorubicin, cisplatin, or 5-fluorouracil). However, the mechanism of the resistance resulting from telomerase alteration remains elusive. There are theories claiming that it might be associated with telomere shortening, genome instability, hTERT translocation, mitochondria functioning modulation, or even alterations in ABC family gen...

  6. Multi-drug resistant Ewingella Americana

    International Nuclear Information System (INIS)

    Bukhari, Syed Z.; Ashshi, Ahmad M.; Hussain, Waleed M.; Fatani, Mohammad I.

    2008-01-01

    We report a case of pneumonia due to multi-drug resistant Ewingella Americana in a young patient admitted in the Intensive Care Unit of Hera General Hospital, Makkah, Saudi Arabia with severe head injury in a road traffic accident. He was an Indonesian pilgrim who had traveled to the Kingdom of Saudi Arabia to perform Hajj in December 2007. Ewingella Americana was identified to be the pathogen of pneumonia with clinical signs and symptoms along with positive radiological findings. (author)

  7. Gene expression analysis of two extensively drug-resistant tuberculosis isolates show that two-component response systems enhance drug resistance.

    Science.gov (United States)

    Yu, Guohua; Cui, Zhenling; Sun, Xian; Peng, Jinfu; Jiang, Jun; Wu, Wei; Huang, Wenhua; Chu, Kaili; Zhang, Lu; Ge, Baoxue; Li, Yao

    2015-05-01

    Global analysis of expression profiles using DNA microarrays was performed between a reference strain H37Rv and two clinical extensively drug-resistant isolates in response to three anti-tuberculosis drug exposures (isoniazid, capreomycin, and rifampicin). A deep analysis was then conducted using a combination of genome sequences of the resistant isolates, resistance information, and related public microarray data. Certain known resistance-associated gene sets were significantly overrepresented in upregulated genes in the resistant isolates relative to that observed in H37Rv, which suggested a link between resistance and expression levels of particular genes. In addition, isoniazid and capreomycin response genes, but not rifampicin, either obtained from published works or our data, were highly consistent with the differentially expressed genes of resistant isolates compared to those of H37Rv, indicating a strong association between drug resistance of the isolates and genes differentially regulated by isoniazid and capreomycin exposures. Based on these results, 92 genes of the studied isolates were identified as candidate resistance genes, 10 of which are known resistance-related genes. Regulatory network analysis of candidate resistance genes using published networks and literature mining showed that three two-component regulatory systems and regulator CRP play significant roles in the resistance of the isolates by mediating the production of essential envelope components. Finally, drug sensitivity testing indicated strong correlations between expression levels of these regulatory genes and sensitivity to multiple anti-tuberculosis drugs in Mycobacterium tuberculosis. These findings may provide novel insights into the mechanism underlying the emergence and development of drug resistance in resistant tuberculosis isolates and useful clues for further studies on this issue. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Regulations And Control Of Food And Drugs

    International Nuclear Information System (INIS)

    Osuide, G.E.; Director General, National Agency For Food And Drugs Administration And Control, Federal Secretariat, Ikoyi, Lagos, Nigeria.

    1996-01-01

    Effective control of processed food and medicines is crucial for the maintenance of public health. Issues of wholesomeness, quality, efficacy and safety are of paramount concern to both consumers and regulatory agencies alike. Laws and regulatory are put in in place to ensure minimum standards of practice by the various operators in the food and pharmaceutical sub-sectors, such as will guarantee that the regulated products (food, drugs, cosmetics, medical devices, chemicals and bottled water) they deal in satisfy all the parameters of quality, wholesomeness, efficacy and safety. National Agency for Food and Drug Administration and Control (NAFDAC) was established to enforce all relevant laws and regulations on food and drugs among other-regulated products. NAFDAC has put in place appropriate administrative structures and procedures in its efforts to fulfill its mandate. Finally, the agency is in the process of extending its regulatory and control activities to cover irradiated food products in order to safeguard public health

  9. Prediction of resistance development against drug combinations by collateral responses to component drugs

    DEFF Research Database (Denmark)

    Munck, Christian; Gumpert, Heidi; Nilsson Wallin, Annika

    2014-01-01

    the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during...... adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance......Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability...

  10. Molecular Genetics of Drug-resistance in Epilepsies

    Directory of Open Access Journals (Sweden)

    Kurupath Radhakrishnan

    2015-06-01

    Full Text Available Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive to antiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genes encoding the proteins that regulate the pharmacokinetics such as P-glycoprotein [ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1, ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7], and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABA receptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intense investigation to unravel the mysteries of AED-resistance. However, till today, a consistent and reliable result that could help the clinician either to predict drug resistance or to overcome it has not been forthcoming. The discrepant results may be related to variations in the definition of drug-resistance, heterogeneous patient populations, ethnic variations in the frequency distribution of single nucleotide polymorphisms (SNPs and the selection of SNPs. Understanding of these limitations of existing studies, hopefully, will help in designing better studies. Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive toantiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genesencoding the proteins that regulate the pharmacokinetics such as P-glycoprotein[ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1,ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7],and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABAreceptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intenseinvestigation to unravel the mysteries of AED-resistance. However, till today, aconsistent and reliable result that could help the clinician either to predict drugresistanceor to overcome it has not been forthcoming. The discrepant results may berelated to variations in the definition of drug-resistance, heterogeneous patientpopulations, ethnic

  11. Lysosomes as mediators of drug resistance in cancer.

    Science.gov (United States)

    Zhitomirsky, Benny; Assaraf, Yehuda G

    2016-01-01

    Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug

  12. Predicted levels of HIV drug resistance

    DEFF Research Database (Denmark)

    Cambiano, Valentina; Bertagnolio, Silvia; Jordan, Michael R

    2014-01-01

    -term effects. METHODS: The previously validated HIV Synthesis model was calibrated to South Africa. Resistance was modeled at the level of single mutations, transmission potential, persistence, and effect on drug activity. RESULTS: We estimate 652 000 people (90% uncertainty range: 543 000-744 000) are living...... are maintained, in 20 years' time HIV incidence is projected to have declined by 22% (95% confidence interval, CI -23 to -21%), and the number of people carrying NNRTI resistance to be 2.9-fold higher. If enhancements in diagnosis and retention in care occur, and ART is initiated at CD4 cell count less than 500......  cells/μl, HIV incidence is projected to decline by 36% (95% CI: -37 to -36%) and the number of people with NNRTI resistance to be 4.1-fold higher than currently. Prevalence of people with viral load more than 500  copies/ml carrying NRMV is not projected to differ markedly according to future ART...

  13. Young Women's Experiences of Resisting Invitations to Use Illicit Drugs

    Science.gov (United States)

    Koehn, Corinne V.; O'Neill, Linda K.

    2011-01-01

    Ten young women were interviewed regarding their experiences of resisting invitations to use illicit drugs. Hermeneutic phenomenology was used to gather and analyze information. One key theme was the motivations that inspired women to refuse drug offers. Young women resisted drug invitations because of their desires to be authentic, protect their…

  14. Prevalence of drug resistant tuberculosis in Arsi Zone, Ethiopia ...

    African Journals Online (AJOL)

    Background: Wide spread of occurrence of multi-drug resistance tuberculosis is becoming a major challenge to effective tuberculosis control. Thus, it is imperative to monitor the sensitivity of anti-TB drugs regularly. Objective: To determine the prevalence resistance to anti-TB drugs in a well established control program area ...

  15. GEAR: A database of Genomic Elements Associated with drug Resistance

    Science.gov (United States)

    Wang, Yin-Ying; Chen, Wei-Hua; Xiao, Pei-Pei; Xie, Wen-Bin; Luo, Qibin; Bork, Peer; Zhao, Xing-Ming

    2017-01-01

    Drug resistance is becoming a serious problem that leads to the failure of standard treatments, which is generally developed because of genetic mutations of certain molecules. Here, we present GEAR (A database of Genomic Elements Associated with drug Resistance) that aims to provide comprehensive information about genomic elements (including genes, single-nucleotide polymorphisms and microRNAs) that are responsible for drug resistance. Right now, GEAR contains 1631 associations between 201 human drugs and 758 genes, 106 associations between 29 human drugs and 66 miRNAs, and 44 associations between 17 human drugs and 22 SNPs. These relationships are firstly extracted from primary literature with text mining and then manually curated. The drug resistome deposited in GEAR provides insights into the genetic factors underlying drug resistance. In addition, new indications and potential drug combinations can be identified based on the resistome. The GEAR database can be freely accessed through http://gear.comp-sysbio.org. PMID:28294141

  16. 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)

  17. A Structural View on Medicinal Chemistry Strategies against Drug Resistance.

    Science.gov (United States)

    Agnello, Stefano; Brand, Michael; Chellat, Mathieu F; Gazzola, Silvia; Riedl, Rainer

    2018-05-30

    The natural phenomenon of drug resistance represents a generic impairment that hampers the benefits of drugs in all major clinical indications. Antibacterials and antifungals are affected as well as compounds for the treatment of cancer, viral infections or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, underlying molecular processes have been identified to understand the emergence of resistance and to overcome this detrimental mechanism. Detailed structural information of the root causes for drug resistance is nowadays frequently available to design next generation drugs anticipated to suffer less from resistance. This knowledge-based approach is a prerequisite in the fight against the inevitable occurrence of drug resistance to secure the achievements of medicinal chemistry in the future. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis

    NARCIS (Netherlands)

    Kamp, Jasper; Bolhuis, Mathieu S.; Tiberi, Simon; Akkerman, Onno W.; Centis, Rosella; de lange, Wiel C.; Kosterink, Jos G.; van der Werf, Tjip S.; Migliori, Giovanni B.; Alffenaar, Jan-Willem C.

    Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed

  19. Multi-drug resistance and molecular pattern of erythromycin and ...

    African Journals Online (AJOL)

    The appearance and dissemination of penicillin resistant and macrolide resistant Streptococcus pneumoniae strains has caused increasing concern worldwide. The aim of this study was to survey drug resistance and genetic characteristics of macrolide and penicillin resistance in S. pneumoniae. This is a cross-sectional ...

  20. Branded prescription drug fee. Final regulations, temporary regulations, and removal of temporary regulations.

    Science.gov (United States)

    2014-07-28

    This document contains final regulations that provide guidance on the annual fee imposed on covered entities engaged in the business of manufacturing or importing branded prescription drugs. This fee was enacted by section 9008 of the Patient Protection and Affordable Care Act, as amended by section 1404 of the Health Care and Education Reconciliation Act of 2010. This document also withdraws the Branded Prescription Drug Fee temporary regulations and contains new temporary regulations regarding the definition of controlled group that apply beginning on January 1, 2015. The final regulations and the new temporary regulations affect persons engaged in the business of manufacturing or importing certain branded prescription drugs. The text of the temporary regulations in this document also serves as the text of proposed regulations set forth in a notice of proposed rulemaking (REG-123286-14) on this subject in the Proposed Rules section in this issue of the Federal Register.

  1. Effect of radiation decontamination on drug-resistant bacteria

    International Nuclear Information System (INIS)

    Ito, Hitoshi

    2006-01-01

    More than 80% of food poisoning bacteria such as Salmonella are reported as antibiotic-resistant to at least one type antibiotic, and more than 50% as resistant to two or more. For the decontamination of food poisoning bacteria in foods, radiation resistibility on drug-resistant bacteria were investigated compared with drug-sensitive bacteria. Possibility on induction of drug-resistant mutation by radiation treatment was also investigated. For these studies, type strains of Escherichia coli S2, Salmonella enteritidis YK-2 and Staphylococcus aureus H12 were used to induce drug-resistant strains with penicillin G. From the study of radiation sensitivity on the drug-resistant strain induced from E. coli S2, D 10 value was obtained to be 0.20 kGy compared with 0.25 kGy at parent strain. On S. enteritidis YK-2, D 10 value was obtained to be 0.14 kGy at drug-resistant strain compared with 0.16 kGy at parent strain. D 10 value was also obtained to be 0.15 kGy at drug-resistant strain compared with 0.21 kGy at parent strain of St. aureus H12. Many isolates of E. coli 157:H7 or other type of E. coli from meats such as beef were resistant to penicillin G, and looked to be no relationship on radiation resistivities between drug-resistant strains and sensitive strains. On the study of radiation sensitivity on E. coli S2 at plate agars containing antibiotics, higher survival fractions were obtained at higher doses compared with normal plate agar. The reason of higher survival fractions at higher doses on plate agar containing antibiotics should be recovery of high rate of injured cells by the relay of cell division, and drug-resistant strains by mutation are hardly induced by irradiation. (author)

  2. Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.

    Science.gov (United States)

    Peng, Huiming; Peng, Tao; Wen, Jianguo; Engler, David A; Matsunami, Risë K; Su, Jing; Zhang, Le; Chang, Chung-Che Jeff; Zhou, Xiaobo

    2014-07-01

    p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown. To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography-mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph. New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NFкB pathway. ERK pathway regulating cell growth is synergistically regulated by p38δ isoform, whereas nuclear factor kappa B (NFкB) pathway regulating cell apoptosis is synergistically regulated by p38α isoform. This finding that p38δ isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NFκB might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection. RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Distribution of red blood cell antigens in drug-resistant and drug ...

    African Journals Online (AJOL)

    sofo

    Frequency distribution of ABO, Rh-Hr, MN, Kell blood group system antigens were studied in 277 TB patients (151-drug-sensitive and 126 drug-resistant) of pulmonary tuberculosis to know whether there was any association between them, and also between drug resistance and sensitiveness. They were compared with 485 ...

  4. Multi-drug resistant tuberculosis in Tanzania: Initial description of ...

    African Journals Online (AJOL)

    Background: Drug resistant Tuberculosis is well documented worldwide and is associated with increasing morbidity and mortality complicating Tuberculosis control with increasing costs of managing the disease. Broad. Objective: To describe clinical and laboratory characteristics of multi-drug resistant Tuberculosis ...

  5. Drug-resistance in chronic tuberculosis cases in Southern Nigeria ...

    African Journals Online (AJOL)

    Nigeria has a high burden of tuberculosis but the drug resistant situationwas previously unknown. This report evaluates the firstline drug resistance and associated factors among chronic tuberculosis cases from the tuberculosis control programme in South south and South east zones ofNigeria. Descriptive study of chronic ...

  6. Tuberculosis drug resistance in the Western Cape | Weyer | South ...

    African Journals Online (AJOL)

    Objectives: Drug resistance is a serious problem in the treatment of tuberculosis and a threat to successful tuberculosis control programmes. Local health workers have expressed concern that the increasing tuberculosis epidemic in the Western Cape is partly attributable to drug resistance. The aim of this study was to ...

  7. Multi drug resistant tuberculosis: a challenge in the management of ...

    African Journals Online (AJOL)

    Multi drug resistant tuberculosis (MDR-TB) will not usually respond to short course chemotherapy. Unless the individual infected with this bug is treated appropriately, they can continue spreading resistant strains in the community and further fuel the tuberculosis epidemic. Diagnosis requires drug sensitivity testing and the ...

  8. Adaptation and evolution of drug-resistant Mycobacterium tuberculosis

    NARCIS (Netherlands)

    Bergval, I.L.

    2013-01-01

    Many studies have been conducted on drug resistance and the evolution of Mycobacterium tuberculosis. Notwithstanding, many molecular mechanisms facilitating the emergence, adaptation and spread of drug-resistant tuberculosis have yet to be discovered. This thesis reports studies of the adaptive

  9. Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives.

    Science.gov (United States)

    Yasinzai, Masoom; Khan, Momin; Nadhman, Akhtar; Shahnaz, Gul

    2013-10-01

    Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The arvailable therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered.

  10. Identifying co-targets to fight drug resistance based on a random walk model

    Directory of Open Access Journals (Sweden)

    Chen Liang-Chun

    2012-01-01

    Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

  11. Early antiretroviral therapy and potent second-line drugs could decrease HIV incidence of drug resistance.

    Science.gov (United States)

    Shen, Mingwang; Xiao, Yanni; Rong, Libin; Meyers, Lauren Ancel; Bellan, Steven E

    2017-06-28

    Early initiation of antiretroviral therapy (ART) reduces the risk of drug-sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age-structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing. © 2017 The Author(s).

  12. Multi drug resistance tuberculosis: pattern seen in last 13 years

    International Nuclear Information System (INIS)

    Iqbal, R.; Shabbir, I.; Munir, K.; Tabassum, M.N.; Khan, S.U.; Khan, M.Z.U.

    2011-01-01

    Background: Drug resistance in tuberculosis is a serious problem throughout the world especially, after the emergence of multi drug resistant TB strains. Objectives: To estimate drug resistance in TB patients and compare it with previous studies to see the changing trends. Materials and Methods: The PMRC Research Centre receives sputum samples from all the leading hospitals of Lahore. This retrospective analysis was done from 1996 to 2008 on the multi drug resistant TB strains that were seen during these years. Five first lines anti tuberculosis drugs were tested on Lowenstein Jensen medium using standard proportion method. Results: A total of 2661 confirmed isolates of Mycobacterium tuberculosis were seen over the past 13 years. Of the total, 2182 were pulmonary and 479 were extra pulmonary specimens. The patients comprised of those with and without history of previous treatment. These specimens were subjected to drug susceptibility testing. Almost half of the patient had some resistance; multiple drug resistance was seen in 12.3% and 23.0% cases without and with history of previous treatment respectively. Overall resistance to rifampicin was 26.4%, isoniazid 24.1% streptomycin 21.6% ethambutol 13.4% and pyrazinamide 28.4% respectively. Statistically significant difference was seen between primary and acquired resistance. When compared with the reports from previous studies from the same area, there was a trend of gradual increase of drug resistance. Conclusions Resistance to anti tuberculosis drugs is high. Policy message. TB Control Program should start 'DOTS Plus' schemes for which drug susceptibility testing facilities should be available for correctly managing the patients. (author)

  13. Multi drug resistance tuberculosis: pattern seen in last 13 years

    Energy Technology Data Exchange (ETDEWEB)

    Iqbal, R; Shabbir, I; Munir, K [King Edward Medical University Hospital, Lahore (Pakistan). Dept. of Research Centre; Tabassum, M N; Khan, S U; Khan, M Z.U. [King Edward Medical University Hospital, Lahore (Pakistan). Dept. of Chest Medicine

    2011-01-15

    Background: Drug resistance in tuberculosis is a serious problem throughout the world especially, after the emergence of multi drug resistant TB strains. Objectives: To estimate drug resistance in TB patients and compare it with previous studies to see the changing trends. Materials and Methods: The PMRC Research Centre receives sputum samples from all the leading hospitals of Lahore. This retrospective analysis was done from 1996 to 2008 on the multi drug resistant TB strains that were seen during these years. Five first lines anti tuberculosis drugs were tested on Lowenstein Jensen medium using standard proportion method. Results: A total of 2661 confirmed isolates of Mycobacterium tuberculosis were seen over the past 13 years. Of the total, 2182 were pulmonary and 479 were extra pulmonary specimens. The patients comprised of those with and without history of previous treatment. These specimens were subjected to drug susceptibility testing. Almost half of the patient had some resistance; multiple drug resistance was seen in 12.3% and 23.0% cases without and with history of previous treatment respectively. Overall resistance to rifampicin was 26.4%, isoniazid 24.1% streptomycin 21.6% ethambutol 13.4% and pyrazinamide 28.4% respectively. Statistically significant difference was seen between primary and acquired resistance. When compared with the reports from previous studies from the same area, there was a trend of gradual increase of drug resistance. Conclusions Resistance to anti tuberculosis drugs is high. Policy message. TB Control Program should start 'DOTS Plus' schemes for which drug susceptibility testing facilities should be available for correctly managing the patients. (author)

  14. Repurposing and Revival of the Drugs: A New Approach to Combat the Drug Resistant Tuberculosis

    Directory of Open Access Journals (Sweden)

    Divakar Sharma

    2017-12-01

    Full Text Available Emergence of drug resistant tuberculosis like multi drug resistant tuberculosis (MDR-TB, extensively drug-resistant tuberculosis (XDR-TB and totally drug resistant tuberculosis (TDR-TB has created a new challenge to fight against these bad bugs of Mycobacterium tuberculosis. Repurposing and revival of the drugs are the new trends/options to combat these worsen situations of tuberculosis in the antibiotics resistance era or in the situation of global emergency. Bactericidal and synergistic effect of repurposed/revived drugs along with the latest drugs bedaquiline and delamanid used in the treatment of MDR-TB, XDR-TB, and TDR-TB might be the choice for future promising combinatorial chemotherapy against these bad bugs.

  15. Quantifying the Determinants of Evolutionary Dynamics Leading to Drug Resistance.

    Directory of Open Access Journals (Sweden)

    Guillaume Chevereau

    Full Text Available The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the "morbidostat", a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations-an almost paradoxical behavior since this drug causes DNA damage and increases the mutation

  16. Shigella Antimicrobial Drug Resistance Mechanisms, 2004-2014.

    Science.gov (United States)

    Nüesch-Inderbinen, Magdalena; Heini, Nicole; Zurfluh, Katrin; Althaus, Denise; Hächler, Herbert; Stephan, Roger

    2016-06-01

    To determine antimicrobial drug resistance mechanisms of Shigella spp., we analyzed 344 isolates collected in Switzerland during 2004-2014. Overall, 78.5% of isolates were multidrug resistant; 10.5% were ciprofloxacin resistant; and 2% harbored mph(A), a plasmid-mediated gene that confers reduced susceptibility to azithromycin, a last-resort antimicrobial agent for shigellosis.

  17. Cancer stem cells and drug resistance: the potential of nanomedicine

    Science.gov (United States)

    Vinogradov, Serguei; Wei, Xin

    2012-01-01

    Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and CSCs. PMID:22471722

  18. Enhanced Transmission of Drug-Resistant Parasites to Mosquitoes following Drug Treatment in Rodent Malaria

    OpenAIRE

    Bell, Andrew S.; Huijben, Silvie; Paaijmans, Krijn P.; Sim, Derek G.; Chan, Brian H. K.; Nelson, William A.; Read, Andrew F.

    2012-01-01

    The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasm...

  19. Diversity and evolution of drug resistance mechanisms in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Al-Saeedi M

    2017-10-01

    Full Text Available Mashael Al-Saeedi, Sahal Al-Hajoj Department of Infection and Immunity, Mycobacteriology Research Section, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Abstract: Despite the efficacy of antibiotics to protect humankind against many deadly pathogens, such as Mycobacterium tuberculosis, nothing can prevent the emergence of drug-resistant strains. Several mechanisms facilitate drug resistance in M. tuberculosis including compensatory evolution, epistasis, clonal interference, cell wall integrity, efflux pumps, and target mimicry. In this study, we present recent findings relevant to these mechanisms, which can enable the discovery of new drug targets and subsequent development of novel drugs for treatment of drug-resistant M. tuberculosis. Keywords: Mycobacterium tuberculosis, antibiotic resistance, compensatory evolution, epistasis, efflux pumps, fitness cost

  20. Drug-resistant gram-negative uropathogens: A review.

    Science.gov (United States)

    Khoshnood, Saeed; Heidary, Mohsen; Mirnejad, Reza; Bahramian, Aghil; Sedighi, Mansour; Mirzaei, Habibollah

    2017-10-01

    Urinary tract infection(UTI) caused by Gram-negative bacteria is the second most common infectious presentation in community medical practice. Approximately 150 million people are diagnosed with UTI each year worldwide. Drug resistance in Gram-negative uropathogens is a major global concern which can lead to poor clinical outcomes including treatment failure, development of bacteremia, requirement for intravenous therapy, hospitalization, and extended length of hospital stay. The mechanisms of drug resistance in these bacteria are important due to they are often not identified by routine susceptibility tests and have an exceptional potential for outbreaks. Treatment of UTIs depends on the access to effective drugs, which is now threatened by antibiotic resistant Gram-negative uropathogens. Although several effective antibiotics with activity against highly resistant Gram-negatives are available, there is not a unique antibiotic with activity against the high variety of resistance. Therefore, antimicrobial susceptibility tests, correlation between clinicians and laboratories, development of more rapid diagnostic methods, and continuous monitoring of drug resistance are urgent priorities. In this review, we will discuss about the current global status of drug-resistant Gram-negative uropathogens and their mechanisms of drug resistance to provide new insights into their treatment options. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  1. Fitness of Leishmania donovani parasites resistant to drug combinations.

    Directory of Open Access Journals (Sweden)

    Raquel García-Hernández

    2015-04-01

    Full Text Available Drug resistance represents one of the main problems for the use of chemotherapy to treat leishmaniasis. Additionally, it could provide some advantages to Leishmania parasites, such as a higher capacity to survive in stress conditions. In this work, in mixed populations of Leishmania donovani parasites, we have analyzed whether experimentally resistant lines to one or two combined anti-leishmanial drugs better support the stress conditions than a susceptible line expressing luciferase (Luc line. In the absence of stress, none of the Leishmania lines showed growth advantage relative to the other when mixed at a 1:1 parasite ratio. However, when promastigotes from resistant lines and the Luc line were mixed and exposed to different stresses, we observed that the resistant lines are more tolerant of different stress conditions: nutrient starvation and heat shock-pH stress. Further to this, we observed that intracellular amastigotes from resistant lines present a higher capacity to survive inside the macrophages than those of the control line. These results suggest that resistant parasites acquire an overall fitness increase and that resistance to drug combinations presents significant differences in their fitness capacity versus single-drug resistant parasites, particularly in intracellular amastigotes. These results contribute to the assessment of the possible impact of drug resistance on leishmaniasis control programs.

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

    Science.gov (United States)

    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.

  3. DNA origami as a carrier for circumvention of drug resistance.

    Science.gov (United States)

    Jiang, Qiao; Song, Chen; Nangreave, Jeanette; Liu, Xiaowei; Lin, Lin; Qiu, Dengli; Wang, Zhen-Gang; Zou, Guozhang; Liang, Xingjie; Yan, Hao; Ding, Baoquan

    2012-08-15

    Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.

  4. Mathematical modeling and computational prediction of cancer drug resistance.

    Science.gov (United States)

    Sun, Xiaoqiang; Hu, Bin

    2017-06-23

    Diverse forms of resistance to anticancer drugs can lead to the failure of chemotherapy. Drug resistance is one of the most intractable issues for successfully treating cancer in current clinical practice. Effective clinical approaches that could counter drug resistance by restoring the sensitivity of tumors to the targeted agents are urgently needed. As numerous experimental results on resistance mechanisms have been obtained and a mass of high-throughput data has been accumulated, mathematical modeling and computational predictions using systematic and quantitative approaches have become increasingly important, as they can potentially provide deeper insights into resistance mechanisms, generate novel hypotheses or suggest promising treatment strategies for future testing. In this review, we first briefly summarize the current progress of experimentally revealed resistance mechanisms of targeted therapy, including genetic mechanisms, epigenetic mechanisms, posttranslational mechanisms, cellular mechanisms, microenvironmental mechanisms and pharmacokinetic mechanisms. Subsequently, we list several currently available databases and Web-based tools related to drug sensitivity and resistance. Then, we focus primarily on introducing some state-of-the-art computational methods used in drug resistance studies, including mechanism-based mathematical modeling approaches (e.g. molecular dynamics simulation, kinetic model of molecular networks, ordinary differential equation model of cellular dynamics, stochastic model, partial differential equation model, agent-based model, pharmacokinetic-pharmacodynamic model, etc.) and data-driven prediction methods (e.g. omics data-based conventional screening approach for node biomarkers, static network approach for edge biomarkers and module biomarkers, dynamic network approach for dynamic network biomarkers and dynamic module network biomarkers, etc.). Finally, we discuss several further questions and future directions for the use of

  5. Drug-Resistant Bacteria: On the Edge of a Crisis | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... drug-resistant bacteria research program. Why are certain bacteria becoming more resistant to drugs? There is a ... a national, even global crisis of drug-resistant bacteria. Why is that? The more we see this ...

  6. Antimicrobial resistance determinant microarray for analysis of multi-drug resistant isolates

    Science.gov (United States)

    Taitt, Chris Rowe; Leski, Tomasz; Stenger, David; Vora, Gary J.; House, Brent; Nicklasson, Matilda; Pimentel, Guillermo; Zurawski, Daniel V.; Kirkup, Benjamin C.; Craft, David; Waterman, Paige E.; Lesho, Emil P.; Bangurae, Umaru; Ansumana, Rashid

    2012-06-01

    The prevalence of multidrug-resistant infections in personnel wounded in Iraq and Afghanistan has made it challenging for physicians to choose effective therapeutics in a timely fashion. To address the challenge of identifying the potential for drug resistance, we have developed the Antimicrobial Resistance Determinant Microarray (ARDM) to provide DNAbased analysis for over 250 resistance genes covering 12 classes of antibiotics. Over 70 drug-resistant bacteria from different geographic regions have been analyzed on ARDM, with significant differences in patterns of resistance identified: genes for resistance to sulfonamides, trimethoprim, chloramphenicol, rifampin, and macrolide-lincosamidesulfonamide drugs were more frequently identified in isolates from sources in Iraq/Afghanistan. Of particular concern was the presence of genes responsible for resistance to many of the last-resort antibiotics used to treat war traumaassociated infections.

  7. 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.

  8. Aggressive chemotherapy and the selection of drug resistant pathogens.

    Directory of Open Access Journals (Sweden)

    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.

  9. Hypoxia-induced cytotoxic drug resistance in osteosarcoma is independent of HIF-1Alpha.

    Directory of Open Access Journals (Sweden)

    Jennifer Adamski

    Full Text Available Survival rates from childhood cancer have improved dramatically in the last 40 years, such that over 80% of children are now cured. However in certain subgroups, including metastatic osteosarcoma, survival has remained stubbornly poor, despite dose intensive multi-agent chemotherapy regimens, and new therapeutic approaches are needed. Hypoxia is common in adult solid tumours and is associated with treatment resistance and poorer outcome. Hypoxia induces chemotherapy resistance in paediatric tumours including neuroblastoma, rhabdomyosarcoma and Ewing's sarcoma, in vitro, and this drug resistance is dependent on the oxygen-regulated transcription factor hypoxia inducible factor-1 (HIF-1. In this study the effects of hypoxia on the response of the osteosarcoma cell lines 791T, HOS and U2OS to the clinically relevant cytotoxics cisplatin, doxorubicin and etoposide were evaluated. Significant hypoxia-induced resistance to all three agents was seen in all three cell lines and hypoxia significantly reduced drug-induced apoptosis. Hypoxia also attenuated drug-induced activation of p53 in the p53 wild-type U2OS osteosarcoma cells. Drug resistance was not induced by HIF-1α stabilisation in normoxia by cobalt chloride nor reversed by the suppression of HIF-1α in hypoxia by shRNAi, siRNA, dominant negative HIF or inhibition with the small molecule NSC-134754, strongly suggesting that hypoxia-induced drug resistance in osteosarcoma cells is independent of HIF-1α. Inhibition of the phosphoinositide 3-kinase (PI3K pathway using the inhibitor PI-103 did not reverse hypoxia-induced drug resistance, suggesting the hypoxic activation of Akt in osteosarcoma cells does not play a significant role in hypoxia-induced drug resistance. Targeting hypoxia is an exciting prospect to improve current anti-cancer therapy and combat drug resistance. Significant hypoxia-induced drug resistance in osteosarcoma cells highlights the potential importance of hypoxia as a target

  10. Human Immunodeficiency Virus Type 1 Protease and the Emergence of Drug Resistance

    DEFF Research Database (Denmark)

    Poulsen, Nina Rødtness

    in multi-drug-resistant PRs. Computational analysis of a vast number of inhibitor-resistant HIV-1 PR variants can broaden the knowledge of how and why the mutations arise, which would be a great advantage in the design on resistance-evading inhibitors. Here we present a diverse system to select...... in the virus life cycle has made it a major target for drug development and active site competitive inhibitors have been successful in the battle against HIV. Unfortunately, the massive drug pressure along with high-level replication and lack of proofreading by the viral reverse transcriptase have resulted...... for catalytically active HIV-1 PR in the presence of inhibitor. The system is based on the protein AraC, which regulates transcription of the araA, araB and araD genes necessary for arabinose catabolism in Escherichia coli, and its effectiveness was demonstrated by the isolation of both known and unknown inhibitor-resistant...

  11. 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.

  12. Life cycle synchronization is a viral drug resistance mechanism.

    Directory of Open Access Journals (Sweden)

    Iulia A Neagu

    2018-02-01

    Full Text Available Viral infections are one of the major causes of death worldwide, with HIV infection alone resulting in over 1.2 million casualties per year. Antiviral drugs are now being administered for a variety of viral infections, including HIV, hepatitis B and C, and influenza. These therapies target a specific phase of the virus's life cycle, yet their ultimate success depends on a variety of factors, such as adherence to a prescribed regimen and the emergence of viral drug resistance. The epidemiology and evolution of drug resistance have been extensively characterized, and it is generally assumed that drug resistance arises from mutations that alter the virus's susceptibility to the direct action of the drug. In this paper, we consider the possibility that a virus population can evolve towards synchronizing its life cycle with the pattern of drug therapy. The periodicity of the drug treatment could then allow for a virus strain whose life cycle length is a multiple of the dosing interval to replicate only when the concentration of the drug is lowest. This process, referred to as "drug tolerance by synchronization", could allow the virus population to maximize its overall fitness without having to alter drug binding or complete its life cycle in the drug's presence. We use mathematical models and stochastic simulations to show that life cycle synchronization can indeed be a mechanism of viral drug tolerance. We show that this effect is more likely to occur when the variability in both viral life cycle and drug dose timing are low. More generally, we find that in the presence of periodic drug levels, time-averaged calculations of viral fitness do not accurately predict drug levels needed to eradicate infection, even if there is no synchronization. We derive an analytical expression for viral fitness that is sufficient to explain the drug-pattern-dependent survival of strains with any life cycle length. We discuss the implications of these findings for

  13. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Science.gov (United States)

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  14. [Mechanisms of endogenous drug resistance acquisition by spontaneous chromosomal gene mutation].

    Science.gov (United States)

    Fukuda, H; Hiramatsu, K

    1997-05-01

    Endogenous resistance in bacteria is caused by a change or loss of function and generally genetically recessive. However, this type of resistance acquisition are now prevalent in clinical setting. Chromosomal genes that afford endogenous resistance are the genes correlated with the target of the drug, the drug inactivating enzymes, and permeability of the molecules including the antibacterial agents. Endogenous alteration of the drug target are mediated by the spontaneous mutation of their structural gene. This mutation provides much lower affinity of the drugs for the target. Gene expression of the inactivating enzymes, such as class C beta-lactamase, is generally regulated by regulatory genes. Spontaneous mutations in the regulatory genes cause constitutive enzyme production and provides the resistant to the agent which is usually stable for such enzymes. Spontaneous mutation in the structural gene gives the enzyme extra-spectrum substrate specificity, like ESBL (Extra-Spectrum-beta-Lactamase). Expression of structural genes encoding the permeability systems are also regulated by some regulatory genes. The spontaneous mutation of the regulatory genes reduce an amount of porin protein. This mutation causes much lower influx of the drug in the cell. Spontaneous mutation in promoter region of the structural gene of efflux protein was observed. This mutation raised the gene transcription and overproduced efflux protein. This protein progresses the drug efflux from the cell.

  15. 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...

  16. Competitive release of drug resistance following drug treatment of mixed Plasmodium chabaudi infections.

    Science.gov (United States)

    de Roode, Jacobus C; Culleton, Richard; Bell, Andrew S; Read, Andrew F

    2004-09-14

    Malaria infections are often genetically diverse, potentially leading to competition between co-infecting strains. Such competition is of key importance in the spread of drug resistance. The effects of drug treatment on within-host competition were studied using the rodent malaria Plasmodium chabaudi. Mice were infected simultaneously with a drug-resistant and a drug-sensitive clone and were then either drug-treated or left untreated. Transmission was assessed by feeding mice to Anopheles stephensi mosquitoes. In the absence of drugs, the sensitive clone competitively suppressed the resistant clone; this resulted in lower asexual parasite densities and also reduced transmission to the mosquito vector. Drug treatment, however, allowed the resistant clone to fill the ecological space emptied by the removal of the sensitive clone, allowing it to transmit as well as it would have done in the absence of competition. These results show that under drug pressure, resistant strains can have two advantages: (1) they survive better than sensitive strains and (2) they can exploit the opportunities presented by the removal of their competitors. When mixed infections are common, such effects could increase the spread of drug resistance.

  17. Plasmid Conjugation in E. coli and Drug Resistance | Igwe ...

    African Journals Online (AJOL)

    This study aimed at determining the antibiotics susceptibility pattern of E. coli isolates claimed to be multidrug resistance using disc diffusion method. It also determined the presence of transferable resistance plasmids through conjugation and evaluated the medical significance of plasmid encoding E. coli and drug ...

  18. Antiretroviral drug resistance: A guide for the southern African clinician

    African Journals Online (AJOL)

    Both private and public sector see a bewildering clinical array of patients taking failing antiretroviral (ARV) regimens. We intend this article to provide a practical guide to help clinicians understand and manage ARV drug resistance in an African context. ARV resistance is a rapidly evolving field, requiring expertise in dealing ...

  19. 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

  20. Characterization of drug resistant Enterobacter species isolated from ...

    African Journals Online (AJOL)

    Enterobacter species are emerging clinical pathogens and they play important roles in the dissemination of drug resistant traits within the food chain due to their intrinsic abilities for resistance to commonly used antibiotics such as cephalosporins. Two Enterobacter cloacae and one Enterobacter hormaechei characterized in ...

  1. Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells

    Science.gov (United States)

    Bansal, Nitu; Mishra, Prasun J.; Stein, Mark; DiPaola, Robert S.; Bertino, Joseph R.

    2015-01-01

    Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial-mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl. PMID:26036314

  2. Drug Resistant Hypertension - No SIMPLE Way Out

    OpenAIRE

    Janusz Skrzypecki; Marcin Ufnal

    2015-01-01

    Hypertension poses growing challenge for health policy-makers and doctors worldwide. Recently published results of Symplicity-III trial (HTN-3), the first blinded, randomized, multicenter study on the efficacy of renal denervation for the treatment of resistant hypertension did not show a significant reduction of BP in patients with resistant hypertension 6 months after renal-artery denervation, as compared with controls. In this paper we review clinical and experimental studies on renal dene...

  3. Multi drug resistance and β-lactamase production by Klebsiella ...

    African Journals Online (AJOL)

    SERVER

    2007-08-06

    Aug 6, 2007 ... *Corresponding author. E-mail: gnsimha123@rediffmail.com. (Rice, 1999). plasmid that can be easily spread from one organisms to another (Sirot, 1995) these enzymes are capable of inactivating a variety of β-lactam drugs (Rice,. 1999). The ESBL producing organisms often show multi- drug resistant as ...

  4. Towards an understanding of drug resistance in malaria

    DEFF Research Database (Denmark)

    Lemcke, T; Christensen, I T; Jørgensen, Flemming Steen

    1999-01-01

    and structural differences. Based on this analysis the molecular consequences of point mutations known to be involved in drug resistance were discussed. The significance of the most important point mutation causing resistance, S108N, could be explained by the model, whereas the point mutations associated...... with enhanced resistance, N51I and C59R, seem to have a more indirect effect on inhibitor binding....

  5. Research Highlights: Helping Adolescents Resist Drugs

    National Research Council Canada - National Science Library

    2000-01-01

    Project ALERT departs boldly from prevention models of the 196Os and 197Os, which emphasized informing adolescents about the long-term consequences of drug use or building their decisionmaking skills...

  6. A study on Prevalence of Drug Resistance in Drug Default ...

    African Journals Online (AJOL)

    ), and particularly multidrug-resistant TB (MDR-TB), has become a significant public health problem in a number of countries and an obstacle to effective global TB control. Method: This is a prospective randomized cross sectional study to ...

  7. Challenges of drug resistance in the management of pancreatic cancer.

    LENUS (Irish Health Repository)

    Sheikh, Rizwan

    2012-02-01

    The current treatment of choice for metastatic pancreatic cancer involves single-agent gemcitabine or a combination of gemcitabine with capecitabine or erlotinib (a tyrosine kinase inhibitor). Only 25–30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, resistance to apoptosis and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target and\\/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments.

  8. 78 FR 35117 - Orphan Drug Regulations

    Science.gov (United States)

    2013-06-12

    ..., ``This [framework] affects the plasma protein therapeutics industry significantly because various drugs... orphan designated.'' Because many plasma protein therapies lack orphan-drug designation, they are... change in delivery system from intravenous (IV) to oral may, in some cases and for some drugs, constitute...

  9. Drug Resistant Hypertension - No SIMPLE Way Out

    Directory of Open Access Journals (Sweden)

    Janusz Skrzypecki

    2015-02-01

    Full Text Available Hypertension poses growing challenge for health policy-makers and doctors worldwide. Recently published results of Symplicity-III trial (HTN-3, the first blinded, randomized, multicenter study on the efficacy of renal denervation for the treatment of resistant hypertension did not show a significant reduction of BP in patients with resistant hypertension 6 months after renal-artery denervation, as compared with controls. In this paper we review clinical and experimental studies on renal denervation. In order to identify causes of inconsistent results in renal denervation studies we look at basic science support for renal denervation and at designs of clinical trials.

  10. Functional miRNAs in breast cancer drug resistance

    Directory of Open Access Journals (Sweden)

    Hu WZ

    2018-03-01

    Full Text Available Weizi Hu,1–3,* Chunli Tan,1–3,* Yunjie He,4 Guangqin Zhang,2 Yong Xu,3,5 Jinhai Tang1 1Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 3Nanjing Medical University Affiliated Cancer Hospital, 4The First Clinical School of Nanjing Medical University, 5Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Owing to improved early surveillance and advanced therapy strategies, the current death rate due to breast cancer has decreased; nevertheless, drug resistance and relapse remain obstacles on the path to successful systematic treatment. Multiple mechanisms responsible for drug resistance have been elucidated, and miRNAs seem to play a major part in almost every aspect of cancer progression, including tumorigenesis, metastasis, and drug resistance. In recent years, exosomes have emerged as novel modes of intercellular signaling vehicles, initiating cell–cell communication through their fusion with target cell membranes, delivering functional molecules including miRNAs and proteins. This review particularly focuses on enumerating functional miRNAs involved in breast cancer drug resistance as well as their targets and related mechanisms. Subsequently, we discuss the prospects and challenges of miRNA function in drug resistance and highlight valuable approaches for the investigation of the role of exosomal miRNAs in breast cancer progression and drug resistance. Keywords: microRNA, exosome, breast cancer, drug resistance

  11. Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

    Directory of Open Access Journals (Sweden)

    Abdullah Mayati

    2017-04-01

    Full Text Available Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug–drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs in transporter regulations are summarized and discussed. Both solute carrier (SLC and ATP-binding cassette (ABC drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner. PKCs are notably implicated in membrane insertion of bile acid transporters in liver and, in this way, are thought to contribute to cholestatic or choleretic effects of endogenous compounds or drugs. The exact clinical relevance of PKCs-related regulation of drug transporters in terms of drug resistance, pharmacokinetics, drug–drug interactions and drug toxicity remains however to be precisely determined. This issue is likely important to consider in the context of the development of new drugs targeting PKCs-mediated signaling pathways, for treating notably cancers, diabetes or psychiatric disorders.

  12. Quantification of Markers of Antimalarial Drug Resistance ...

    African Journals Online (AJOL)

    MALISA DR

    2012-08-28

    Aug 28, 2012 ... vivo method for the detection of resistance, and has the potential to guide public health policy in a timely manner. .... signal such that the greater the intensity the greater the parasite .... was carried out by light box illumination, while the phophoimager ..... weakness of underestimation of SNPs/haplotypes.

  13. Insulin resistance induced by antiretroviral drugs: Current ...

    African Journals Online (AJOL)

    Treatment with highly active antiretroviral therapy (HAART) has improved the prognosis of patients with AIDS, but it has also increased the incidence of various metabolic disorders, in particular insulin resistance accompanied by dyslipidaemia, hyperglycaemia and lipodystrophy. This is often accompanied by frank type 2 ...

  14. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a

  15. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

    Directory of Open Access Journals (Sweden)

    Olliaro P

    2004-01-01

    Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

  16. Establishing Drug Resistance in Microorganisms by Mass Spectrometry

    Science.gov (United States)

    Demirev, Plamen A.; Hagan, Nathan S.; Antoine, Miquel D.; Lin, Jeffrey S.; Feldman, Andrew B.

    2013-08-01

    A rapid method to determine drug resistance in bacteria based on mass spectrometry is presented. In it, a mass spectrum of an intact microorganism grown in drug-containing stable isotope-labeled media is compared with a mass spectrum of the intact microorganism grown in non-labeled media without the drug present. Drug resistance is determined by predicting characteristic mass shifts of one or more microorganism biomarkers using bioinformatics algorithms. Observing such characteristic mass shifts indicates that the microorganism is viable even in the presence of the drug, thus incorporating the isotopic label into characteristic biomarker molecules. The performance of the method is illustrated on the example of intact E. coli, grown in control (unlabeled) and 13C-labeled media, and analyzed by MALDI TOF MS. Algorithms for data analysis are presented as well.

  17. Antifolate drug resistance: Novel mutations and haplotype ...

    Indian Academy of Sciences (India)

    N P Sarmah

    2017-09-27

    Sep 27, 2017 ... distribution in dhps and dhfr from Northeast India ... The findings of this study strongly discourage the use SP as a partner drug in ACT. ... led to critical hindrances in controlling of Plasmodium fal- ciparum (Pf) malaria in this part of India. ..... alignment editor and analysis programme for Windows95/98/. NT.

  18. Profiling evolutionary landscapes underlying drug resistance

    DEFF Research Database (Denmark)

    Hickman, Rachel

    bacterial communities i.e. biofilms or dormant metabolic states. Antibiotic drugs are currently our best medicine to treat (against) bacterial pathogens due to antibiotics unique properties of being small molecules that are soluble and act systemically. These qualities allow for many modern medical...

  19. Efflux Pump-mediated Drug Resistance in Burkholderia

    Directory of Open Access Journals (Sweden)

    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.

  20. Global transcriptional profiling of longitudinal clinical isolates of Mycobacterium tuberculosis exhibiting rapid accumulation of drug resistance.

    Directory of Open Access Journals (Sweden)

    Anirvan Chatterjee

    Full Text Available The identification of multidrug resistant (MDR, extensively and totally drug resistant Mycobacterium tuberculosis (Mtb, in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB, cell wall biosynthesis (emb genes, protein synthesis (rpl and additional central metabolic pathways (ppdK, pknH, pfkB were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with

  1. TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells

    DEFF Research Database (Denmark)

    Hekmat, Omid; Munk, Stephanie; Fogh, Louise

    2013-01-01

    may explain the resistance phenotype to topoisomerase inhibitors that was observed in cells with high TIMP-1 levels. Pathway analysis showed an enrichment of proteins from functional categories such as apoptosis, cell cycle, DNA repair, transcription factors, drug targets and proteins associated......Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a protein with a potential biological role in drug resistance. To elucidate the unknown molecular mechanisms underlying the association between high TIMP-1 levels and increased chemotherapy resistance, we employed SILAC-based quantitative mass...... spectrometry to analyze global proteome and phosphoproteome differences of MCF-7 breast cancer cells expressing high or low levels of TIMP-1. In TIMP-1 high expressing cells, 312 proteins and 452 phosphorylation sites were up-regulated. Among these were the cancer drug targets topoisomerase 1, 2A and 2B, which...

  2. Extensively Drug-Resistant Tuberculosis: Principles of Resistance, Diagnosis, and Management.

    Science.gov (United States)

    Wilson, John W; Tsukayama, Dean T

    2016-04-01

    Extensively drug-resistant (XDR) tuberculosis (TB) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. Although new drug developments have enabled TB to be more readily curable, inappropriate TB management has led to the emergence of drug-resistant disease. Extensively drug-resistant TB describes Mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. It proliferates when established case management and infection control procedures are not followed. Optimized treatment outcomes necessitate time-sensitive diagnoses, along with expanded combinations and prolonged durations of antimicrobial drug therapy. The challenges to public health institutions are immense and most noteworthy in underresourced communities and in patients coinfected with human immunodeficiency virus. A comprehensive and multidisciplinary case management approach is required to optimize outcomes. We review the principles of TB drug resistance and the risk factors, diagnosis, and managerial approaches for extensively drug-resistant TB. Treatment outcomes, cost, and unresolved medical issues are also discussed. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  3. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes

    Directory of Open Access Journals (Sweden)

    Gudepalya Renukaiah Rudramurthy

    2016-06-01

    Full Text Available Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals. Antimicrobials are considered “miracle drugs” and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, which is one of the greatest challenges for healthcare practitioners and is a significant global threat. The major concern with the development of antimicrobial resistance is the spread of resistant organisms. The replacement of conventional antimicrobials by new technology to counteract antimicrobial resistance is ongoing. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug resistance. Nanomaterials have tremendous potential in both the medical and veterinary fields. Several nanostructures comprising metallic particles have been developed to counteract microbial pathogens. The effectiveness of nanoparticles (NPs depends on the interaction between the microorganism and the NPs. The development of effective nanomaterials requires in-depth knowledge of the physicochemical properties of NPs and the biological aspects of microorganisms. However, the risks associated with using NPs in healthcare need to be addressed. The present review highlights the antimicrobial effects of various nanomaterials and their potential advantages, drawbacks, or side effects. In addition, this comprehensive information may be useful in the discovery of broad-spectrum antimicrobial drugs for use against multi-drug-resistant microbial pathogens in the near future.

  4. An investigation of classification algorithms for predicting HIV drug resistance without genotype resistance testing

    CSIR Research Space (South Africa)

    Brandt, P

    2014-01-01

    Full Text Available is limited in low-resource settings. In this paper we investigate machine learning techniques for drug resistance prediction from routine treatment and laboratory data to help clinicians select patients for confirmatory genotype testing. The techniques...

  5. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  6. mTOR Signaling Confers Resistance to Targeted Cancer Drugs.

    Science.gov (United States)

    Guri, Yakir; Hall, Michael N

    2016-11-01

    Cancer is a complex disease and a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, the clinical benefits of such drugs are at best transient due to tumors displaying intrinsic or adaptive resistance. The underlying compensatory pathways that allow cancer cells to circumvent a drug blockade are poorly understood. We review here recent studies suggesting that mammalian TOR (mTOR) signaling is a major compensatory pathway conferring resistance to many cancer drugs. mTOR-mediated resistance can be cell-autonomous or non-cell-autonomous. These findings suggest that mTOR signaling should be monitored routinely in tumors and that an mTOR inhibitor should be considered as a co-therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. [A novel chemo-resistant gene MSX2 discovered by establishment of two pancreatic cancer drug resistant cell lines JF305/CDDP and PANC-1/GEM].

    Science.gov (United States)

    Yuan, W; Sui, C G; Ma, X; Ma, J

    2018-05-23

    Objective: To explore new multidrug resistant genes of pancreatic cancer by establishment and characterization of chemo-resistant cell lines. Methods: The cisplatin-resistant cell line JF305/CDDP and the gemcitabine-resistant cell line PANC-1/GEM were induced by high-dose intermittent treatment. CCK-8 assay was used to detect the 50% inhibiting concentration (IC(50)), drug resistance index (R), cross-resistance, and growth difference of different cells. The changes of cell cycle and migration ability of drug-resistant cells were determined by flow cytometry and transwell assay, respectively. And then real-time fluorescence quantitative PCR was used to detect the expression of multidrug resistance-related genes. Results: The drug resistance indexes of JF305/CDDP and PANC-1/GEM were 15.3 and 27.31, respectively, and there was cross-resistance. Compared with the parental cells, the proliferation rate of JF305/CDDP was decreased by 40% on the fourth day ( P PANC-1 cells upregulated MRP2 level ( P PANC-1/GEM, were successfully established. MSX2 might be a new drug resistance related gene in pancreatic cancer cells by up-regulation of MRP2 expression.

  8. Co-induction of glucose regulated proteins and adriamycin resistance in Chinese hamster cells

    International Nuclear Information System (INIS)

    Shen, J.; Hughes, C.; Cai, J.; Bartels, C.; Gessner, T.; Subjeck, J.

    1987-01-01

    Glucose deprivation, anoxia, calcium ionophore A23187 or 2-deoxyglucose all inducers of glucose regulated proteins (grps), also lead to a significant induction of resistance to the drug adriamycin. In the case of anoxia, A23187 and 2-deoxyglucose, the induction of resistance correlates with both the application of the inducing stress and the induction of grps. In the case of glucose deprivation, the onset of resistance correlates with the onset of glucose deprivation and precedes grp induction. Removal of each grp including condition results in the rapid disappearance of this resistance in a manner which correlates with the repression of the grps. This drug resistance can be induced in confluent cells or in actively proliferating cells, although the effect is greater in the more sensitive proliferating cells. Induction of heat shock proteins (hsps) does not appear to lead to any major change in adriamycin resistance. Grp induced cells retain less adriamycin than do controls with the greatest reduction occurring during anoxia, which is also the strongest inducer of grps and resistance. The authors propose that the application of a grp inducing stress leads to a concurrent induction in drug resistance, possibly via the translocation of grps in the cell. Finally, they also observed that adriamycin itself can induce both hsps and grps. It is possible that adriamycin exposure may correspondingly induce auto-resistance

  9. Prevalence of genotypic HIV-1 drug resistance in Thailand, 2002

    Directory of Open Access Journals (Sweden)

    Watitpun Chotip

    2003-03-01

    Full Text Available Abstract Background The prices of reverse transcriptase (RT inhibitors in Thailand have been reduced since December 1, 2001. It is expected that reduction in the price of these inhibitors may influence the drug resistance mutation pattern of HIV-1 among infected people. This study reports the frequency of HIV-1 genetic mutation associated with drug resistance in antiretroviral-treated patients from Thailand. Methods Genotypic resistance testing was performed on samples collected in 2002 from 88 HIV-1 infected individuals. Automated DNA sequencing was used to genotype the HIV-1 polymerase gene isolated from patients' plasma. Results Resistance to protease inhibitors, nucleoside and non-nucleoside reverse transcriptase inhibitors were found in 10 (12%, 42 (48% and 19 (21% patients, respectively. The most common drug resistance mutations in the protease gene were at codon 82 (8%, 90 (7% and 54 (6%, whereas resistant mutations at codon 215 (45%, 67 (40%, 41 (38% and 184 (27% were commonly found in the RT gene. This finding indicates that genotypic resistance to nucleoside reverse transcriptase inhibitors was prevalent in 2002. The frequency of resistant mutations corresponding to non-nucleoside reverse transcriptase inhibitors was three times higher-, while resistant mutation corresponding to protease inhibitors was two times lower than those frequencies determined in 2001. Conclusion This study shows that the frequencies of RT inhibitor resistance mutations have been increased after the reduction in the price of RT inhibitors since December 2001. We believe that this was an important factor that influenced the mutation patterns of HIV-1 protease and RT genes in Thailand.

  10. Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria.

    Directory of Open Access Journals (Sweden)

    Andrew S Bell

    Full Text Available The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

  11. Dynamic optical tweezers based assay for monitoring early drug resistance

    International Nuclear Information System (INIS)

    Wu, Xiaojing; Zhu, Siwei; Feng, Jie; Zhang, Yuquan; Min, Changjun; Yuan, X-C

    2013-01-01

    In this letter, a dynamic optical tweezers based assay is proposed and investigated for monitoring early drug resistance with Pemetrexed-resistant non-small cell lung cancer (NSCLC) cell lines. The validity and stability of the method are verified experimentally in terms of the physical parameters of the optical tweezers system. The results demonstrate that the proposed technique is more convenient and faster than traditional techniques when the capability of detecting small variations of the response of cells to a drug is maintained. (letter)

  12. Multi drug resistance to cancer chemotherapy: Genes involved and blockers

    International Nuclear Information System (INIS)

    Sayed-Ahmed, Mohamed M.

    2007-01-01

    During the last three decades, important and considerable research efforts had been performed to investigate the mechanism through which cancer cells overcome the cytotoxic effects of a variety of chemotherapeutic drugs. Most of the previously published work has been focused on the resistance of tumor cells to those anticancer drugs of natural source. Multidrug resistance (MDR) is a cellular cross-resistance to a broad spectrum of natural products used in cancer chemotherapy and is believed to be the major cause of the therapeutic failures of the drugs belonging to different naturally obtained or semisynthetic groups including vinca alkaloids, taxans, epipodophyllotoxins and certain antibiotics. This phenomenon results from overexpression of four MDR genes and their corresponding proteins that act as membrane-bound ATP consuming pumps. These proteins mediate the efflux of many structurally and functionally unrelated anticancer drugs of natural source. MDR may be intrinsic or acquired following exposure to chemotherapy. The existence of intrinsically resistant tumor cell clone before and following chemotherapeutic treatment has been associated with a worse final outcome because of increased incidence of distant metasis. In view of irreplaceability of natural product anticancer drugs as effective chemotherapeutic agents, and in view of MDR as a major obstacle to successful chemotherapy, this review is aimed to highlight the genes involved in MDR, classical MDR blockers and gene therapy approaches to overcome MDR. (author)

  13. "A'ole" Drugs! Cultural Practices and Drug Resistance of Rural Hawai'ian Youths

    Science.gov (United States)

    Po'A-Kekuawela, Ka'Ohinani; Okamoto, Scott K.; Nebre, La Risa H.; Helm, Susana; Chin, Coralee I. H.

    2009-01-01

    This qualitative study examined how Native Hawai'ian youths from rural communities utilized cultural practices to promote drug resistance and/or abstinence. Forty-seven students from five different middle schools participated in gender-specific focus groups that focused on the cultural and environmental contexts of drug use for Native Hawai'ian…

  14. Hepatitis C Virus and Antiviral Drug Resistance.

    Science.gov (United States)

    Kim, Seungtaek; Han, Kwang-Hyub; Ahn, Sang Hoon

    2016-11-15

    Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens.

  15. Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions

    OpenAIRE

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-01-01

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g....

  16. Role of endocannabinoids in regulating drug dependence

    Directory of Open Access Journals (Sweden)

    Daniela Parolaro

    2007-01-01

    Full Text Available Daniela Parolaro, Daniela Vigano’, Natalia Realini, Tiziana RubinoNeuroscience Center, DBSF, University of Insubria, Busto Arsizio, ItalyAbstract: This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CB1 receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs.Keywords: Endocannabinoids, drug dependence, opioids, nicotine, alcohol, psychostimulants

  17. Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy

    Directory of Open Access Journals (Sweden)

    Jinsoo Lee

    2016-01-01

    Full Text Available Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p=0.0284, Fisher’s exact test. Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children.

  18. Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines.

    Directory of Open Access Journals (Sweden)

    William A May

    Full Text Available Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32, two after chemotherapy and progressive disease (CHLA-10, CHLA-25, and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT (CHLA-258, COG-E-352. The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR analysis, p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC or the lower tested concentration (LTC: (cyclophosphamide (as 4-HC and doxorubicin at CAC, etoposide, irinotecan (as SN-38 and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.

  19. The Emerging Role of Extracellular Vesicle-Mediated Drug Resistance in Cancers: Implications in Advanced Prostate Cancer.

    Science.gov (United States)

    Soekmadji, Carolina; Nelson, Colleen C

    2015-01-01

    Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

  20. Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism.

    Science.gov (United States)

    Joyce, Helena; McCann, Andrew; Clynes, Martin; Larkin, Annemarie

    2015-05-01

    Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment.

  1. Emerging drug -resistance and guidelines for treatment of malaria

    International Nuclear Information System (INIS)

    Khan, M.A.; Smego Jr, R.A.; Razi, S.T.; Beg, M.A.

    2004-01-01

    The increasing prevalence of multi-resistant Plasmodium falciparum malaria worldwide is a serious public health threat to the global control of malaria, especially in poor countries like Pakistan. In many countries chloroquine-resistance is a huge problem, accounting for more than 90% of malaria cases. In Pakistan, resistance to chloroquine is on the rise and reported in up to 16- 62% of Plasmodium falciparum. Four to 25% of Plasmodium falciparum also reported to be resistant to sulfadoxine-pyrimethamine and several cases of delayed parasite clearance have been observed in patients with Plasmodium falciparum malaria treated with quinine. In this article we have introduced the concept of artemisinin- based combination therapy (ACT) and emphasize the use of empiric combination therapy for all patients with Plasmodium falciparum malaria to prevent development of drug resistance and to obtain additive and synergistic killing of parasite. (author)

  2. 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.

  3. Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

    Science.gov (United States)

    Upcroft, Peter; Upcroft, Jacqueline A.

    2001-01-01

    The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently

  4. Ribonucleotide reductase as a drug target against drug resistance Mycobacterium leprae: A molecular docking study.

    Science.gov (United States)

    Mohanty, Partha Sarathi; Bansal, Avi Kumar; Naaz, Farah; Gupta, Umesh Datta; Dwivedi, Vivek Dhar; Yadava, Umesh

    2018-06-01

    Leprosy is a chronic infection of skin and nerve caused by Mycobacterium leprae. The treatment is based on standard multi drug therapy consisting of dapsone, rifampicin and clofazamine. The use of rifampicin alone or with dapsone led to the emergence of rifampicin-resistant Mycobacterium leprae strains. The emergence of drug-resistant leprosy put a hurdle in the leprosy eradication programme. The present study aimed to predict the molecular model of ribonucleotide reductase (RNR), the enzyme responsible for biosynthesis of nucleotides, to screen new drugs for treatment of drug-resistant leprosy. The study was conducted by retrieving RNR of M. leprae from GenBank. A molecular 3D model of M. leprae was predicted using homology modelling and validated. A total of 325 characters were included in the analysis. The predicted 3D model of RNR showed that the ϕ and φ angles of 251 (96.9%) residues were positioned in the most favoured regions. It was also conferred that 18 α-helices, 6 β turns, 2 γ turns and 48 helix-helix interactions contributed to the predicted 3D structure. Virtual screening of Food and Drug Administration approved drug molecules recovered 1829 drugs of which three molecules, viz., lincomycin, novobiocin and telithromycin, were taken for the docking study. It was observed that the selected drug molecules had a strong affinity towards the modelled protein RNR. This was evident from the binding energy of the drug molecules towards the modelled protein RNR (-6.10, -6.25 and -7.10). Three FDA-approved drugs, viz., lincomycin, novobiocin and telithromycin, could be taken for further clinical studies to find their efficacy against drug resistant leprosy. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. The Food and Drug Administration and Drug Legalization: A Brief Model of Regulation

    OpenAIRE

    Kalam, Murad

    2002-01-01

    This paper offers a brief model of FDA regulation of currently illegal narcotics in the United States. Given that nearly three out of four Americans believe that the drug war has failed, recent calls from prominent liberal and conservative thinkers to legalize drugs, and state “compassionate use†ballot initiatives, future drug legalization is at least conceivable in the United States. Yet, how would the FDA regulate NLD’s under its current st...

  6. Mycobacterium tuberculosis drug-resistance in previously treated ...

    African Journals Online (AJOL)

    Corresponding to: Professor Lassana Sangaré, Department of Bacteriology and Virology, University Hospital Centre. Yalgado Ouedraogo, 03 BP 7022 Ouagadougou 03, Burkina Faso. E-mail: sangarel@hotmail.com. Abstract. Background: Tuberculosis drug-resistance becomes common in sub-Saharan Africa; however, ...

  7. Diversity of Urinary Tract Pathogens and Drug Resistant Isolates of ...

    African Journals Online (AJOL)

    Purpose: This paper was mainly aimed to investigate drug resistance of the various urinary tract infection (UTI) pathogens from patients of different gender and age groups of Pakistanis. Method: For these purposes, urine samples of 109 patients were analyzed. Samples were screened on CLED agar. Antimicrobial ...

  8. Beijing/W genotype Mycobacterium tuberculosis and drug resistance.

    NARCIS (Netherlands)

    Glynn, Judith R; Kremer, Kristin; Borgdorff, Martien W; Rodriguez, Mar Pujades; Soolingen, Dick van

    2006-01-01

    Beijing/W genotype Mycobacterium tuberculosis is widespread, may be increasing, and may have a predilection for drug resistance. Individual-level data on >29,000 patients from 49 studies in 35 countries were combined to assess the Beijing genotype's prevalence worldwide, trends over time and with

  9. National anti-tuberculosis drug resistance study in Tanzania

    NARCIS (Netherlands)

    Chonde, T. M.; Basra, D.; Mfinanga, S. G. M.; Range, N.; Lwilla, F.; Shirima, R. P.; van Deun, A.; Zignol, M.; Cobelens, F. G.; Egwaga, S. M.; van Leth, F.

    2010-01-01

    OBJECTIVE: To assess the prevalence of anti-tuberculosis drug resistance in a national representative sample of tuberculosis (TB) patients in Tanzania according to recommended methodology. DESIGN: Cluster survey, with 40 clusters sampled proportional to size, of notified TB patients from all

  10. Drug-resistant tuberculosis: time for visionary political leadership.

    Science.gov (United States)

    Abubakar, Ibrahim; Zignol, Matteo; Falzon, Dennis; Raviglione, Mario; Ditiu, Lucica; Masham, Susan; Adetifa, Ifedayo; Ford, Nathan; Cox, Helen; Lawn, Stephen D; Marais, Ben J; McHugh, Timothy D; Mwaba, Peter; Bates, Matthew; Lipman, Marc; Zijenah, Lynn; Logan, Simon; McNerney, Ruth; Zumla, Adam; Sarda, Krishna; Nahid, Payam; Hoelscher, Michael; Pletschette, Michel; Memish, Ziad A; Kim, Peter; Hafner, Richard; Cole, Stewart; Migliori, Giovanni Battista; Maeurer, Markus; Schito, Marco; Zumla, Alimuddin

    2013-06-01

    Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans. Copyright © 2013 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd. All rights reserved.

  11. Drug-resistant post-neurosurgical nosocomial Acinetobacter ...

    African Journals Online (AJOL)

    Drug-resistant post-neurosurgical nosocomial Acinetobacter baumannii meningitis in two Iranian hospitals. ... Vol 11, No 17 (2012) >. Log in or Register to get access to full text downloads. ... Acinetobacter baumannii may cause meningitis and ventriculitis, particularly after head trauma and/or neurosurgery. The rate of ...

  12. Laboratory methods for diagnosis and detection of drug resistant ...

    African Journals Online (AJOL)

    Data source: Published series of peer reviewed journals and manuals written on laboratory methods that are currently used for diagnosis and detection of drug resistance of Mycobacterium tuberculosis complex were reviewed using the index medicus, pubmed and medline search. Conventional bacteriological microscopy ...

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

    Science.gov (United States)

    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.

  14. Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.

    Science.gov (United States)

    Ragland, Debra A; Whitfield, Troy W; Lee, Sook-Kyung; Swanstrom, Ronald; Zeldovich, Konstantin B; Kurt-Yilmaz, Nese; Schiffer, Celia A

    2017-11-14

    HIV-1 protease is responsible for the cleavage of 12 nonhomologous sites within the Gag and Gag-Pro-Pol polyproteins in the viral genome. Under the selective pressure of protease inhibition, the virus evolves mutations within (primary) and outside of (secondary) the active site, allowing the protease to process substrates while simultaneously countering inhibition. The primary protease mutations impede inhibitor binding directly, while the secondary mutations are considered accessory mutations that compensate for a loss in fitness. However, the role of secondary mutations in conferring drug resistance remains a largely unresolved topic. We have shown previously that mutations distal to the active site are able to perturb binding of darunavir (DRV) via the protein's internal hydrogen-bonding network. In this study, we show that mutations distal to the active site, regardless of context, can play an interdependent role in drug resistance. Applying eigenvalue decomposition to collections of hydrogen bonding and van der Waals interactions from a series of molecular dynamics simulations of 15 diverse HIV-1 protease variants, we identify sites in the protease where amino acid substitutions lead to perturbations in nonbonded interactions with DRV and/or the hydrogen-bonding network of the protease itself. While primary mutations are known to drive resistance in HIV-1 protease, these findings delineate the significant contributions of accessory mutations to resistance. Identifying the variable positions in the protease that have the greatest impact on drug resistance may aid in future structure-based design of inhibitors.

  15. 76 FR 64868 - Orphan Drug Regulations

    Science.gov (United States)

    2011-10-19

    ...: Pharmacological Property: The mechanism of action is a common principle for limiting the investigation and use of... drug, even in the face of a holder's exclusive marketing rights, if the subsequent sponsor advances a... appropriate, for those additional subsets from the date of such additional marketing approval(s). Before...

  16. Mechanisms of antifungal drug resistance in Candida dubliniensis.

    LENUS (Irish Health Repository)

    Coleman, David C

    2010-06-01

    Candida dubliniensis was first described in 1995 and is the most closely related species to the predominant human fungal pathogen Candida albicans. C. dubliniensis is significantly less prevalent and less pathogenic than C. albicans and is primarily associated with infections in HIV-infected individuals and other immunocompromised cohorts. The population structure of C. dubliniensis consists of three well-defined major clades and is significantly less diverse than C. albicans. The majority of C. dubliniensis isolates are susceptible to antifungal drugs commonly used to treat Candida infections. To date only two major patterns of antifungal drug resistance have been identified and the molecular mechanisms of these are very similar to the resistance mechanisms that have been described previously in C. albicans. However, significant differences are evident in the predominant antifungal drug mechanisms employed by C. dubliniensis, differences that reflect its more clonal nature, its lower prevalence and characteristics of its genome, the complete sequence of which has only recently been determined.

  17. DNA origami/gold nanorod hybrid nanostructures for the circumvention of drug resistance.

    Science.gov (United States)

    Song, Linlin; Jiang, Qiao; Liu, Jianbing; Li, Na; Liu, Qing; Dai, Luru; Gao, Yuan; Liu, Weili; Liu, Dongsheng; Ding, Baoquan

    2017-06-14

    We herein demonstrate that DNA origami can work as a multifunctional platform integrating a chemotherapeutic drug (doxorubicin), gold nanorods and a tumour-specific aptamer MUC-1, to realize the effective circumvention of drug resistance. Doxorubicin (DOX) was loaded efficiently onto DNA origami through base pair intercalation and surface-modified gold nanorods (AuNRs) were assembled onto the DNA origami through DNA hybridization. Due to the active targeting effect of the assembled aptamers, the multifunctional nanostructures achieved increased cellular internalization of DOX and AuNRs. Upon near-infrared (NIR) laser irradiation, the P-glycoprotein (multidrug resistance pump) expression of multidrug resistant MCF-7 (MCF-7/ADR) cells was down-regulated, achieving the synergistically chemotherapeutic (DOX) and photothermal (AuNRs) effects.

  18. Molecular mechanisms of drug resistance and tumor promotion involving mammalian ribonucleotide reductase

    Energy Technology Data Exchange (ETDEWEB)

    Choy, B.B.K.

    1991-01-01

    Mammalian ribonucleotide reductase is a highly regulated, rate-limiting activity responsible for converting ribonucleoside diphosphates to the deoxyribonucleotide precursors of DNA. The enzyme consists of two nonidentical proteins called M1 and M2, both of which are required for activity. Hydroxyurea is an antitumor agent which inhibits ribonucleotide reductase by interacting with the M2 component specifically at a unique tyrosyl free radical. Studies were conducted on a series of drug resistant mouse cell lines, selected by a step-wise procedure for increasing levels of resistance to the cytotoxic effects of hydroxyurea. Each successive drug selection step leading to the isolation of highly resistant cells was accompanied by stable elevations in cellular resistance and ribonucleotide reductase activity. The drug resistant cell lines exhibited gene amplification of the M2 gene, elevated M2 mRNA, and M2 protein. In addition to M2 gene amplification, posttranscriptional modulation also occurred during the drug selection. Studies of the biosynthesis rates with exogenously added iron suggest a role for iron in regulating the level of M2 protein when cells are cultured in the presence of hydroxyurea. The hydroxyurea-inactivated ribonucleotide reductase protein M2 has a destabilized iron centre, which readily releases iron. Altered expression of ferritin appears to be required for the development of hydroxyurea resistance in nammalian cells. The results show an interesting relationship between the expressions of ribonucleotide reductase and ferritin. The phorbol ester tumor promoter, TPA, is also able to alter the expression of M2. TPA was able to induce M2 mRNA levels transiently up to 18-fold within 1/2 hour. This rapid and large elevation of ribonucleotide reductase suggests that the enzyme may play a role in tumor promotion. Studies of the M2 promoter region were undertaken to better understand the mechanism of TPA induction of M2.

  19. Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.

    Science.gov (United States)

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-09-04

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

  20. Illicit drugs policy through the lens of regulation.

    Science.gov (United States)

    Ritter, Alison

    2010-07-01

    The application of regulatory theory to the problem of illicit drugs has generally been thought about only in terms of 'command and control'. The international treaties governing global illicit drug control and the use of law enforcement to dissuade and punish offenders have been primary strategies. In this paper I explore the application of other aspects of regulatory theory to illicit drugs-primarily self-regulation and market regulation. There has been an overreliance on strategies from the top of the regulatory pyramid. Two other regulatory strategies--self-regulation and market regulation--can be applied to illicit drugs. Self-regulation, driven by the proactive support of consumer groups may reduce drug-related harms. Market strategies such as pill-testing can change consumer preferences and encourage alternate seller behaviour. Regulatory theory is also concerned with partnerships between the state and third parties: strategies in these areas include partnerships between police and pharmacies regarding sale of potential precursor chemicals. Regulatory theory and practice is a rich and well-developed field in the social sciences. I argue that governments should consider the full array of regulatory strategies. Using regulatory theory provides a rationale and justification to strategies that are currently at the whim of politics, such as funding for user groups. The greater application of regulatory approaches may produce more flexible and structured illicit drug policies. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  1. Resistance patterns and trends of extensively drug-resistant tuberculosis: 5-year experience

    Directory of Open Access Journals (Sweden)

    Amresh Kumar Singh

    2013-12-01

    Full Text Available Objective:Extensively drug-resistant tuberculosis (XDR-TB strains were emerged when multidrug-resistant TB (MDR- TB was inadequately treated. Inadequate treatment of MDR-TB cases may result in additional resistance especially non-XDR-TB and then XDR-TB. The aim of this study was to know the prevalence, resistance patterns and trends of the XDR-TB strains among the MDR-TB at a tertiary care hospital in Lucknow, India Methods: A total of 430 Mycobacterium isolates were underwent NAP test and TB MPT64 Ag test for the identification of Mycobacterium tuberculosis complex (MTBC. Drug-susceptibility test (DST was performed over MTBC for the first line drugs by 1% proportion method (Bactec and for the second-line drugs by 1% proportion method (Lowenstein- Jensen media. The XDR-TB status was further confirmed by line probe assay (GenoType® MTBDRsl assay. Results: Among the 430 isolates of mycobacterium, 365 (84.9% were MTBC and 139 (38.1% were MDR-TB respectively. Further 97 MDR-TB from “highly suspected drug resistant-TB (DR-TB” cases among MDR-TB were tested with second line drugs in which 15 (15.5% XDR-TB and 82 (84.5% were non-XDR-TB. Regarding XDR-TB status, using the 1% proportion method a 100% agreement was seen with the GenoType® MTBDRsl assay. Resistance patterns of XDR-TB were as; 10/15 (66.7% as isoniazid + rifampicin + ciprofloxacin + amikacin resistance and 5/15 (33.3% as isoniazid + rifampicin + ciprofloxacin + amikacin + kanamycin resistance. Conclusion:The prevalence of XDR-TB was 15.5% among MDR-TB. Hence laboratory testing of “highly suspected drug resistant-TB” isolates should be done for both first and second line drugs simultaneously especially in developing countries.J Microbiol Infect Dis 2013;3(4: 169-175

  2. Thermoresponsive Supramolecular Chemotherapy by "V"-Shaped Armed β-Cyclodextrin Star Polymer to Overcome Drug Resistance.

    Science.gov (United States)

    Fan, Xiaoshan; Cheng, Hongwei; Wang, Xiaoyuan; Ye, Enyi; Loh, Xian Jun; Wu, Yun-Long; Li, Zibiao

    2018-04-01

    Pump mediated drug efflux is the key reason to result in the failure of chemotherapy. Herein, a novel star polymer β-CD-v-(PEG-β-PNIPAAm) 7 consisting of a β-CD core, grafted with thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(ethylene glycol) (PEG) in the multiple "V"-shaped arms is designed and further fabricated into supramolecular nanocarriers for drug resistant cancer therapy. The star polymer could encapsulate chemotherapeutics between β-cyclodextrin and anti-cancer drug via inclusion complex (IC). Furthermore, the temperature induced chain association of PNIPAAm segments facilitated the IC to form supramolecular nanoparticles at 37 °C, whereas the presence of PEG impart great stability to the self-assemblies. When incubated with MDR-1 membrane pump regulated drug resistant tumor cells, much higher and faster cellular uptake of the supramolecular nanoparticles were detected, and the enhanced intracellular retention of drugs could lead to significant inhibition of cell growth. Further in vivo evaluation showed high therapeutic efficacy in suppressing drug resistant tumor growth without a significant impact on the normal functions of main organs. This work signifies thermo-responsive supramolecular chemotherapy is promising in combating pump mediated drug resistance in both in vitro and in vivo models, which may be encouraging for the advanced drug delivery platform design to overcome drug resistant cancer. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Modeling HIV-1 drug resistance as episodic directional selection.

    Science.gov (United States)

    Murrell, Ben; de Oliveira, Tulio; Seebregts, Chris; Kosakovsky Pond, Sergei L; Scheffler, Konrad

    2012-01-01

    The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  4. Modeling HIV-1 drug resistance as episodic directional selection.

    Directory of Open Access Journals (Sweden)

    Ben Murrell

    Full Text Available The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  5. Molecular Basis for Drug Resistance in HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Celia A. Schiffer

    2010-11-01

    Full Text Available HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.

  6. Insulin resistance in human subjects having impaired glucose regulation

    International Nuclear Information System (INIS)

    Khan, S.H.; Khan, F.A.; Ijaz, A.

    2007-01-01

    To determine insulin resistance in human subjects having impaired glucose regulation (IGR) by Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). A total of 100 subjects with impaired glucose regulation were selected for evaluation of metabolic syndrome as per the criteria of National Cholesterol Education Program, Adult Treatment Panel III (NCEP, ATP III), along with 47 healthy age and gender-matched controls. Physical examination to determine blood pressure and waist circumference was carried out and so was sampling for plasma glucose, serum triglycerides, HDL-cholesterol and insulin. Insulin resistance was calculated by the HOMA-IR. Finally, subjects with and without metabolic syndrome were compared with controls (n=47), using one-way ANOVA for studying insulin resistance between groups, with Tukey's post-hoc comparison. The frequency of finding metabolic syndrome in cases of IGR remained 47%. The insulin resistance demonstrated stepwise worsening from control population (mean=1.54, 95 % CI: 1.77 - 2.37) to subjects suffering from only IGR (mean=2.07, 95 % CI: 1.77- 2.37) to metabolic syndrome (mean=2.67, 95 %, CI: 2.34 - 3.00) (p < 0.001). Patients with impaired glucose regulation may have significant insulin resistance. It is, thus, recommended that a vigorous search be made to measure insulin resistance in all cases diagnosed to have impaired glucose regulation. (author)

  7. Neurological autoantibodies in drug-resistant epilepsy of unknown cause.

    Science.gov (United States)

    Tecellioglu, Mehmet; Kamisli, Ozden; Kamisli, Suat; Yucel, Fatma Ebru; Ozcan, Cemal

    2018-03-09

    Autoimmune epilepsy is a rarely diagnosed condition. Recognition of the underlying autoimmune condition is important, as these patients can be resistant to antiepileptic drugs. To determine the autoimmune and oncological antibodies in adult drug-resistant epilepsy of unknown cause and identify the clinical, radiological, and EEG findings associated with these antibodies according to data in the literature. Eighty-two patients with drug-resistant epilepsy of unknown cause were prospectively identified. Clinical features were recorded. The levels of anti-voltage-gated potassium channel complex (anti-VGKCc), anti-thyroid peroxidase (anti-TPO), anti-nuclear antibody (ANA), anti-glutamic acid decarboxylase (anti-GAD), anti-phospholipid IgG and IgM, anti-cardiolipin IgG and IgM, and onconeural antibodies were determined. Serum antibody positivity suggesting the potential role of autoimmunity in the aetiology was present in 17 patients with resistant epilepsy (22.0%). Multiple antibodies were found in two patients (2.6%). One of these patients (1.3%) had anti-VGKCc and ANA, whereas another (1.3%) had anti-VGKCc and anti-TPO. A single antibody was present in 15 patients (19.5%). Of the 77 patients finally included in the study, 4 had anti-TPO (5.2%), 1 had anti-GAD (1.3%), 4 had anti-VGKCc (5.2%) 8 had ANA (10.3%), and 2 had onconeural antibodies (2.6%) (1 patient had anti-Yo and 1 had anti-MA2/TA). The other antibodies investigated were not detected. EEG abnormality (focal), focal seizure incidence, and frequent seizures were more common in antibody-positive patients. Autoimmune factors may be aetiologically relevant in patients with drug-resistant epilepsy of unknown cause, especially if focal seizures are present together with focal EEG abnormality and frequent seizures.

  8. HLA-class II alleles in patients with drug-resistant pulmonary tuberculosis in Kazakhstan.

    Science.gov (United States)

    Kuranov, A B; Kozhamkulov, U A; Vavilov, M N; Belova, E S; Bismilda, V L; Alenova, A H; Ismailov, S S; Momynaliev, K T

    2014-02-01

    The human leukocyte antigen (HLA) system has a major role in the regulation of the immune response as it is involved in the defense against pathogens. Some studies have reported that HLA class II genes play a strong role in severe cases of pulmonary tuberculosis (PTB) in several populations. Thus the aim of the study was to compare the HLA-class II alleles of patients with drug resistant tuberculosis with those of healthy controls from the same ethnic group in Kazakhstan. The aim of the present study was to evaluate the correlation of HLA-class II alleles by patients with drug resistant tuberculosis and the healthy controls of the same ethnic group in Kazakhstan. The HLA-class II alleles of 76 patients with tuberculosis (TB) and 157 healthy volunteers were investigated using sequence-based typing (SBT)-method. HLA-DQA1*03:02 HLA-DRB1*08:01 and DRB1*08:03 occurred more frequently (P = 0.05) in patients with drug resistant tuberculosis than in controls. We observed a possible association between certain HLA alleles and TB that are specific for the Kazakh population. Further studies are needed to confirm our findings using a larger number of patients with drug resistant tuberculosis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

    International Nuclear Information System (INIS)

    Hopwood, L.E.; Davies, B.M.; Moulder, J.E.

    1990-01-01

    RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance

  10. Drug resistance patterns of acinetobacter baumannii in makkah, saudi arabia

    International Nuclear Information System (INIS)

    Khan, M.A.; Ashshi, A.M.; Mahomed, M.F.

    2012-01-01

    Background: Acinetobacter baumannii causes infections of respiratory, urinary tract, blood stream and surgical sites. Its clinical significance has increased due to its rapidly developing resistance to major groups of antibiotics used for its treatment. There is limited data available on antimicrobial susceptibility of A. baumannii from Saudi Arabia. Objectives: To determine the patterns of drug resistance of Acinetobacter baumannii and predisposing factors for its acquisition.Subjects and Methods: In this descriptive study, 72 hospitalized patients infected with A baumannii were studied. The clinical and demographic data of the patients were collected using a predesigned questionnaire. Isolation and identification of A.baumannii from all clinical specimens were done using standard microbiological methods. Antibiotic susce ptibility testing was performed by disk diffusion method recommended by Clinical Laboratory Standards Institute. Results: Majority of the isolates (61.1%) were from respiratory tract infections. A.baumannii isolates showed high drug resistance to piperacil lin (93.1%), aztreonam (80.5%), ticarcillin, ampicillin, and tetracycline (76.4%, each) and cefotaxime (75%). Only amikacin showed low rate of resistance compared to other antibiotics (40.3%). About 36% patients had some underlying diseases with diabetes mellitus (11%) being the predominant underlying disease. Conclusions: High antimicrobial resistance to commonly used antibiotics was seen against A.baumannii isolates. Only amikacin was most effective against it. (author)

  11. Multi drug resistant tuberculosis presenting as anterior mediastinal mass

    Directory of Open Access Journals (Sweden)

    Parmarth Chandane

    2016-01-01

    Full Text Available Enlargement of the mediastinal lymphatic glands is a common presentation of intrathoracic tuberculosis (TB in children. However, usually, the mediastinal TB nodes enlarge to 2.8 ± 1.0 cm. In this report, we describe a case of anterior mediastinal lymphnode TB seen as huge mass (7 cm on computed tomography (CT thorax without respiratory or food pipe compromise despite anterior mediastinum being an enclosed space. CT guided biopsy of the mass cultured Mycobacterium TB complex which was resistant to isoniazide, rifampicin, streptomycin ofloxacin, moxifloxacin, and pyrazinamide. Hence, we report primary multi drug resistant TB presenting as anterior mediastinal mass as a rare case report.

  12. Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance

    Science.gov (United States)

    Gonzalez de Castro, D; Clarke, P A; Al-Lazikani, B; Workman, P

    2013-01-01

    The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution. PMID:23361103

  13. Drug membrane interaction and the importance for drug transport, distribution, accumulation, efficacy and resistance.

    Science.gov (United States)

    Seydel, J K; Coats, E A; Cordes, H P; Wiese, M

    1994-10-01

    Some aspects of drug membrane interaction and its influence on drug transport, accumulation, efficacy and resistance have been discussed. The interactions manifest themselves macroscopically in changes in the physical and thermodynamic properties of "pure membranes" or bilayers. As various amounts of foreign molecules enter the membrane, in particular the main gel to liquid crystalline phase transition can be dramatically changed. This may change permeability, cell-fusion, cell resistance and may also lead to changes in conformation of the embedded receptor proteins. Furthermore, specific interactions with lipids may lead to drug accumulation in membranes and thus to much larger concentrations at the active site than present in the surrounding water phase. The lipid environment may also lead to changes in the preferred conformation of drug molecules. These events are directly related to drug efficacy. The determination of essential molecular criteria for the interaction could be used to design new and more selective therapeutics. This excursion in some aspects of drug membrane interaction underlines the importance of lipids and their interaction with drug molecules for our understanding of drug action, but this is not really a new thought but has been formulated in 1884 by THUDICUM: "Phospholipids are the centre, life and chemical soul of all bioplasm whatsoever, that of plants as well as of animals".

  14. Drug accumulation in the presence of the multidrug resistance pump

    DEFF Research Database (Denmark)

    Ayesh, S; Litman, Thomas; Stein, W D

    1997-01-01

    We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant...... P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced...

  15. Androgen receptor variation affects prostate cancer progression and drug resistance.

    Science.gov (United States)

    McCrea, Edel; Sissung, Tristan M; Price, Douglas K; Chau, Cindy H; Figg, William D

    2016-12-01

    Significant therapeutic progress has been made in treating prostate cancer in recent years. Drugs such as enzalutamide, abiraterone, and cabazitaxel have expanded the treatment armamentarium, although it is not completely clear which of these drugs are the most-effective option for individual patients. Moreover, such advances have been tempered by the development of therapeutic resistance. The purpose of this review is to summarize the current literature pertaining to the biochemical effects of AR variants and their consequences on prostate cancer therapies at both the molecular level and in clinical treatment. We address how these AR splice variants and mutations affect tumor progression and therapeutic resistance and discuss potential novel therapeutic strategies under development. It is hoped that these therapies can be administered with increasing precision as tumor genotyping methods become more sophisticated, thereby lending clinicians a better understanding of the underlying biology of prostate tumors in individual patients. Published by Elsevier Ltd.

  16. Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids.

    Science.gov (United States)

    He, Susu; Chandler, Michael; Varani, Alessandro M; Hickman, Alison B; Dekker, John P; Dyda, Fred

    2016-12-06

    The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content) of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE) from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance. The spread of antibiotic resistance among Gram-negative bacteria is a serious public health threat, as it can critically limit the types of drugs that can be used to treat infected patients. In particular, carbapenem-resistant members of the Enterobacteriaceae family are responsible for a significant and growing burden of morbidity and mortality. Here, we report on the mechanisms underlying the evolution of several plasmids carried by previously sequenced clinical Enterobacteriaceae isolates from the National Institutes of Health Clinical Center (NIH CC). Our ability to track genetic rearrangements that occurred within resistance plasmids was dependent on accurate annotation of the mobile genetic elements within the plasmids, which was greatly aided by access to long-read DNA sequencing data and knowledge of their mechanisms. Mobile genetic elements such as

  17. 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

  18. 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.

  19. Implementation of a national anti-tuberculosis drug resistance survey in Tanzania

    NARCIS (Netherlands)

    Chonde, Timothy M.; Doulla, Basra; van Leth, Frank; Mfinanga, Sayoki G. M.; Range, Nyagosya; Lwilla, Fred; Mfaume, Saidi M.; van Deun, Armand; Zignol, Matteo; Cobelens, Frank G.; Egwaga, Saidi M.

    2008-01-01

    BACKGROUND: A drug resistance survey is an essential public health management tool for evaluating and improving the performance of National Tuberculosis control programmes. The current manuscript describes the implementation of the first national drug resistance survey in Tanzania. METHODS:

  20. Rationale and uses of a public HIV drug-resistance database.

    Science.gov (United States)

    Shafer, Robert W

    2006-09-15

    Knowledge regarding the drug resistance of human immunodeficiency virus (HIV) is critical for surveillance of drug resistance, development of antiretroviral drugs, and management of infections with drug-resistant viruses. Such knowledge is derived from studies that correlate genetic variation in the targets of therapy with the antiretroviral treatments received by persons from whom the variant was obtained (genotype-treatment), with drug-susceptibility data on genetic variants (genotype-phenotype), and with virological and clinical response to a new treatment regimen (genotype-outcome). An HIV drug-resistance database is required to represent, store, and analyze the diverse forms of data underlying our knowledge of drug resistance and to make these data available to the broad community of researchers studying drug resistance in HIV and clinicians using HIV drug-resistance tests. Such genotype-treatment, genotype-phenotype, and genotype-outcome correlations are contained in the Stanford HIV RT and Protease Sequence Database and have specific usefulness.

  1. The role of exosomes and miRNAs in drug-resistance of cancer cells.

    Science.gov (United States)

    Bach, Duc-Hiep; Hong, Ji-Young; Park, Hyen Joo; Lee, Sang Kook

    2017-07-15

    Chemotherapy, one of the principal approaches for cancer patients, plays a crucial role in controlling tumor progression. Clinically, tumors reveal a satisfactory response following the first exposure to the chemotherapeutic drugs in treatment. However, most tumors sooner or later become resistant to even chemically unrelated anticancer agents after repeated treatment. The reduced drug accumulation in tumor cells is considered one of the significant mechanisms by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell membrane. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated, including drug efflux, which is mediated by extracellular vesicles (EVs). Exosomes, a subset of EVs with a size range of 40-150 nm and a lipid bilayer membrane, can be released by all cell types. They mediate specific cell-to-cell interactions and activate signaling pathways in cells they either fuse with or interact with, including cancer cells. Exosomal RNAs are heterogeneous in size but enriched in small RNAs, such as miRNAs. In the primary tumor microenvironment, cancer-secreted exosomes and miRNAs can be internalized by other cell types. MiRNAs loaded in these exosomes might be transferred to recipient niche cells to exert genome-wide regulation of gene expression. How exosomal miRNAs contribute to the development of drug resistance in the context of the tumor microenvironment has not been fully described. In this review, we will highlight recent studies regarding EV-mediated microRNA delivery in formatting drug resistance. We also suggest the use of EVs as an advancing method in antiresistance treatment. © 2017 UICC.

  2. Cytochrome P450s--Their expression, regulation, and role in insecticide resistance.

    Science.gov (United States)

    Liu, Nannan; Li, Ming; Gong, Youhui; Liu, Feng; Li, Ting

    2015-05-01

    P450s are known to be critical for the detoxification and/or activation of xenobiotics such as drugs and pesticides and overexpression of P450 genes can significantly affect the disposition of xenobiotics in the tissues of organisms, altering their pharmacological/toxicological effects. In insects, P450s play an important role in detoxifying exogenous compounds such as insecticides and plant toxins and their overexpression can result in increased levels of P450 proteins and P450 activities. This has been associated with enhanced metabolic detoxification of insecticides and has been implicated in the development of insecticide resistance in insects. Multiple P450 genes have been found to be co-overexpressed in individual insect species via several constitutive overexpression and induction mechanisms, which in turn are co-responsible for high levels of insecticide resistance. Many studies have also demonstrated that the transcriptional overexpression of P450 genes in resistant insects is regulated by trans and/or cis regulatory genes/factors. Taken together, these earlier findings suggest not only that insecticide resistance is conferred via multi-resistance P450 genes, but also that it is mediated through the interaction of regulatory genes/factors and resistance genes. This chapter reviews our current understanding of how the molecular mechanisms of P450 interaction/gene regulation govern the development of insecticide resistance in insects and our progress along the road to a comprehensive characterization of P450 detoxification-mediated insecticide resistance. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Drug resistance-related mutations in multidrug-resistant Mycobacterium tuberculosis isolates from diverse geographical regions

    Directory of Open Access Journals (Sweden)

    Senia Rosales-Klintz

    2012-01-01

    Conclusion: This study confirms that there are significant geographical differences in the distribution of resistance-related mutations and suggests that an increased understanding of such differences in the specific distribution of resistance conferring mutations is crucial for development of new, generally applicable, molecular tools for rapid diagnosis of drug-resistant TB. The fact that a narrower distribution of mutations in high MDR-TB prevalence settings was seen suggests that much of the problems in these settings can be a result of an ongoing transmission of certain MDR-TB strains.

  4. Changing prevalence and resistance patterns in children with drug-resistant tuberculosis in Mumbai.

    Science.gov (United States)

    Shah, Ira; Shah, Forum

    2017-05-01

    The prevalence of drug-resistant (DR) tuberculosis (TB) in children is increasing. Although, in India, multi-drug-resistant (MDR) TB rates have been relatively stable, the number of children with pre-extensively drug-resistant and extensively drug-resistant (XDR) TB is increasing. To determine whether the prevalence of DR TB in children in Mumbai is changing and to study the evolving patterns of resistance. A retrospective study was undertaken in 1311 paediatric patients referred between April 2007 and March 2013 to the Paediatric TB clinic at B. J. Wadia Hospital for Children, Mumbai. Children were defined as having DR TB on the basis of drug susceptibility testing (DST) of Mycobacterium tuberculosis grown on culture of body fluids (in the case of extra pulmonary TB) or from gastric lavage/bronchi-alveolar lavage/sputum in patients with pulmonary TB or from DST of the contacts. The prevalence of DR TB was calculated and the type of DR was evaluated yearly and in the pre-2010 and post-2010 eras. The overall prevalence of DR TB was 86 (6.6%) with an increase from 23 (5.6%) patients pre-2010 to 63 (7%) post-2010 (P = 0.40). Nine (10.4%) patients were diagnosed on the basis of contact with a parent with DR TB. Overall fluoroquinolone resistance increased from 9 (39.1%) pre-2010 to 59 (93.7%) post-2010 (P = 0.0001): moxifloxacin resistance increased from 2 (8.7%) to 29 (46%) (P = 0.0018) and ofloxacin resistance increased from 7 (30.4%) to 30 (47.6%) (P = 0.14). Ethionamide resistance also increased from 6 (26.1%) to 31 (49.2%) (P = 0.04), aminoglycoside resistance was one (4.3%) pre-2010 and 12 (19%) post-2010 (P = 0.17) and resistance remained virtually the same for both amikacin [0 pre-2010 and 6 (9.5%) after 2010] and kanamycin [one (4.3%) pre- and 6 (9.5%) post-2010]. Of the first-line drugs, resistance remained the same for isoniazid [23 (100%) to 61 (96.8%)], rifampicin [22 (95.7%) to 51 (80.9%),P = 0.17], pyrazinamide [15 (65.2%) to

  5. Impact of drug resistance on the tuberculosis treatment outcome

    Directory of Open Access Journals (Sweden)

    E. Lesnic

    2017-03-01

    Full Text Available Background. The standard treatment of a new case of multidrug-resistant tuberculosis (MDR-TB according to WHO recommendations in the Republic of Moldova is performed since 2005 showing a low treatment succes. Actually the treatment success rate increased due to excluding of MDR-TB patients from the general cohort. The major rate of patients with low outcome is represented by the failed and lost to follow-up cases. The purpose of the study was to assess the impact of multidrug-resiatnce and MDR-TB on the tuberculosis treatment outcome. Materials and methods. A retrospective selective, descriptive study targeting social, demographic, economic and epidemiological peculiarities, case-management, diagnostic radiological aspects and microbiological characteristics of 187 patients with pulmonary tuberculosis registered during 2013–2015 distributed in two groups: 1st group (61 patients with established multidrug-resistant strains using conventional cultural methods and the 2nd group (126 patients with MDR-TB. Results. Multidrug-resistance was established more frequently in new cases and MDR-TB in two thirds of retreated patients. No difference was identified in gender and age distribution, social, economical, educational characteristics; case-management assessment identified a similar proportion of patients revealed by general practitioners and specialists, with low rate of screened high risk groups. All patients from the multidrug-resistant group began the standard treatment for drug-responsiveness tuberculosis before drug susceptibility testing and one third of MDR-TB group was treated from the onset with the DOTS-Plus regimen. Highest success rate was identified in the new-case subgroups of both groups and higher rate of died patients was determined in the retreated subgroups. Such a low rate of patients aggrevates the resistance. Conclusions. Early diagnosis, drug responsiveness testing and raising awareness among about treatment compliance will

  6. Drug Resistance Mechanisms of Mycoplasma pneumoniae to Macrolide Antibiotics

    Directory of Open Access Journals (Sweden)

    Xijie Liu

    2014-01-01

    Full Text Available Throat swabs from children with suspected Mycoplasma pneumoniae (M. pneumoniae infection were cultured for the presence of M. pneumoniae and its species specificity using the 16S rRNA gene. Seventy-six M. pneumoniae strains isolated from 580 swabs showed that 70 were erythromycin resistant with minimum inhibitory concentrations (MIC around 32–512 mg/L. Fifty M. pneumoniae strains (46 resistant, 4 sensitive were tested for sensitivity to tetracycline, ciprofloxacin, and gentamicin. Tetracycline and ciprofloxacin had some effect, and gentamicin had an effect on the majority of M. pneumoniae strains. Domains II and V of the 23S rRNA gene and the ribosomal protein L4 and L22 genes, both of which are considered to be associated with macrolide resistance, were sequenced and the sequences were compared with the corresponding sequences in M129 registered with NCBI and the FH strain. The 70 resistant strains all showed a 2063 or 2064 site mutation in domain V of the 23S rRNA but no mutations in domain II. Site mutations of L4 or L22 can be observed in either resistant or sensitive strains, although it is not known whether this is associated with drug resistance.

  7. Surgery for Drug-Resistant Epilepsy in Children.

    Science.gov (United States)

    Dwivedi, Rekha; Ramanujam, Bhargavi; Chandra, P Sarat; Sapra, Savita; Gulati, Sheffali; Kalaivani, Mani; Garg, Ajay; Bal, Chandra S; Tripathi, Madhavi; Dwivedi, Sada N; Sagar, Rajesh; Sarkar, Chitra; Tripathi, Manjari

    2017-10-26

    Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials. In this single-center trial, we randomly assigned 116 patients who were 18 years of age or younger with drug-resistant epilepsy to undergo brain surgery appropriate to the underlying cause of epilepsy along with appropriate medical therapy (surgery group, 57 patients) or to receive medical therapy alone (medical-therapy group, 59 patients). The patients in the medical-therapy group were assigned to a waiting list for surgery. The primary outcome was freedom from seizures at 12 months. Secondary outcomes were the score on the Hague Seizure Severity scale, the Binet-Kamat intelligence quotient, the social quotient on the Vineland Social Maturity Scale, and scores on the Child Behavior Checklist and the Pediatric Quality of Life Inventory. At 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (Pchildren and adolescents with drug-resistant epilepsy who had undergone epilepsy surgery had a significantly higher rate of freedom from seizures and better scores with respect to behavior and quality of life than did those who continued medical therapy alone at 12 months. Surgery resulted in anticipated neurologic deficits related to the region of brain resection. (Funded by the Indian Council of Medical Research and others; Clinical Trial Registry-India number, CTRI/2010/091/000525 .).

  8. Sleep instability and cognitive status in drug-resistant epilepsies.

    Science.gov (United States)

    Pereira, Alessandra Marques; Bruni, Oliviero; Ferri, Raffaele; Nunes, Magda Lahorgue

    2012-05-01

    The aims of this study were to evaluate the sleep habits of children with drug resistant epilepsy and to correlate sleep abnormalities with epilepsy and level of intelligence. Twenty five subjects with drug resistant epilepsy (14 males, age range 2-16.4 years) were recruited for this study. A control group was formed by 23 normal children. Two instruments to assess sleep habits were administered to the patients with epilepsy: a questionnaire on sleep habits (to preschool children) and a questionnaire on sleep behavior (for children aged more than seven years old); a cognitive test (Wechsler Intelligence Scale for Children-WISC) was also performed. Patients underwent a complete polysomnographic study and sleep parameters, including CAP, were analyzed and correlated according to cognitive-behavioral measures in children with epilepsy. Children with drug-resistant epilepsy and severe mental retardation showed sleep abnormalities such as low sleep efficiency, high percentage of wakefulness after sleep onset, reduced slow wave sleep, and reduced REM sleep. Sleep microstructure evaluated by means of CAP analysis showed a decrease in A1 index during N3 in patients with more severe cognitive impairment. Children with epilepsy and cognitive impairment (n=10) had higher Sleep Behavior Questionnaire for Children (SBQC) total scores (65.60 ± 18.56) compared to children with epilepsy and normal IQ (50.00 ± 10.40), pintellectual disability. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Investigational drugs to treat methicillin-resistant Staphylococcus aureus

    Science.gov (United States)

    Vuong, Cuong; Yeh, Anthony J; Cheung, Gordon YC; Otto, Michael

    2016-01-01

    Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise. PMID:26536498

  10. Inhibition of c-Myc overcomes cytotoxic drug resistance in acute myeloid leukemia cells by promoting differentiation.

    Directory of Open Access Journals (Sweden)

    Xiao-Na Pan

    Full Text Available Nowadays, drug resistance still represents a major obstacle to successful acute myeloid leukemia (AML treatment and the underlying mechanism is not fully elucidated. Here, we found that high expression of c-Myc was one of the cytogenetic characteristics in the drug-resistant leukemic cells. c-Myc over-expression in leukemic cells induced resistance to chemotherapeutic drugs, enhanced colony formation capacity and inhibited cell differentiation induced by all-trans retinoic acid (ATRA. Meanwhile, inhibition of c-Myc by shRNA or specific c-Myc inhibitor 10058-F4 rescued the sensitivity to cytotoxic drugs, restrained the colony formation ability and promoted differentiation. RT-PCR and western blotting analysis showed that down-regulation of C/EBPβ contributed to the poor differentiation state of leukemic cells induced by c-Myc over-expression. Importantly, over-expression of C/EBPβ could reverse c-Myc induced drug resistance. In primary AML cells, the c-Myc expression was negatively correlated with C/EBPβ. 10058-F4, displayed anti-proliferative activity and increased cellular differentiation with up-regulation of C/EBPβ in primary AML cells. Thus, our study indicated that c-Myc could be a novel target to overcome drug resistance, providing a new approach in AML therapy.

  11. CHEMOTHERAPY, WITHIN-HOST ECOLOGY AND THE FITNESS OF DRUG-RESISTANT MALARIA PARASITES

    OpenAIRE

    Huijben, Silvie; Nelson, William A.; Wargo, Andrew R.; Sim, Derek G.; Drew, Damien R.; Read, Andrew F.

    2010-01-01

    A major determinant of the rate at which drug-resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug-sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria mod...

  12. Molecular biological studies on the human radioresistance and drug resistance

    International Nuclear Information System (INIS)

    Kim, Chang Min; Hong, Weon Seon

    1992-04-01

    We irradiated the MKN45 and PC14 cell lines with 500 rads and also established the adriamycin-resistant and cis-platinum resistant cell line. The genomic DNA and total RNA were extracted and subjected to the Southern and Northern analysis using various probes including heat shock protein 70, MDR1, fos, TGFb etc. The mRNA transcript was increased 1 hour after the irradiation and sustained during the 48 hours and returned to the level of pre-irradiation. No significant change was observed with the drug resistant cell lines at the level of gene dosage. We suggest that the marked increase of the hsp70 transcript is very important finding and is believed to be a good candidate for the modulation of the cellular response to irradiation and the radioresistance. (Author)

  13. SURGERY FOR DRUG-RESISTANT DESTRUCTIVE PULMONARY TUBERCULOSIS

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    S. N. Skornyakov

    2015-01-01

    Full Text Available The paper presents the experience in surgically treating 145 patients with destructive, mainly fibrocavernous pulmonary tuberculosis. All the patients completed treatment. In the preoperative preparation, particular emphasis is laid on the promptest determination of a spectrum of pathogen susceptibility/resistance, individualized chemotherapy, and collapse therapy options. Postoperative complications occurred in 27 (18.6% patients, fatal outcomes in 4 (2.7%. The former were recorded most frequently after pneumonectomy in 13 (37.1% cases, the later were seen in 3 (8.6%. Sputum culture conversion was generally achieved in 111 (78% patients, particularly in 97 (78.2% patients with multidrug-resistant tuberculosis and in 14 (66.7% with a broad drug resistance in the pathogen. Out of the 64 patients followed up for more than 3 years, 48 (75.0% were in clinical and bacteriological remission.

  14. Mechanisms of first-line antimicrobial resistance in multi-drug and extensively drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa

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    Navisha Dookie

    2016-10-01

    Full Text Available Abstract Background In South Africa, drug resistant tuberculosis is a major public health crisis in the face of the colossal HIV pandemic. Methods In an attempt to understand the distribution of drug resistance in our setting, we analysed the rpoB, katG, inhA, pncA and embB genes associated with resistance to key drugs used in the treatment of tuberculosis in clinical isolates of Mycobacterium tuberculosis in the KwaZulu-Natal province. Results Classical mutations were detected in the katG, inhA and embB genes associated with resistance to isoniazid and ethambutol. Diverse mutations were recorded in the multidrug resistant (MDR and extensively drug resistant (XDR isolates for the rpoB and pncA gene associated with resistance to rifampicin and pyrazinamide. Conclusions M.tuberculosis strains circulating in our setting display a combination of previously observed mutations, each mediating resistance to a different drug. The MDR and XDR TB isolates analysed in this study displayed classical mutations linked to INH and EMB resistance, whilst diverse mutations were linked to RIF and PZA resistance. The similarity of the XDR strains confirms reports of the clonality of the XDR epidemic. The successful dissemination of the drug resistant strains in the province underscores the need for rapid diagnostics to effectively diagnose drug resistance and guide treatment.

  15. Characterization of extensively drug-resistant Mycobacterium tuberculosis in Nepal.

    Science.gov (United States)

    Poudel, Ajay; Maharjan, Bhagwan; Nakajima, Chie; Fukushima, Yukari; Pandey, Basu D; Beneke, Antje; Suzuki, Yasuhiko

    2013-01-01

    The emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised public health concern for global control of TB. Although molecular characterization of drug resistance-associated mutations in multidrug-resistant isolates in Nepal has been made, mutations in XDR isolates and their genotypes have not been reported previously. In this study, we identified and characterized 13 XDR Mycobacterium tuberculosis isolates from clinical isolates in Nepal. The most prevalent mutations involved in rifampicin, isoniazid, ofloxacin, and kanamycin/capreomycin resistance were Ser531Leu in rpoB gene (92.3%), Ser315Thr in katG gene (92.3%), Asp94Gly in gyrA gene (53.9%) and A1400G in rrs gene (61.5%), respectively. Spoligotyping and multilocus sequence typing revealed that 69% belonged to Beijing family, especially modern types. Further typing with 26-loci variable number of tandem repeats suggested the current spread of XDR M. tuberculosis. Our result highlights the need to reinforce the TB policy in Nepal with regard to control and detection strategies. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Drug Resistance and the Kinetics of Metastatic Cancer

    Science.gov (United States)

    Blagoev, Krastan B.

    2012-02-01

    Most metastatic cancers after initial response to current drug therapies develop resistance to the treatment. We present cancer data and a theory that explains the observed kinetics of tumor growth in cancer patients and using a stochastic model based on this theory we relate the kinetics of tumor growth to Kaplan-Meyer survival curves. The theory points to the tumor growth rate as the most important parameter determining the outcome of a drug treatment. The overall tumor growth or decay rate is a reflection of the balance between cell division, senescence and apoptosis and we propose that the deviation of the decay rate from exponential is a measure of the emergence of drug resistance. In clinical trials the progression free survival, the overall survival, and the shape of the Kaplan-Meyer plots are determined by the tumor growth rate probability distribution among the patients in the trial. How drug treatments modify this distribution will also be described. At the end of the talk we will discuss the connection between the theory described here and the age related cancer mortality rates in the United States.

  17. Exosomes in development, metastasis and drug resistance of breast cancer.

    Science.gov (United States)

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-08-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  18. Novel diagnostics and therapeutics for drug-resistant tuberculosis.

    Science.gov (United States)

    Toosky, Melody; Javid, Babak

    2014-06-01

    Drug-resistant tuberculosis (DR-TB) is associated with increased mortality and morbidity. This is at least partly due to late diagnosis and ineffective treatment of drug-resistant status. Selective search of the literature on DR-TB supplemented by recent guidelines from the World Health Organization. Better and more rapid diagnosis of DR-TB by new techniques such as Xpert Mtb/RIF are likely to make a substantial impact on the disease. New therapeutics for DR-TB are entering, or about to enter the market for the first time in decades. It is not clear whether new treatments should be restricted for DR-TB or also used for drug-susceptible tuberculosis. With several new agents on the horizon, there is the real possibility of an entirely new regimen for tuberculosis. An inexpensive 'near-patient' diagnostic test is still needed. Optimizing new drug combination regimens in a timely manner is urgently required. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. Fibrocytes: A Novel Stromal Cells to Regulate Resistance to Anti-Angiogenic Therapy and Cancer Progression.

    Science.gov (United States)

    Goto, Hisatsugu; Nishioka, Yasuhiko

    2017-12-29

    An adequate blood supply is essential for cancer cells to survive and grow; thus, the concept of inhibiting tumor angiogenesis has been applied to cancer therapy, and several drugs are already in clinical use. It has been shown that treatment with those anti-angiogenic drugs improved the response rate and prolonged the survival of patients with various types of cancer; however, it is also true that the effect was mostly limited. Currently, the disappointing clinical results are explained by the existence of intrinsic or acquired resistance to the therapy mediated by both tumor cells and stromal cells. This article reviews the mechanisms of resistance mediated by stromal cells such as endothelial cells, pericytes, fibroblasts and myeloid cells, with an emphasis on fibrocytes, which were recently identified as the cell type responsible for regulating acquired resistance to anti-angiogenic therapy. In addition, the other emerging role of fibrocytes as mediator-producing cells in tumor progression is discussed.

  20. Does drug price-regulation affect healthcare expenditures?

    Science.gov (United States)

    Ben-Aharon, Omer; Shavit, Oren; Magnezi, Racheli

    2017-09-01

    Increasing health costs in developed countries are a major concern for decision makers. A variety of cost containment tools are used to control this trend, including maximum price regulation and reimbursement methods for health technologies. Information regarding expenditure-related outcomes of these tools is not available. To evaluate the association between different cost-regulating mechanisms and national health expenditures in selected countries. Price-regulating and reimbursement mechanisms for prescription drugs among OECD countries were reviewed. National health expenditure indices for 2008-2012 were extracted from OECD statistical sources. Possible associations between characteristics of different systems for regulation of drug prices and reimbursement and health expenditures were examined. In most countries, reimbursement mechanisms are part of publicly financed plans. Maximum price regulation is composed of reference-pricing, either of the same drug in other countries, or of therapeutic alternatives within the country, as well as value-based pricing (VBP). No association was found between price regulation or reimbursement mechanisms and healthcare costs. However, VBP may present a more effective mechanism, leading to reduced costs in the long term. Maximum price and reimbursement mechanism regulations were not found to be associated with cost containment of national health expenditures. VBP may have the potential to do so over the long term.

  1. Definition of drug resistance of Mycobacterium tuberculosis to antituberculosis drugs in patients with multidrugresistant tuberculosis and TB with extremely drug resistant depending on the case of the disease

    Directory of Open Access Journals (Sweden)

    Kryzhanovsky D.G.

    2014-11-01

    Full Text Available There was studied the profile of drug resistance to the main (I line and reserve (II line antituberculosis drugs in patients with MDR and XDR tuberculosis, depending of the case of the disease. According to the randomized retrospective research 200 patients with MDR and XDR tuberculosis, who received treatment in the clinic of hospital Municipal institution «Dnipropetrovsk rigional clinical association «Phthisiology» Dnipropetrovsk regional Council» during the period 2010 – 2012 were involved. Data about patients contained the data on a case of the disease and the results of the test of drug sensitivity to MBT. XDR – TB was revealed in 7.5% of patients with MDR tuberculosis. In patients with MDR tuberculosis as compared with patients with XDR tuberculosis «new cases» were diagnosed in 19.5% against 18.5% (p <0.05. In patients with MDR tuberculosis and with XDR tuberculosis resistance to the antituberculosis drug more commonly developed to S - 88.5%, E - 55% and Z - 24%. The presence of MDR-TB and XDR-TB prevails in patients, who underwent previous courses of treatment with anti-TB drugs in case history as compared with patients with «new cases» of treatment. The development of resistance to anti-TB drugs depends on the availability of these drugs in the previous treatment regimens.

  2. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system.

    Science.gov (United States)

    Kibria, Golam; Hatakeyama, Hiroto; Harashima, Hideyoshi

    2014-01-01

    Multidrug resistance (MDR), the principal mechanism by which many cancers develop resistance to chemotherapy, is one of the major obstacles to the successful clinical treatment of various types of cancer. Several key regulators are responsible for mediating MDR, a process that renders chemotherapeutic drugs ineffective in the internal organelles of target cells. A nanoparticulate drug delivery system (DDS) is a potentially promising tool for circumventing such MDR, which can be achieved by targeting tumor cells themselves or tumor endothelial cells that support the survival of MDR cancer cells. The present article discusses key factors that are responsible for MDR in cancer cells, with a specific focus on the application of DDS to overcome MDR via the use of chemotherapy or macromolecules.

  3. SOS response and its regulation on the fluoroquinolone resistance.

    Science.gov (United States)

    Qin, Ting-Ting; Kang, Hai-Quan; Ma, Ping; Li, Peng-Peng; Huang, Lin-Yan; Gu, Bing

    2015-12-01

    Bacteria can survive fluoroquinolone antibiotics (FQs) treatment by becoming resistant through a genetic change-mutation or gene acquisition. The SOS response is widespread among bacteria and exhibits considerable variation in its composition and regulation, which is repressed by LexA protein and derepressed by RecA protein. Here, we take a comprehensive review of the SOS gene network and its regulation on the fluoroquinolone resistance. As a unique survival mechanism, SOS may be an important factor influencing the outcome of antibiotic therapy in vivo.

  4. The risks of risk aversion in drug regulation.

    Science.gov (United States)

    Eichler, Hans-Georg; Bloechl-Daum, Brigitte; Brasseur, Daniel; Breckenridge, Alasdair; Leufkens, Hubert; Raine, June; Salmonson, Tomas; Schneider, Christian K; Rasi, Guido

    2013-12-01

    Drugs are approved by regulatory agencies on the basis of their assessment of whether the available evidence indicates that the benefits of the drug outweigh its risks. In recent years, regulatory agencies have been criticized both for being overly tolerant of risks or being excessively risk-averse, which reflects the challenge in determining an appropriate balance between benefit and risk with the limited data that is typically available before drug approval. The negative consequences of regulatory tolerance in allowing drugs onto the market that turn out to be unsafe are obvious, but the potential for adverse effects on public health owing to the absence of new drugs because of regulatory risk-aversion is less apparent. Here, we discuss the consequences of regulatory risk-aversion for public health and suggest what might be done to best align acceptance of risk and uncertainty by regulators with the interests of public health.

  5. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

    Directory of Open Access Journals (Sweden)

    Shankar Thangamani

    Full Text Available Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90 were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

  6. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

    Science.gov (United States)

    Thangamani, Shankar; Younis, Waleed; Seleem, Mohamed N

    2015-01-01

    Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90) were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA) in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

  7. Analysis of metal and biocides resistance genes in drug resistance and susceptible Salmonella enterica from food animals

    Science.gov (United States)

    Background Generally drug resistant bacteria carry antibiotic resistance genes and heavy metal and biocide resistance genes on large conjugative plasmids. The presence of these metal and biocide resistance genes in susceptible bacteria are not assessed comprehensively. Hence, WGS data of susceptib...

  8. "DRUG RESISTANCE PATTERN IN ISOLATED BACTERIA FROM BLOOD CULTURES"

    Directory of Open Access Journals (Sweden)

    A. Sobhani

    2004-05-01

    Full Text Available Bacteremia is an important infectious disease which may lead to death. Common bacteria and pattern of antibiotic resistance in different communities are different and understanding these differences is important. In the present study, relative frequency and pattern of drug resistance have been examined in bacteria isolated from blood cultures in Razi Hospital laboratory. The method of the study was descriptive. Data collection was carried out retrospectively. Total sample consisted of 311 positive blood cultures from 1999 to 2001. Variables under study were bacterial strains, antibiotics examined in antibiogram, microbial resistance, and patients' age and sex. The most common isolated bacteria were Salmonella typhi (22.2% and the least common ones were Citrobacter (1.6%. The highest antibiotic resistance was seen against amoxicillin (88.4%. The proportion of males to females was1: 1/1 and the most common age group was 15-44 (47.3%. Common bacteria and pattern of antibiotic resistance were different in some areas and this subject requires further studies in the future.

  9. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer.

    Science.gov (United States)

    Shah, Neel; Wang, Ping; Wongvipat, John; Karthaus, Wouter R; Abida, Wassim; Armenia, Joshua; Rockowitz, Shira; Drier, Yotam; Bernstein, Bradley E; Long, Henry W; Freedman, Matthew L; Arora, Vivek K; Zheng, Deyou; Sawyers, Charles L

    2017-09-11

    In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.

  10. Regulation of multidrug resistance by microRNAs in anti-cancer therapy

    Directory of Open Access Journals (Sweden)

    Xin An

    2017-01-01

    Full Text Available Multidrug resistance (MDR remains a major clinical obstacle to successful cancer treatment. Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosis and autophagy machinery, alterations of drug metabolism and drug targets, disrupti on of redox homeostasis, the exact mechanisms of MDR in a specific cancer patient and the cross-talk among these different mechanisms and how they are regulated are poorly understood. MicroRNAs (miRNAs are a new class of small noncoding RNAs that could control the global activity of the cell by post-transcriptionally regulating a large variety of target genes and proteins expression. Accumulating evidence shows that miRNAs play a key regulatory role in MDR through modulating various drug resistant mechanisms mentioned above, thereby holding much promise for developing novel and more effective individualized therapies for cancer treatment. This review summarizes the various MDR mechanisms and mainly focuses on the role of miRNAs in regulating MDR in cancer treatment.

  11. Characterization of Taurine Transporting Systems During Acquirement of Resistance to Platinum(II)-based, Chemotherapeutic Drugs

    DEFF Research Database (Denmark)

    Sørensen, Belinda Halling

    Although, cisplatin is one of the most effective broad-spectrum anticancer drugs, prolonged cisplatin treatment often results in development of chemoresistance and subsequent therapeutic failure. Dysregulation of the taurine transporting systems i.e., the taurine transporter (TauT) and volume....... Cisplatin resistance correlates with a reduction in the volume regulated anion current and taurine release mediated by VRACs, as well as an improved cellular accumulation of taurine through TauT. In human ovarian A2780 cancer cells, for instance, cisplatin resistance is associated with an absent swelling......-induced taurine release and inability to volume regulate. The dismissed taurine release was due to an almost absent leucin-rich-repeat containing 8A (LRRC8A) total protein expression. LRRC8A is an important component of VRACs. Cellular taurine contributes to the intracellular pool of organic osmolytes. Moreover...

  12. Accelerating resistance, inadequate antibacterial drug pipelines and international responses.

    Science.gov (United States)

    Theuretzbacher, Ursula

    2012-04-01

    The pandemic of multidrug-resistant (MDR) pathogens and their continuing spread is beyond dispute. In contrast to the past, today's antibacterial research and development (R&D) pipelines are nearly dry, failing to provide the flow of novel antibiotics required to match the clinical challenges of the multidrug resistance (MDR) crisis. Concerned over the rapidly worsening potential global healthcare crisis caused by MDR bacteria and the lack of robust drug pipelines, several multinational campaigns have issued policy recommendations and have initiated broad discussion with a goal of stimulating the development of novel antibacterial drugs and technologies. These activities have resulted in intensified co-operation between the USA and the EU. The recently announced extensive 'Action plan against the rising threats from antimicrobial resistance' substantially ramps up action within the EU. In recognising the potential crisis caused by MDR and the limited treatment options, the European Commission decided on an unprecedented approach to drive the search for novel antibiotics by integrating the pharmaceutical industry, the research capacities of universities and small companies supported by public funding along with pricing/reimbursement and regulatory bodies. The European Commission has shown leadership and put action plans in place. Only the future will tell whether these initiatives will help curb the impact of the MDR pandemic. Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  13. 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....

  14. Lin28 Mediates Cancer Chemotherapy Resistance via Regulation of miRNA Signaling.

    Science.gov (United States)

    Xu, Chaoyang; Xie, Shuduo; Song, Chunjiao; Huang, Liming; Jiang, Zhinong

    2014-06-01

    Chemotherapy resistance is one of the major obstacles limiting the success of cancer drug treatment. Among the mechanisms of resistance to chemotherapy treatment, there are those closely related to P-Glycoprotein, multidrug resistance-related protein, glutathione S-transferase pi and topoisomerase-II. Lin28 is a highly conserved RNA-binding protein, it consists of a cold shock domain and retroviral-type (CCHC) zinc finger motifs. In previous preclinical and clinical studies, positive Lin28 expression in cancer cells was correlated with decreased sensitivity to chemotherapy. And Lin28 could mediate cancer chemotherapy resistance via regulation of miR107 and Let-7 MiRNA. This article reviews current knowledge on predictive value of Lin28 in response to chemotherapy. Better understanding of its role may facilitate patient's selection of therapeutic regimen and lead to optimal clinical outcome.

  15. Definition of drug-resistant epilepsy: is it evidence based?

    Science.gov (United States)

    Wiebe, Samuel

    2013-05-01

    Clinical case definitions are the cornerstone of clinical communication and of clinical and epidemiologic research. The ramifications of establishing a case definition are extensive, including potentially large changes in epidemiologic estimates of frequency, and decisions for clinical management. Yet, defining a condition entails numerous challenges such as defining the scope and purpose, incorporating the strongest evidence base with clinical expertise, accounting for patients' values, and considering impact on care. The clinical case definition of drug-resistant epilepsy, in addition, must address what constitutes an adequate intervention for an individual drug, what are the outcomes of relevance, what period of observation is sufficient to determine success or failure, how many medications should be tried, whether seizure frequency should play a role, and what is the role of side effects and tolerability. On the other hand, the principles of evidence-based medicine (EBM) aim at providing a systematic approach to incorporating the best available evidence into the process of clinical decision for individual patients. The case definition of drug-resistant epilepsy proposed by the the International League Against Epilepsy (ILAE) in 2009 is evaluated in terms of the principles of EBM as well as the stated goals of the authors of the definition. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

  16. 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

  17. Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus

    DEFF Research Database (Denmark)

    de Evgrafov, Mari Cristina Rodriguez; Gumpert, Heidi; Munck, Christian

    2015-01-01

    As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations......, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased significantly beyond wild......-type levels. All drug combinations, irrespective of interaction types, effectively limited resistance evolution compared with monotreatment. Cross-resistance and collateral sensitivity were found to be important factors in the extent of resistance evolution toward a combination. Comparative genomic analyses...

  18. Low-level quinolone-resistance in multi-drug resistant typhoid

    Energy Technology Data Exchange (ETDEWEB)

    Mirza, S H; Khan, M A [Armed Forces Inst. of Pathology, Rawalpindi (Pakistan). Dept. of Microbiolgy

    2008-01-15

    To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)

  19. Low-level quinolone-resistance in multi-drug resistant typhoid

    International Nuclear Information System (INIS)

    Mirza, S.H.; Khan, M.A.

    2008-01-01

    To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)

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

    Science.gov (United States)

    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

  1. Genetic Regulation of Virulence and Antibiotic Resistance in Acinetobacter baumannii

    Science.gov (United States)

    Kröger, Carsten; Kary, Stefani C.; Schauer, Kristina; Cameron, Andrew D. S.

    2016-01-01

    Multidrug resistant microorganisms are forecast to become the single biggest challenge to medical care in the 21st century. Over the last decades, members of the genus Acinetobacter have emerged as bacterial opportunistic pathogens, in particular as challenging nosocomial pathogens because of the rapid evolution of antimicrobial resistances. Although we lack fundamental biological insight into virulence mechanisms, an increasing number of researchers are working to identify virulence factors and to study antibiotic resistance. Here, we review current knowledge regarding the regulation of virulence genes and antibiotic resistance in Acinetobacter baumannii. A survey of the two-component systems AdeRS, BaeSR, GacSA and PmrAB explains how each contributes to antibiotic resistance and virulence gene expression, while BfmRS regulates cell envelope structures important for pathogen persistence. A. baumannii uses the transcription factors Fur and Zur to sense iron or zinc depletion and upregulate genes for metal scavenging as a critical survival tool in an animal host. Quorum sensing, nucleoid-associated proteins, and non-classical transcription factors such as AtfA and small regulatory RNAs are discussed in the context of virulence and antibiotic resistance. PMID:28036056

  2. Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

    Science.gov (United States)

    Pei, Xin-Yan; Dai, Yun; Felthousen, Jessica; Chen, Shuang; Takabatake, Yukie; Zhou, Liang; Youssefian, Leena E; Sanderson, Michael W; Bodie, Wesley W; Kramer, Lora B; Orlowski, Robert Z; Grant, Steven

    2014-01-01

    The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

  3. Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Xin-Yan Pei

    Full Text Available The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

  4. Dodecyltriphenylphosphonium inhibits multiple drug resistance in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Knorre, Dmitry A; Markova, Olga V; Smirnova, Ekaterina A; Karavaeva, Iuliia E; Sokolov, Svyatoslav S; Severin, Fedor F

    2014-08-08

    Multiple drug resistance pumps are potential drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G - a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. HIV protease drug resistance and its impact on inhibitor design.

    Science.gov (United States)

    Ala, P J; Rodgers, J D; Chang, C H

    1999-07-01

    The primary cause of resistance to the currently available HIV protease inhibitors is the accumulation of multiple mutations in the viral protease. So far more than 20 substitutions have been observed in the active site, dimer interface, surface loops and flaps of the homodimer. While many mutations reduce the protease's affinity for inhibitors, others appear to enhance its catalytic efficiency. This high degree of genetic flexibility has made the protease an elusive drug target. The design of the next generation of HIV protease inhibitors will be discussed in light of the current structural information.

  6. Cattle breeding, trypanosomosis prevalence and drug resistance in Northern Togo.

    Science.gov (United States)

    Tchamdja, E; Kulo, A E; Vitouley, H S; Batawui, K; Bankolé, A A; Adomefa, K; Cecchi, G; Hoppenheit, A; Clausen, P H; De Deken, R; Van Den Abbeele, J; Marcotty, T; Delespaux, V

    2017-03-15

    African Animal Trypanosomosis (AAT) is a major disease of cattle in Togo and its control is essentially based on chemotherapy. However, because of excessive use of trypanocides during the past decades, chemo-resistance in the parasites has developed. In order to assess the current situation of AAT and resistance to trypanocidal drugs in Northern Togo, a study was conducted on cattle from December 2012 to August 2013 in the regions of Kara and Savanes. An initial cross-sectional survey was carried out in 40 villages using the Haematocrit Centrifugation Technique (HCT). Out of these, 5 villages with a trypanosome prevalence of >10% were selected for a block treatment study (BT) with diminazene diaceturate (DA: 3.5mg/kg for a 14-day follow-up) and isometamidium chloride (ISM: 0.5mg/kg for a 28-day follow-up). Positive blood samples collected during the parasitological surveys and an equivalent number of negatives were further analyzed by PCR-RFLP for trypanosome species confirmation and molecular diagnosis of resistance to DA in Trypanosoma congolense. The results from 1883 bovine blood samples confirmed a high overall trypanosome prevalence of 10.8% in Northern Togo. PCR-RFLP revealed that T. congolense is the dominant pathogenic trypanosome species (50.5%) followed by T. vivax (27.3%), and T. brucei (16.2%). The BT showed varying levels of treatment failures ranging from 0 to 30% and from 0 to 50% for DA and for ISM respectively, suggesting the existence of resistant trypanosome populations in the study area. Our results show that AAT still represents a major obstacle to the development of cattle husbandry in Northern Togo. In areas of high AAT risk, a community-based integrated strategy combining vector control, rational use of trypanocidal drugs and improving the general condition of the animals is recommended to decision makers. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Oxidative Stress in Patients with Drug Resistant Partial Complex Seizure

    Directory of Open Access Journals (Sweden)

    Lourdes Lorigados Pedre

    2018-06-01

    Full Text Available Oxidative stress (OS has been implicated as a pathophysiological mechanism of drug-resistant epilepsy, but little is known about the relationship between OS markers and clinical parameters, such as the number of drugs, age onset of seizure and frequency of seizures per month. The current study’s aim was to evaluate several oxidative stress markers and antioxidants in 18 drug-resistant partial complex seizure (DRPCS patients compared to a control group (age and sex matched, and the results were related to clinical variables. We examined malondialdehyde (MDA, advanced oxidation protein products (AOPP, advanced glycation end products (AGEs, nitric oxide (NO, uric acid, superoxide dismutase (SOD, glutathione, vitamin C, 4-hydroxy-2-nonenal (4-HNE and nitrotyrosine (3-NT. All markers except 4-HNE and 3-NT were studied by spectrophotometry. The expressions of 4-HNE and 3-NT were evaluated by Western blot analysis. MDA levels in patients were significantly increased (p ≤ 0.0001 while AOPP levels were similar to the control group. AGEs, NO and uric acid concentrations were significantly decreased (p ≤ 0.004, p ≤ 0.005, p ≤ 0.0001, respectively. Expressions of 3-NT and 4-HNE were increased (p ≤ 0.005 similarly to SOD activity (p = 0.0001, whereas vitamin C was considerably diminished (p = 0.0001. Glutathione levels were similar to the control group. There was a positive correlation between NO and MDA with the number of drugs. The expression of 3-NT was positively related with the frequency of seizures per month. There was a negative relationship between MDA and age at onset of seizures, as well as vitamin C with seizure frequency/month. We detected an imbalance in the redox state in patients with DRCPS, supporting oxidative stress as a relevant mechanism in this pathology. Thus, it is apparent that some oxidant and antioxidant parameters are closely linked with clinical variables.

  8. Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

    Science.gov (United States)

    Lukianova-Hleb, Ekaterina Y.; Ren, Xiaoyang; Townley, Debra; Wu, Xiangwei; Kupferman, Michael E.; Lapotko, Dmitri O.

    2012-01-01

    The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment. PMID:23139725

  9. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-04-17

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  10. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M.; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-05-01

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  11. MicroRNA expression profiles of drug-resistance breast cancer cells and their exosomes.

    Science.gov (United States)

    Zhong, Shanliang; Chen, Xiu; Wang, Dandan; Zhang, Xiaohui; Shen, Hongyu; Yang, Sujin; Lv, Mengmeng; Tang, Jinhai; Zhao, Jianhua

    2016-04-12

    Exosomes have been shown to transmit drug resistance through delivering miRNAs. We aimed to explore their roles in breast cancer. Three resistant sublines were established by exposing parental MDA-MB-231 cell line to docetaxel, epirubicin and vinorelbine, respectively. Preneoadjuvant chemotherapy biopsies and paired surgically-resected specimens embedded in paraffin from 23 breast cancer patients were collected. MiRNA expression profiles of the cell lines and their exosomes were evaluated using microarray. The result showed that most miRNAs in exosomes had a lower expression level than that in cells, however, some miRNAs expressed higher in exosomes than in cells, suggesting a number of miRNAs is concentrated in exosomes. Among the dysregulated miRNAs, 22 miRNAs were consistently up-regulated in exosomes and their cells of origin. We further found that 12 of the 22 miRNAs were significantly up-regulated after preneoadjuvant chemotherapy. Further study of the role of these 12 miRNAs in acquisition of drug resistance is needed to clarify their contribution to chemoresistance.

  12. Radiation induction of drug resistance in RIF-1: Correlation of tumor and cell culture results

    International Nuclear Information System (INIS)

    Moulder, J.E.; Hopwood, L.E.; Volk, D.M.; Davies, B.M.

    1991-01-01

    The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors

  13. Radiation induction of drug resistance in RIF-1 tumors and tumor cells

    International Nuclear Information System (INIS)

    Hopwood, L.E.; Moulder, J.E.

    1989-01-01

    The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not for ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance

  14. Extensively and Pre-Extensively Drug Resistant Tuberculosis in Clinical Isolates of Multi-Drug Resistant Tuberculosis Using Classical Second Line Drugs (Levofloxacin and Amikacin)

    International Nuclear Information System (INIS)

    Mirza, I. A.; Khan, F. A.; Khan, K. A.; Satti, L.; Ghafoor, T.; Fayyaz, M.

    2015-01-01

    Objective:To find out the frequency of Extensively Drug Resistant (XDR) and pre-XDR tuberculosis in clinical isolates of Multi-Drug Resistant (MDR) Tuberculosis (TB) by determining the susceptibilities against Levofloxacin and Amikacin (classical second line antituberculosis drugs). Study Design: A descriptive cross-sectional study. Place and Duration of Study: Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013. Methodology: Amikacin (AK) and Levofloxacin (LEVO) were obtained in chemically pure form from Sigma (Taufkirchen, Germany). The breakpoint concentration used for AK was 1.0 micro g/ml and for LEVO 2.0 micro g/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol. Results: A total of 3 MDR-TB isolates (3 percentage) turned out to be XDR-TB based upon simultaneous resistance to injectable second line antituberculosis drug AK and one of the fluoro-quinolones (LEVO). A total of 24 MDR-TB isolates (24 percentage) were found to be pre-XDR based upon resistance to LEVO alone. Treatment status record of patients with XDR and pre-XDRTB isolates revealed that majority of patients had received fluoroquinolones (FQs) during the course of treatment. Conclusion: XDR-TB has started to emerge in MDR-TB isolates in our set up. The worrying sign is the high frequency of pre-XDR tuberculosis. Urgent steps need to be taken to stem the tide of pre-XDR-TB in our population. It is thus recommended to develop facilities to carry out drug susceptibility testing to monitor the status of pre-XDR and XDR-TB in our population. (author)

  15. Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis.

    Directory of Open Access Journals (Sweden)

    Elizabeth J Polvi

    2016-10-01

    Full Text Available Fungal pathogens have evolved diverse strategies to sense host-relevant cues and coordinate cellular responses, which enable virulence and drug resistance. Defining circuitry controlling these traits opens new opportunities for chemical diversity in therapeutics, as the cognate inhibitors are rarely explored by conventional screening approaches. This has great potential to address the pressing need for new therapeutic strategies for invasive fungal infections, which have a staggering impact on human health. To explore this approach, we focused on a leading human fungal pathogen, Candida albicans, and screened 1,280 pharmacologically active compounds to identify those that potentiate the activity of echinocandins, which are front-line therapeutics that target fungal cell wall synthesis. We identified 19 compounds that enhance activity of the echinocandin caspofungin against an echinocandin-resistant clinical isolate, with the broad-spectrum chelator DTPA demonstrating the greatest synergistic activity. We found that DTPA increases susceptibility to echinocandins via chelation of magnesium. Whole genome sequencing of mutants resistant to the combination of DTPA and caspofungin identified mutations in the histidine kinase gene NIK1 that confer resistance to the combination. Functional analyses demonstrated that DTPA activates the mitogen-activated protein kinase Hog1, and that NIK1 mutations block Hog1 activation in response to both caspofungin and DTPA. The combination has therapeutic relevance as DTPA enhanced the efficacy of caspofungin in a mouse model of echinocandin-resistant candidiasis. We found that DTPA not only reduces drug resistance but also modulates morphogenesis, a key virulence trait that is normally regulated by environmental cues. DTPA induced filamentation via depletion of zinc, in a manner that is contingent upon Ras1-PKA signaling, as well as the transcription factors Brg1 and Rob1. Thus, we establish a new mechanism by which

  16. Ectoparasites of medical and veterinary importance: drug resistance and the need for alternative control methods.

    Science.gov (United States)

    McNair, Carol M

    2015-03-01

    Despite multiple attempts at eradication, many ectoparasites of humans and domestic livestock remain a persistent problem in the modern world. For many years, a range of pesticide drugs including organophosphates, organochlorides and synthetic pyrethroids provided effective control of these parasites; but intensive use of these drugs has led to the evolution of resistance in many target species. This paper aims to review the effectiveness of current control methods and discuss potential alternatives for the long term sustainable control of ectoparasites. Important medical ectoparasites such as scabies mites, head lice and bed bugs present a significant public health problem, and so adequate control methods are essential. Ectoparasites of domestic livestock and farmed fish (for example sheep scab mites, poultry mites and sea lice) are also of concern given the increasing strain on the world's food supply. These parasites have become resistant to several classes of pesticide, making control very difficult. Recently, an increasing amount of research has focussed on alternative control methods such as insect growth regulators, biological control using essential oils or fungi, as well as vaccine development against some ectoparasites of medical and veterinary importance. Drug resistance is prevalent in all of the ectoparasites discussed in this review. A wide variety of alternative control methods have been identified, however further research is necessary in order for these to be used to successfully control ectoparasitic diseases in the future. © 2015 Royal Pharmaceutical Society.

  17. Detection of First-Line Drug Resistance Mutations and Drug-Protein Interaction Dynamics from Tuberculosis Patients in South India.

    Science.gov (United States)

    Nachappa, Somanna Ajjamada; Neelambike, Sumana M; Amruthavalli, Chokkanna; Ramachandra, Nallur B

    2018-05-01

    Diagnosis of drug-resistant tuberculosis predominantly relies on culture-based drug susceptibility testing, which take weeks to produce a result and a more time-efficient alternative method is multiplex allele-specific PCR (MAS-PCR). Also, understanding the role of mutations in causing resistance helps better drug designing. To evaluate the ability of MAS-PCR in the detection of drug resistance and to understand the mechanism of interaction of drugs with mutant proteins in Mycobacterium tuberculosis. Detection of drug-resistant mutations using MAS-PCR and validation through DNA sequencing. MAS-PCR targeted five loci on three genes, katG 315 and inhA -15 for the drug isoniazid (INH), and rpoB 516, 526, and 531 for rifampicin (RIF). Furthermore, the sequence data were analyzed to study the effect on interaction of the anti-TB drug molecule with the target protein using in silico docking. We identified drug-resistant mutations in 8 out of 114 isolates with 2 of them as multidrug-resistant TB using MAS-PCR. DNA sequencing confirmed only six of these, recording a sensitivity of 85.7% and specificity of 99.3% for MAS-PCR. Molecular docking showed estimated free energy of binding (ΔG) being higher for RIF binding with RpoB S531L mutant. Codon 315 in KatG does not directly interact with INH but blocks the drug access to active site. We propose DNA sequencing-based drug resistance detection for TB, which is more accurate than MAS-PCR. Understanding the action of resistant mutations in disrupting the normal drug-protein interaction aids in designing effective drug alternatives.

  18. Ion channels and transporters in the development of drug resistance in cancer cells

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay; Lambert, Ian Henry

    2014-01-01

    Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of i...

  19. 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.

  20. Antihypertensive drug use in resistant and nonresistant hypertension and in controlled and uncontrolled resistant hypertension.

    Science.gov (United States)

    de la Sierra, Alejandro; Armario, Pedro; Oliveras, Anna; Banegas, José R; Gorostidi, Manuel; Vinyoles, Ernest; de la Cruz, Juan J; Segura, Julián; Ruilope, Luis M

    2018-07-01

    Treatment-resistant hypertension (TRH) is associated with particular clinical features, nonadherence, and suboptimal treatment. We assessed possible associations of antihypertensive drug classes, specific agents inside each class, and types of combinations, with the presence of non-TRH vs. TRH, and with controlled vs. uncontrolled TRH. Comparisons were done in 14 264 patients treated with three drugs (non-TRH: 2988; TRH: 11 276) and in 6974 treated with at least four drugs (controlled TRH: 1383; uncontrolled TRH: 5591). Associations were adjusted for age, sex, and previous cardiovascular event. In both groups of patients treated with three or with at least four drugs, aldosterone antagonists among drug classes [adjusted odds ratio (OR): 1.82 and 1.41, respectively], and ramipril (OR: 1.28 and 1.30), olmesartan (OR: 1.31 and 1.37), and amlodipine (OR: 1.11 and 1.41) inside each class were significantly associated with blood pressure control (non-TRH or controlled TRH). In patients treated with three drugs, non-TRH was also associated with the use of chlorthalidone (OR: 1.50) and bisoprolol (OR: 1.19), whereas in patients treated with at least four drugs, controlled TRH was significantly associated with the triple combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic (OR: 1.17). The use of aldosterone antagonists is associated with blood pressure control in patients treated with three or more drugs. Similar results are observed with specific agents inside each class, being ramipril, olmesartan, chlorthalidone, amlodipine, and bisoprolol those exhibiting significant results. An increased use of these drugs might probably reduce the burden of TRH.

  1. Surgical management of cavernous malformations coursing with drug resistant epilepsy

    Directory of Open Access Journals (Sweden)

    Mario Arturo Alonso-Vanegas

    2012-01-01

    Full Text Available Cerebral cavernous malformations (CM are dynamic lesions characterized by continuous size changes and repeated bleeding. When involving cortical tissue, CM pose a significant risk for the development of drug-resistant epilepsy, which is thought to be result of an altered neuronal network caused by the lesion itself and its blood degradation products. Preoperative evaluation should comprise a complete seizure history, neurological examination, epilepsy-oriented MRI, EEG, video-EEG, completed with SPECT, PET, functional MRI and/or invasive monitoring as needed. Radiosurgery shows variable rates of seizure freedom and a high incidence of complications, thus microsurgical resection remains the optimal treatment for CM coursing with drug-resistant epilepsy.Two thirds of patients reach Engel I class at three-year follow-up, regardless of lobar location. Those with secondarily generalized seizures, a higher seizure frequency, and generalized abnormalities on preoperative or postoperative EEG, show poorer outcomes, while factors such as gender, duration of epilepsy, lesion size, age, bleeding at the time of surgery, do not correlate consistently with seizure outcome. Electrocorticography and a meticulous removal of all cortical hemosiderin –beyond pure lesionectomy– reduce the risk of symptomatic recurrences.

  2. Drug Resistance versus Spiritual Resistance: A Comparative Analysis from the Perspective of Spiritual Health

    Directory of Open Access Journals (Sweden)

    Mohammad Baqer Mohammadi Laini

    2014-12-01

    Full Text Available Background and Objectives: Taking into account a few principles concerning human being, it becomes plausible that the human spirit would also have a similar reaction to spiritual “medicine” provided to it. In order to better understand how this is possible, we must consider the means by which the human spirit becomes resistant to spiritual remedies and compare them with the resistance developed by the body against physical drugs. As such, this research aimed at creating a comparative analysis between the elements that cause the human spirit to become resistant against spiritual remedies in comparison to the body’s resistance against physical treatments (e.g. drugs and other physical treatment. Methods: The research at hand highlights the conclusions of an overall study of the Holy Quran, books of Islamic narration, and extensive Internet research concerning this subject. With these resources, the various aspects of the spirit’s resistance against spiritual remedies were discussed in detail. Results: According to Holy Quran and Islamic narrations: Based on the expectations which God has of man, his heart (i.e. spirit has the potential to fall under one of two categories – positive or negative. An afflicted heart may at times, like an afflicted body, become resistant against a remedy designed to cure it. In both cases of physical or metaphysical resistance, the underlying element that causes this resistance as well as the symptoms which accompany it are similar to one another. Having considered the teachings found in religious texts, this research discovered the underlying causes of spiritual resistance, and outlined some solutions which can prevent this issue from arising in the first place. Conclusion: Based on the standards of health and spiritual wellbeing as outlined in Holy Quran, it is said that some hearts are unhealthy and require treatment and healing. In Holy Quran, there is also no doubt in it, guidance to the God wary

  3. Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells.

    Science.gov (United States)

    Abdelfatah, Sara A A; Efferth, Thomas

    2015-02-15

    The antihypertensive reserpine is an indole alkaloid from Rauwolfia serpentina and exerts also profound activity against cancer cells in vitro and in vivo. The present investigation was undertaken to investigate possible modes of action to explain its activity toward drug-resistant tumor cells. Sensitive and drug-resistant tumor cell lines overexpressing P-glycoprotein (ABCB1/MDR1), breast cancer resistance protein (ABCG2/BCRP), mutation-activated epidermal growth factor receptor (EGFR), wild-type and p53-knockout cells as well as the NCI panel of cell lines from different tumor origin were analyzed. Reserpine's cytotoxicity was investigated by resazurin and sulforhodamine assays, flow cytometry, and COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based RNA expressions. P-glycoprotein- or BCRP overexpressing tumor cells did not reveal cross-resistance to reserpine. EGFR-overexpressing cells were collateral sensitive and p53- Knockout cells cross-resistant to this drug compared to their wild-type parental cell lines. Reserpine increased the uptake of doxorubicin in P-glycoprotein-overexpressing cells, indicating that reserpine inhibited the efflux function of P-glycoprotein. Using molecular docking, we found that reserpine bound with even higher binding energy to P-glycoprotein and EGFR than the control drugs verapamil (P-glycoprotein inhibitor) and erlotinib (EGFR inhibitor). COMPARE and cluster analyses of microarray data showed that the mRNA expression of a panel of genes predicted the sensitivity or resistance of the NCI tumor cell line panel with statistical significance. The genes belonged to diverse pathways and biological functions, e.g. cell survival and apoptosis, EGFR activation, regulation of angiogenesis, cell mobility, cell adhesion, immunological functions, mTOR signaling, and Wnt signaling. The lack of cross-resistance to most resistance mechanisms and the collateral sensitivity in EGFR-transfectants compared to wild

  4. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis.

    Science.gov (United States)

    Kamp, Jasper; Bolhuis, Mathieu S; Tiberi, Simon; Akkerman, Onno W; Centis, Rosella; de Lange, Wiel C; Kosterink, Jos G; van der Werf, Tjip S; Migliori, Giovanni B; Alffenaar, Jan-Willem C

    2017-06-01

    Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed to develop a population pharmacokinetic model to predict the area under the concentration curve (AUC) for linezolid using a limited number of blood samples. Data from patients with MDR-/XDR-TB who received linezolid and therapeutic drug monitoring as part of their TB treatment were used. Mw\\Pharm 3.82 (Mediware, Zuidhorn, The Netherlands) was used to develop a population pharmacokinetic model and limited sampling strategy (LSS) for linezolid. LSS was evaluated over a time span of 6 h. Blood sampling directly before linezolid administration and 2 h after linezolid administration were considered to be the most clinically relevant sampling points. The model and LSS were evaluated by analysing the correlation between AUC 12h,observed and AUC 12h,estimated . In addition, LSS was validated with an external group of patients with MDR-/XDR-TB from Sondalo, Italy. Fifty-two pharmacokinetic profiles were used to develop the model. Thirty-three profiles with a 300 mg dosing regimen and 19 profiles with a 600 mg dosing regimen were obtained. Model validation showed prediction bias of 0.1% and r 2 of 0.99. Evaluation of the most clinically relevant LSS showed prediction bias of 4.8% and r 2 of 0.97. The root mean square error corresponding to the most relevant LSS was 6.07%. The developed LSS could be used to enable concentration-guided dosing of linezolid. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  5. Structural Biology Meets Drug Resistance: An Overview on Multidrug Resistance Transporters

    DEFF Research Database (Denmark)

    Shaheen, Aqsa; Iqbal, Mazhar; Mirza, Osman

    2017-01-01

    . Research on the underlying causes of multidrug resistance in cancerous cells and later on in infectious bacteria revealed the involvement of integral membrane transporters, capable of recognizing a broad range of structurally different molecules as substrates and exporting them from the cell using cellular...... superfamilies, viz., ATP-binding cassette superfamily, major facilitator superfamily and resistance nodulation division superfamily are presented. Further, the future role of structural biology in improving our understanding of drug-transporter interactions and in designing novel inhibitors against MDR pump...... century, mankind has become aware and confronted with the emergence of antibiotic-resistant pathogens. In parallel to the failure of antibiotic therapy against infectious pathogens, there had been continuous reports of cancerous cells not responding to chemotherapy with increase in the duration of therapy...

  6. Childhood Idiopathic Steroid Resistant Nephrotic Syndrome, Different Drugs and Outcome

    International Nuclear Information System (INIS)

    Shah, S. S. H.; Hafeez, F.

    2016-01-01

    Background: The management of steroid resistant nephrotic syndrome (SRNS) is quite difficult in paediatric patients. Not only the remission is difficult but also these patients are at risk of progression to end stage renal disease (ESRD). The goal of treatment is either to achieve complete remission or even partial remission as it is the most important predictor of disease outcome. Methods: This study was conducted at The Children Hospital, Lahore from February 2014 to May 2015. The SRNS patients of either sex between ages of 1-12 years were included with histology showing mesangioproliferative glomerulonephritis (MesangioPGN), focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Patients were given different immunosuppressant drugs and steroid 30 mg/m/sup 2/ alternate day therapy on case to case basis and kept on regular follow up to check for response and adverse effects. Results: Total of 105 patients included, 63 (60 percent) male and 42 (40 percent) female patients. The age ranges from 1.08 to 12 years, mean age of 6.53 years and SD of ±3.17. Tacrolimus was the most common drug used 43 (41 percent) patients followed by cyclosporine in 38 (36.2 percent) patients, while Mycophenolate mofetil (MMF) was prescribed in 21 (20 percent) patients. Complete response was in 96 (91.4 percent) initially while partial response was seen in 8 (7.6 percent) patients. On follow up, 92 (87.6 percent) patients showed complete response and partial response was in 5 (4.7 percent) patients. Cushingoid features and hypertrichosis were the most common adverse effect seen. Conclusion: Steroid resistant nephrotic syndrome can be managed well with various immunosuppressant drugs and steroids but treatment should be individualized according to clinical presentation, disease histology and cost/social factors. (author)

  7. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump

    NARCIS (Netherlands)

    Zaman, G. J.; Flens, M. J.; van Leusden, M. R.; de Haas, M.; Mülder, H. S.; Lankelma, J.; Pinedo, H. M.; Scheper, R. J.; Baas, F.; Broxterman, H. J.

    1994-01-01

    The multidrug-resistance associated protein MRP is a 180- to 195-kDa membrane protein associated with resistance of human tumor cells to cytotoxic drugs. We have investigated how MRP confers drug resistance in SW-1573 human lung carcinoma cells by generating a subline stably transfected with an

  8. Drug resistance and genetic diversity of Plasmodium falciparum parasites from Suriname

    NARCIS (Netherlands)

    Peek, Ron; van Gool, Tom; Panchoe, Daynand; Greve, Sophie; Bus, Ellen; Resida, Lesley

    2005-01-01

    Plasmodium falciparum in Suriname was studied for the presence of drug resistance and genetic variation in blood samples of 86 patients with symptomatic malaria. Drug resistance was predicted by determining point mutations in the chloroquine resistance marker of the P. falciparum chloroquine

  9. A meta-analysis of Drug resistant Tuberculosis in Sub-Saharan Africa

    African Journals Online (AJOL)

    Background: In Sub-Saharan Africa, the fight against tuberculosis (TB) has encountered a great challenge because of the emergence of drug resistant TB strains and the high prevalence of HIV infection. The aim of this meta-analysis was to determine the association of drug-resistant TB with anti-TB drug treatment history ...

  10. New-Onset Psychosis in a Multi-Drug Resistant Tuberculosis Patient ...

    African Journals Online (AJOL)

    Drug-resistant tuberculosis poses a serious challenge to global control of TB. These forms of TB do not respond to the standard six-month treatment; it can take two years or more to treat with category IV drugs that are less potent, more toxic and much more expensive. Treatment of multi-drug resistant tuberculosis is still ...

  11. Deciphering mechanisms of drug sensitivity and resistance to Selective Inhibitor of Nuclear Export (SINE) compounds

    International Nuclear Information System (INIS)

    Crochiere, Marsha; Kashyap, Trinayan; Kalid, Ori; Shechter, Sharon; Klebanov, Boris; Senapedis, William; Saint-Martin, Jean-Richard; Landesman, Yosef

    2015-01-01

    Exportin 1 (XPO1) is a well-characterized nuclear export protein whose expression is up-regulated in many types of cancers and functions to transport key tumor suppressor proteins (TSPs) from the nucleus. Karyopharm Therapeutics has developed a series of small-molecule Selective Inhibitor of Nuclear Export (SINE) compounds, which have been shown to block XPO1 function both in vitro and in vivo. The drug candidate, selinexor (KPT-330), is currently in Phase-II/IIb clinical trials for treatment of both hematologic and solid tumors. The present study sought to decipher the mechanisms that render cells either sensitive or resistant to treatment with SINE compounds, represented by KPT-185, an early analogue of KPT-330. Using the human fibrosarcoma HT1080 cell line, resistance to SINE was acquired over a period of 10 months of constant incubation with increasing concentration of KPT-185. Cell viability was assayed by MTT. Immunofluorescence was used to compare nuclear export of TSPs. Fluorescence activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), and immunoblots were used to measure effects on cell cycle, gene expression, and cell death. RNA from naïve and drug treated parental and resistant cells was analyzed by Affymetrix microarrays. Treatment of HT1080 cells with gradually increasing concentrations of SINE resulted in > 100 fold decrease in sensitivity to SINE cytotoxicity. Resistant cells displayed prolonged cell cycle, reduced nuclear accumulation of TSPs, and similar changes in protein expression compared to parental cells, however the magnitude of the protein expression changes were more significant in parental cells. Microarray analyses comparing parental to resistant cells indicate that a number of key signaling pathways were altered in resistant cells including expression changes in genes involved in adhesion, apoptosis, and inflammation. While the patterns of changes in transcription following drug treatment are similar in parental

  12. Simple PCR assays improve the sensitivity of HIV-1 subtype B drug resistance testing and allow linking of resistance mutations.

    Directory of Open Access Journals (Sweden)

    Jeffrey A Johnson

    Full Text Available BACKGROUND: The success of antiretroviral therapy is known to be compromised by drug-resistant HIV-1 at frequencies detectable by conventional bulk sequencing. Currently, there is a need to assess the clinical consequences of low-frequency drug resistant variants occurring below the detection limit of conventional genotyping. Sensitive detection of drug-resistant subpopulations, however, requires simple and practical methods for routine testing. METHODOLOGY: We developed highly-sensitive and simple real-time PCR assays for nine key drug resistance mutations and show that these tests overcome substantial sequence heterogeneity in HIV-1 clinical specimens. We specifically used early wildtype virus samples from the pre-antiretroviral drug era to measure background reactivity and were able to define highly-specific screening cut-offs that are up to 67-fold more sensitive than conventional genotyping. We also demonstrate that sequencing the mutation-specific PCR products provided a direct and novel strategy to further detect and link associated resistance mutations, allowing easy identification of multi-drug-resistant variants. Resistance mutation associations revealed in mutation-specific amplicon sequences were verified by clonal sequencing. SIGNIFICANCE: Combined, sensitive real-time PCR testing and mutation-specific amplicon sequencing provides a powerful and simple approach that allows for improved detection and evaluation of HIV-1 drug resistance mutations.

  13. Regulation of chromatin states by drugs of abuse.

    Science.gov (United States)

    Walker, Deena M; Cates, Hannah M; Heller, Elizabeth A; Nestler, Eric J

    2015-02-01

    Drug addiction involves long-term behavioral abnormalities and gene expression changes throughout the mesolimbic dopamine system. Epigenetic mechanisms establish/maintain alterations in gene expression in the brain, providing the impetus for investigations characterizing how epigenetic processes mediate the effects of drugs of abuse. This review focuses on evidence that epigenetic events, specifically histone modifications, regulate gene expression changes throughout the reward circuitry. Drugs of abuse induce changes in histone modifications throughout the reward circuitry by altering histone-modifying enzymes, manipulation of which reveals a role for histone modification in addiction-related behaviors. There is a complex interplay between these enzymes, resulting in a histone signature of the addicted phenotype. Insights gained from these studies are key to identifying novel targets for diagnosis and therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Impact of treatment heterogeneity on drug resistance and supply chain costs.

    Science.gov (United States)

    Spiliotopoulou, Eirini; Boni, Maciej F; Yadav, Prashant

    2013-09-01

    The efficacy of scarce drugs for many infectious diseases is threatened by the emergence and spread of resistance. Multiple studies show that available drugs should be used in a socially optimal way to contain drug resistance. This paper studies the tradeoff between risk of drug resistance and operational costs when using multiple drugs for a specific disease. Using a model for disease transmission and resistance spread, we show that treatment with multiple drugs, on a population level, results in better resistance-related health outcomes, but more interestingly, the marginal benefit decreases as the number of drugs used increases. We compare this benefit with the corresponding change in procurement and safety stock holding costs that result from higher drug variety in the supply chain. Using a large-scale simulation based on malaria transmission dynamics, we show that disease prevalence seems to be a less important factor when deciding the optimal width of drug assortment, compared to the duration of one episode of the disease and the price of the drug(s) used. Our analysis shows that under a wide variety of scenarios for disease prevalence and drug cost, it is optimal to simultaneously deploy multiple drugs in the population. If the drug price is high, large volume purchasing discounts are available, and disease prevalence is high, it may be optimal to use only one drug. Our model lends insights to policy makers into the socially optimal size of drug assortment for a given context.

  15. High Levels of Transmitted HIV Drug Resistance in a Study in Papua New Guinea.

    Science.gov (United States)

    Lavu, Evelyn; Kave, Ellan; Mosoro, Euodia; Markby, Jessica; Aleksic, Eman; Gare, Janet; Elsum, Imogen A; Nano, Gideon; Kaima, Petronia; Dala, Nick; Gurung, Anup; Bertagnolio, Silvia; Crowe, Suzanne M; Myatt, Mark; Hearps, Anna C; Jordan, Michael R

    2017-01-01

    Papua New Guinea is a Pacific Island nation of 7.3 million people with an estimated HIV prevalence of 0.8%. ART initiation and monitoring are guided by clinical staging and CD4 cell counts, when available. Little is known about levels of transmitted HIV drug resistance in recently infected individuals in Papua New Guinea. Surveillance of transmitted HIV drug resistance in a total of 123 individuals recently infected with HIV and aged less than 30 years was implemented in Port Moresby (n = 62) and Mount Hagen (n = 61) during the period May 2013-April 2014. HIV drug resistance testing was performed using dried blood spots. Transmitted HIV drug resistance was defined by the presence of one or more drug resistance mutations as defined by the World Health Organization surveillance drug resistance mutations list. The prevalence of non-nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 16.1% (95% CI 8.8%-27.4%) and 8.2% (95% CI 3.2%-18.2%) in Port Moresby and Mount Hagen, respectively. The prevalence of nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 3.2% (95% CI 0.2%-11.7%) and 3.3% (95% CI 0.2%-11.8%) in Port Moresby and Mount Hagen, respectively. No protease inhibitor transmitted HIV drug resistance was observed. The level of non-nucleoside reverse transcriptase inhibitor drug resistance in antiretroviral drug naïve individuals recently infected with HIV in Port Moresby is amongst the highest reported globally. This alarming level of transmitted HIV drug resistance in a young sexually active population threatens to limit the on-going effective use of NNRTIs as a component of first-line ART in Papua New Guinea. To support the choice of nationally recommended first-line antiretroviral therapy, representative surveillance of HIV drug resistance among antiretroviral therapy initiators in Papua New Guinea should be urgently implemented.

  16. Drug resistance detection and mutation patterns of multidrug resistant tuberculosis strains from children in Delhi

    Directory of Open Access Journals (Sweden)

    Jyoti Arora

    2017-06-01

    Full Text Available A total of 312 sputum samples from pediatric patients presumptive of multidrug resistant tuberculosis were tested for the detection of drug resistance using the GenoTypeMTBDRplus assay. A total of 193 (61.8% patients were smear positive and 119 (38.1% were smear negative by Ziehl–Neelsen staining. Line probe assay (LPA was performed for 208 samples/cultures (193 smear positive samples and 15 cultures from smear negative samples. Valid results were obtained from 198 tests. Of these, 125/198 (63.1% were sensitive to both rifampicin (RIF and isoniazid (INH. 73/198 (36.9% were resistant to at least INH/RIF, out of which 49 (24.7% were resistant to both INH and RIF (multidrug resistant. Children with tuberculosis are often infected by someone close to them, so strengthening of contact tracing in the program may help in early diagnosis to identify additional cases within the household. There is a need to evaluate newer diagnostic assays which have a high sensitivity in the case of smear negative samples, additional samples other than sputum among young children not able to expectorate, and also to fill the gap between estimated and reported cases under the program.

  17. Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

    Science.gov (United States)

    Fernández, Lucía

    2012-01-01

    Summary: The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms. PMID:23034325

  18. Proteomics of drug resistance in Candida glabrata biofilms.

    Science.gov (United States)

    Seneviratne, C Jayampath; Wang, Yu; Jin, Lijian; Abiko, Y; Samaranayake, Lakshman P

    2010-04-01

    Candida glabrata is a fungal pathogen that causes a variety of mucosal and systemic infections among compromised patient populations with higher mortality rates. Previous studies have shown that biofilm mode of the growth of the fungus is highly resistant to antifungal agents compared with the free-floating or planktonic mode of growth. Therefore, in the present study, we used 2-D DIGE to evaluate the differential proteomic profiles of C. glabrata under planktonic and biofilm modes of growth. Candida glabrata biofilms were developed on polystyrene surfaces and age-matched planktonic cultures were obtained in parallel. Initially, biofilm architecture, viability, and antifungal susceptibility were evaluated. Differentially expressed proteins more than 1.5-fold in DIGE analysis were subjected to MS/MS. The transcriptomic regulation of these biomarkers was evaluated by quantitative real-time PCR. Candida glabrata biofilms were highly resistant to the antifungals and biocides compared with the planktonic mode of growth. Candida glabrata biofilm proteome when compared with its planktonic proteome showed upregulation of stress response proteins, while glycolysis enzymes were downregulated. Similar trend could be observed at transcriptomic level. In conclusion, C. glabrata biofilms possess higher amount of stress response proteins, which may potentially contribute to the higher antifungal resistance seen in C. glabrata biofilms.

  19. HIV-1 evolution, drug resistance, and host genetics: The Indian scenario

    OpenAIRE

    Shankarkumar, U.; Pawar,Aruna; Ghosh,Kanjaksha

    2009-01-01

    U Shankarkumar, A Pawar, K GhoshNational Institute of Immunohaematology (ICMR), KEM Hospital, Parel, Mumbai, Maharashtra, IndiaAbstract: A regimen with varied side effects and compliance is of paramount importance to prevent viral drug resistance. Most of the drug-resistance studies, as well as interpretation algorithms, are based on sequence data from HIV-1 subtype B viruses. Increased resistance to antiretroviral drugs leads to poor prognosis by restricting treatment optio...

  20. Experimental studies on the ecology and evolution of drug-resistant malaria parasites

    OpenAIRE

    Huijben, Silvie

    2010-01-01

    Drug resistance is a serious problem in health care in general, and in malaria treatment in particular, rendering many of our previously considered ‘wonder drugs’ useless. Recently, large sums of money have been allocated for the continuous development of new drugs to replace the failing ones. We seem to be one step behind the evolution of antimalarial resistance; is it possible to get one step ahead? Are interventions which slow down the evolution and spread of drug-resistant ...

  1. 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.

  2. Nanoantibiotics: strategic assets in the fight against drug- resistant superbugs

    Directory of Open Access Journals (Sweden)

    Khurana C

    2018-03-01

    Full Text Available Chandni Khurana, Bhupendra Chudasama Laboratory of Nanomedicine, School of Physics and Materials Science, Thapar University, Patiala, Punjab, India Abstract: Antimicrobial characteristics of metals reveal that Ag despite its economic constraints remains the most popular antibiotic agent. Antimicrobial characteristics of copper nanoparticles (CNPs are not well understood. To our knowledge, no systematic comparative study on microbial properties of silver nanoparticles (SNPs and CNPs exists. In this article, a comparative study on microbial properties of engineered metal nanoantibiotics against clinically important strains has been attempted. Our results indicate that biocidal activities of CNPs are better than SNPs. Minimum inhibitory concentration (MIC values of CNPs are 10 times lower than the corresponding MICs of SNPs. These improved biocidal activities of CNPs would make it affordable and potent nontraditional antibiotics against which microbes are least susceptible to develop any drug resistance. Keywords: antibiotics, silver, copper, nanoparticles

  3. The problem of resistant Trichomonas vaginalis to antiprotozoal drugs

    Directory of Open Access Journals (Sweden)

    A. L. Poznyak

    2011-01-01

    Full Text Available This review presents recent data on the energy metabolism of Trichomonas vaginalis and ways the activation of metronidazole. The sensitivity of microorganisms to the 5-nitroimidazole by the presence of their enzyme systems, generating and transporting electrons, which can then transfer them to the nitro group of the drug. In T.vaginalis these are pyruvate ferredoxin-oxydoreductase, thioredoxin reductase and flavin reductase. The development of resistance T.vaginalis to metronidazole preparations of this multistep process, based on the gradual reduction (up to a loss activity hydrogenosomal enzymes and / or violation of the flavindependent metabolic pathways.

  4. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Göllner, Stefanie; Oellerich, Thomas; Agrawal-Singh, Shuchi

    2017-01-01

    In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction...

  5. Mosaic Structure of a Multiple-Drug-Resistant, Conjugative Plasmid from Campylobacter jejuni

    National Research Council Canada - National Science Library

    Nirdnoy, Warawadee; Mason, Carl J; Guerry, Patricia

    2005-01-01

    ..., where it apparently integrated into the chromosome and expressed high-level resistance to multiple aminoglycoside antibiotics. This work provides new information about both the nature of drug resistance in C...

  6. Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia

    NARCIS (Netherlands)

    A. Holleman (Amy); M.L. den Boer (Monique); K.M. Kazemier (Karin); G.E. Janka-Schaub (Gritta); R. Pieters (Rob)

    2003-01-01

    textabstractResistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in

  7. Tuberculosis drug resistance isolates from pulmonary tuberculosis patients, Kassala State, Sudan

    Directory of Open Access Journals (Sweden)

    Fatima A Khalid

    2015-01-01

    This study revealed that high resistance to rifampicin was associated with various point mutations in and out of the RRDR of the rpoB gene. Molecular methods are needed for early detection of TB disease and drug resistance.

  8. Drug resistant Salmonella in broiler chicken sold at local market in ...

    African Journals Online (AJOL)

    user

    2015-10-28

    Oct 28, 2015 ... Key words: Antibiogram, Salmonellosis, PCR, broiler chicken, drug resistance. ... of zoonotic origin and have gained their resistance in an animal host ..... dynamics of Salmonella enterica serotypes in commercial egg and.

  9. Molecular Evidence of Drug Resistance in Asymptomatic Malaria Infections, Myanmar, 2015.

    Science.gov (United States)

    Nyunt, Myat Htut; Shein, Thinzar; Zaw, Ni Ni; Han, Soe Soe; Muh, Fauzi; Lee, Seong-Kyun; Han, Jin-Hee; Thant, Kyaw Zin; Han, Eun-Taek; Kyaw, Myat Phone

    2017-03-01

    Artemisinin resistance containment in Myanmar was initiated in 2011 after artemisinin-resistant Plasmodium falciparum malaria was reported. Molecular evidence suggests that asymptomatic malaria infections harboring drug resistance genes are present among residents of the Myanmar artemisinin resistance containment zone. This evidence supports efforts to eliminate these hidden infections.

  10. Disinfectant-susceptibility of multi-drug-resistant Mycobacterium tuberculosis isolated in Japan

    Directory of Open Access Journals (Sweden)

    Noriko Shinoda

    2016-02-01

    Full Text Available Abstract Background Multi-drug-resistant Mycobacterium tuberculosis has been an important problem in public health around the world. However, limited information about disinfectant-susceptibility of multi-drug-resistant strain of M. tuberculosis was available. Findings We studied susceptibility of several Japanese isolates of multi-drug-resistant M. tuberculosis against disinfectants, which are commonly used in clinical and research laboratories. We selected a laboratory reference strain (H37Rv and eight Japanese isolates, containing five drug-susceptible strains and three multi-drug-resistant strains, and determined profiles of susceptibility against eight disinfectants. The M. tuberculosis strains were distinguished into two groups by the susceptibility profile. There was no relationship between multi-drug-resistance and disinfectant-susceptibility in the M. tuberculosis strains. Cresol soap and oxydol were effective against all strains we tested, regardless of drug resistance. Conclusions Disinfectant-resistance is independent from multi-drug-resistance in M. tuberculosis. Cresol soap and oxydol were effective against all strains we tested, regardless of drug resistance.

  11. Primary drug resistance in a region with high burden of tuberculosis. A critical problem.

    Science.gov (United States)

    Villa-Rosas, Cecilia; Laniado-Laborín, Rafael; Oceguera-Palao, Lorena

    2015-01-01

    To determine rates of drug resistance in new cases of pulmonary tuberculosis in a region with a high burden of the disease. New case suspects were referred for drug susceptibility testing. 28.9% of new cases were resistant to at least one first line drug; 3.9% had a multidrug-resistant strain, 15.6% a monoresistant strain and 9.4% a polyresistant strain. Our rate of drug resistant tuberculosis in new cases is very high; this has important clinical implications, since even monoresistance can have a negative impact on the outcome of new cases treated empirically with a six month regimen.

  12. PPARγ1 phosphorylation enhances proliferation and drug resistance in human fibrosarcoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Pang, Xiaojuan; Shu, Yuxin; Niu, Zhiyuan; Zheng, Wei; Wu, Haochen [State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Lu, Yan, E-mail: luyan@nju.edu.cn [State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Shen, Pingping, E-mail: ppshen@nju.edu.cn [State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Model Animal Research Center (MARC), Nanjing University, Nanjing (China)

    2014-03-10

    Post-translational regulation plays a critical role in the control of cell growth and proliferation. The phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) is the most important post-translational modification. The function of PPARγ phosphorylation has been studied extensively in the past. However, the relationship between phosphorylated PPARγ1 and tumors remains unclear. Here we investigated the role of PPARγ1 phosphorylation in human fibrosarcoma HT1080 cell line. Using the nonphosphorylation (Ser84 to alanine, S84A) and phosphorylation (Ser84 to aspartic acid, S84D) mutant of PPARγ1, the results suggested that phosphorylation attenuated PPARγ1 transcriptional activity. Meanwhile, we demonstrated that phosphorylated PPARγ1 promoted HT1080 cell proliferation and this effect was dependent on the regulation of cell cycle arrest. The mRNA levels of cyclin-dependent kinase inhibitor (CKI) p21{sup Waf1/Cip1} and p27{sup Kip1} descended in PPARγ1{sup S84D} stable HT1080 cell, whereas the expression of p18{sup INK4C} was not changed. Moreover, compared to the PPARγ1{sup S84A}, PPARγ1{sup S84D} up-regulated the expression levels of cyclin D1 and cyclin A. Finally, PPARγ1 phosphorylation reduced sensitivity to agonist rosiglitazone and increased resistance to anticancer drug 5-fluorouracil (5-FU) in HT1080 cell. Our findings establish PPARγ1 phosphorylation as a critical event in human fibrosarcoma growth. These findings raise the possibility that chemical compounds that prevent the phosphorylation of PPARγ1 could act as anticancer drugs. - Highlights: • Phosphorylation attenuates PPARγ1 transcriptional activity. • Phosphorylated PPARγ1 promotes HT1080 cells proliferation. • PPARγ1 phosphorylation regulates cell cycle by mediating expression of cell cycle regulators. • PPARγ1 phosphorylation reduces sensitivity to agonist and anticancer drug. • Our findings establish PPARγ1 phosphorylation as a critical event in HT1080

  13. Reaching consensus on drug resistance conferring mutations (Part 1

    Directory of Open Access Journals (Sweden)

    Daniela M Cirillo

    2016-01-01

    A user-friendly interface designed for nonexpert or expert operability.A standardized and validated analysis pipeline for variant analyses of M. tuberculosis next-generation sequencing (NGS data.Access to data beyond the published literature with dynamic and iterative updates of new data generated by global surveillance and clinical trials.A well-developed legal structure to ensure intellectual property rights and data ownership remain with contributors.A structured data-sharing architecture to restrict access to sensitive or unpublished data sets.Metadata standardization using CDISC: supports global, platform-independent data standards that enable information system interoperability.An emphasis on data quality and rigorous, expert curation with multiple quality control checks for whole-genome sequencing and other metadata.Validation of NGS analysis output by an expert committee with grading of resistance conferring mutations based on rigorous statistical standards.Regulatory-compliant analysis pipeline and database architecture. Successful execution of such an extensive database platform requires substantial collaboration from scientists investigating the genetic basis for drug resistance worldwide, and from developers with expertise in database design and implementation.

  14. Molecular detection methods of resistance to antituberculosis drugs in Mycobacterium tuberculosis.

    Science.gov (United States)

    Brossier, F; Sougakoff, W

    2017-09-01

    Molecular methods predict drug resistance several weeks before phenotypic methods and enable rapid implementation of appropriate therapeutic treatment. We aimed to detail the most representative molecular tools used in routine practice for the rapid detection of resistance to antituberculosis drugs among Mycobacterium tuberculosis strains. The molecular diagnosis of resistance to antituberculosis drugs in clinical samples or from in vitro cultures is based on the detection of the most common mutations in the genes involved in the development of resistance in M. tuberculosis strains (encoding either protein targets of antibiotics, or antibiotic activating enzymes) by commercial molecular kits or by sequencing. Three hypotheses could explain the discrepancies between the genotypic results and the phenotypic drug susceptibility testing results: a low percentage of resistant mutants precluding the detection by genotypic methods on the primary culture; a low level of resistance not detected by phenotypic testing; and other resistance mechanisms not yet characterized. Molecular methods have varying sensitivity with regards to detecting antituberculosis drug resistance; that is why phenotypic susceptibility testing methods are mandatory for detecting antituberculosis drug-resistant isolates that have not been detected by molecular methods. The questionable ability of existing phenotypic and genotypic drug susceptibility testing to properly classify strains as susceptible or resistant, and at what level of resistance, was raised for several antituberculosis agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Detection of low frequency multi-drug resistance and novel putative maribavir resistance in immunocompromised paediatric patients with cytomegalovirus

    Directory of Open Access Journals (Sweden)

    Charlotte Jane Houldcroft

    2016-09-01

    Full Text Available Human cytomegalovirus (HCMV is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed paediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analysed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54 and C480F (UL97. In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of eleven subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome.

  16. The role of compensatory mutations in the emergence of drug resistance.

    Directory of Open Access Journals (Sweden)

    Andreas Handel

    2006-10-01

    Full Text Available Pathogens that evolve resistance to drugs usually have reduced fitness. However, mutations that largely compensate for this reduction in fitness often arise. We investigate how these compensatory mutations affect population-wide resistance emergence as a function of drug treatment. Using a model of gonorrhea transmission dynamics, we obtain generally applicable, qualitative results that show how compensatory mutations lead to more likely and faster resistance emergence. We further show that resistance emergence depends on the level of drug use in a strongly nonlinear fashion. We also discuss what data need to be obtained to allow future quantitative predictions of resistance emergence.

  17. Malaria medicines to address drug resistance and support malaria elimination efforts.

    Science.gov (United States)

    Achan, Jane; Mwesigwa, Julia; Edwin, Chinagozi Precious; D'alessandro, Umberto

    2018-01-01

    Antimalarial drugs are essential weapons to fight malaria and have been used effectively since the 17 th century. However, P.falciparum resistance has been reported to almost all available antimalarial drugs, including artemisinin derivatives, raising concerns that this could jeopardize malaria elimination. Areas covered: In this article, we present a historical perspective of antimalarial drug resistance, review current evidence of resistance to available antimalarial drugs and discuss possible mitigating strategies to address this challenge. Expert commentary: The historical approach to drug resistance has been to change the national treatment policy to an alternative treatment. However, alternatives to artemisinin-based combination treatment are currently extremely limited. Innovative approaches utilizing available schizonticidal drugs such as triple combination therapies or multiple first line treatments could delay the emergence and spread of drug resistance. Transmission blocking drugs like primaquine may play a key role if given to a substantial proportion of malaria infected persons. Deploying antimalarial medicines in mass drug administration or mass screening and treatment campaigns could also contribute to containment efforts by eliminating resistant parasites in some settings. Ultimately, response to drug resistance should also include further investment in the development of new antimalarial drugs.

  18. Status of drug-resistant tuberculosis in China: A systematic review and meta-analysis.

    Science.gov (United States)

    Zhang, Jingya; Gou, Haimei; Hu, Xuejiao; Hu, Xin; Shang, Mengqiao; Zhou, Juan; Zhou, Yi; Ye, Yuanxin; Song, Xingbo; Lu, Xiaojun; Chen, Xuerong; Ying, Binwu; Wang, Lanlan

    2016-06-01

    We conducted a systematic review and meta-analysis on drug-resistant tuberculosis in China to provide useful data for tuberculosis (TB) surveillance and treatment. Several databases, including PubMed, Embase, and the Chinese Biological Medical Database, were systematically searched between January 1, 1999, and August 31, 2015, using strict inclusion and exclusion criteria. The corresponding drug-resistant TB prevalence between the new and previously treated cases was significantly different in almost all of the economic regions. The Eastern coastal region is the most developed economic region with the lowest total drug-resistant TB prevalence (any drug resistance: 28%; 95% confidence interval [CI], 25%-32%; multidrug resistance: 9%; 95% CI, 8%-12%) and the lowest number of new cases (any drug resistance: 21%; 95% CI, 19%-23%; multidrug resistance: 4%; 95% CI, 3%-5%). The Northwest is the least developed area with the lowest drug-resistant TB prevalence for previously treated cases (any drug resistance: 45%; 95% CI, 36%-55%; multidrug resistance: 17%; 95% CI, 11%-26%). The prevalence (multidrug and first-line drug resistance) exhibited a downward trend from 1996-2014. The extensively drug-resistant prevalence in China was 3% (95% CI, 2%-5%) in this review. Overall, the status of drug-resistant tuberculosis in China is notably grim and exhibits regional epidemiologic characteristics. We are in urgent need of several comprehensive and effective control efforts to reverse this situation. Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

  19. Genome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole

    KAUST Repository

    Campos, Mônica C.

    2017-10-25

    Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 5–8 million people in Latin America. Although the nitroheterocyclic compound benznidazole has been the front-line drug for several decades, treatment failures are common. Benznidazole is a pro-drug and is bio-activated within the parasite by the mitochondrial nitroreductase TcNTR-1, leading to the generation of reactive metabolites that have trypanocidal activity. To better assess drug action and resistance, we sequenced the genomes of T. cruzi Y strain (35.5 Mb) and three benznidazole-resistant clones derived from a single drug-selected population. This revealed the genome-wide accumulation of mutations in the resistant parasites, in addition to variations in DNA copy-number. We observed mutations in DNA repair genes, linked with increased susceptibility to DNA alkylating and inter-strand cross-linking agents. Stop-codon-generating mutations in TcNTR-1 were associated with cross-resistance to other nitroheterocyclic drugs. Unexpectedly, the clones were also highly resistant to the ergosterol biosynthesis inhibitor posaconazole, a drug proposed for use against T. cruzi infections, in combination with benznidazole. Our findings therefore identify the highly mutagenic activity of benznidazole metabolites in T. cruzi, demonstrate that this can result in multi-drug resistance, and indicate that vigilance will be required if benznidazole is used in combination therapy.

  20. Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast.

    Directory of Open Access Journals (Sweden)

    Zoey Tay

    Full Text Available Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.

  1. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Ladislau C. Kovari

    2012-05-01

    Full Text Available Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

  2. Prevalence of transmitted drug resistance and impact of transmitted resistance on treatment success in the German HIV-1 Seroconverter Cohort.

    Directory of Open Access Journals (Sweden)

    Barbara Bartmeyer

    Full Text Available BACKGROUND: The aim of this study is to analyse the prevalence of transmitted drug resistance, TDR, and the impact of TDR on treatment success in the German HIV-1 Seroconverter Cohort. METHODS: Genotypic resistance analysis was performed in treatment-naïve study patients whose sample was available 1,312/1,564 (83.9% October 2008. A genotypic resistance result was obtained for 1,276/1,312 (97.3%. The resistance associated mutations were identified according to the surveillance drug resistance mutations list recommended for drug-naïve patients. Treatment success was determined as viral suppression below 500 copies/ml. RESULTS: Prevalence of TDR was stable at a high level between 1996 and 2007 in the German HIV-1 Seroconverter Cohort (N = 158/1,276; 12.4%; CI(wilson 10.7-14.3; p(for trend = 0.25. NRTI resistance was predominant (7.5% but decreased significantly over time (CI(Wilson: 6.2-9.1, p(for trend = 0.02. NNRTI resistance tended to increase over time (NNRTI: 3.5%; CI(Wilson: 2.6-4.6; p(for trend= 0.07, whereas PI resistance remained stable (PI: 3.0%; CI(Wilson: 2.1-4.0; p(for trend = 0.24. Resistance to all drug classes was frequently caused by singleton resistance mutations (NRTI 55.6%, PI 68.4%, NNRTI 99.1%. The majority of NRTI-resistant strains (79.8% carried resistance-associated mutations selected by the thymidine analogues zidovudine and stavudine. Preferably 2NRTI/1PIr combinations were prescribed as first line regimen in patients with resistant HIV as well as in patients with susceptible strains (susceptible 45.3%; 173/382 vs. resistant 65.5%; 40/61. The majority of patients in both groups were treated successfully within the first year after ART-initiation (susceptible: 89.9%; 62/69; resistant: 7/9; 77.8%. CONCLUSION: Overall prevalence of TDR remained stable at a high level but trends of resistance against drug classes differed over time. The significant decrease of NRTI-resistance in patients newly infected

  3. 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.

  4. Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib.

    Science.gov (United States)

    Amengual, Jennifer E; Prabhu, Sathyen A; Lombardo, Maximilian; Zullo, Kelly; Johannet, Paul M; Gonzalez, Yulissa; Scotto, Luigi; Serrano, Xavier Jirau; Wei, Ying; Duong, Jimmy; Nandakumar, Renu; Cremers, Serge; Verma, Akanksha; Elemento, Olivier; O'Connor, Owen A

    2017-06-15

    Purpose: Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first-in-class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215. Experimental Design: The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line. Gene expression profiling (GEP) was performed to investigate differentially expressed genes. Combination studies of ACY-1215 and ibrutinib were performed in cell lines, primary human lymphoma tissue, and a xenograft mouse model. Results: Systematic incremental increases in drug exposure led to the development of distinct resistant cell lines with IC 50 values 10- to 20-fold greater than that for parental lines. GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. Gene-set enrichment analysis (GSEA) revealed modulation of the BTK pathway. Ibrutinib was found to be synergistic with ACY-1215 in cell lines as well as in 3 primary patient samples of lymphoma. In vivo confirmation of antitumor synergy was demonstrated with a xenograft of DLBCL. Conclusions: The development of this ACY-1215-resistant cell line has provided valuable insights into the mechanistic role of HDAC6 in lymphoma and offered a novel method to identify rational synergistic drug combinations. Translation of these findings to the clinic is underway. Clin Cancer Res; 23(12); 3084-96. ©2016 AACR . ©2016 American Association for Cancer Research.

  5. Drug-resistant tuberculosis in two children in Greece: report of the first extensively drug-resistant case.

    Science.gov (United States)

    Katragkou, Aspasia; Antachopoulos, Charalampos; Hatziagorou, Elpis; Sdougka, Maria; Roilides, Emmanuel; Tsanakas, John

    2013-04-01

    Extensively drug-resistant (XDR) tuberculosis (TB) represents a serious and growing problem in both endemic and non-endemic countries. We describe a 2.5-year-old girl with XDR-pulmonary TB and an 18-month-old boy with pre-XDR-central nervous system TB. Patients received individualized treatment with second-line anti-TB agents based on genotypic and phenotypic drug susceptibility testing results. Both children achieved culture conversion 3 months and 1 month after treatment initiation, respectively. The child with XDR-pulmonary TB showed evidence of cure while treatment adverse events were managed without treatment interruption. The child with pre-XDR-central nervous system TB after 6-month hospitalization with multiple infectious complications had a dismal end due to hepatic insufficiency possibly related to anti-TB treatment. This is the first report of children with pre-XDR and XDR TB in Greece, emphasizing the public health dimensions and management complexity of XDR TB.

  6. Time-programmable drug dosing allows the manipulation, suppression and reversal of antibiotic drug resistance in vitro

    OpenAIRE

    Yoshida, Mari; Galiñanes Reyes, Sabrina Galiñanes; Tsuda, Soichiro; Horinouchi, Takaaki; Furusawa, Chikara; Cronin, Leroy

    2017-01-01

    Multi-drug strategies have been attempted to prolong the efficacy of existing antibiotics, but with limited success. Here we show that the evolution of multi-drug-resistant Escherichia coli can be manipulated in vitro by administering pairs of antibiotics and switching between them in ON/OFF manner. Using a multiplexed cell culture system, we find that switching between certain combinations of antibiotics completely suppresses the development of resistance to one of the antibiotics. Using thi...

  7. 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.

  8. Drug ratio-dependent antagonism: a new category of multidrug resistance and strategies for its circumvention.

    Science.gov (United States)

    Harasym, Troy O; Liboiron, Barry D; Mayer, Lawrence D

    2010-01-01

    A newly identified form of multidrug resistance (MDR) in tumor cells is presented, pertaining to the commonly encountered resistance of cancer cells to anticancer drug combinations at discrete drug:drug ratios. In vitro studies have revealed that whether anticancer drug combinations interact synergistically or antagonistically can depend on the ratio of the combined agents. Failure to control drug ratios in vivo due to uncoordinated pharmacokinetics could therefore lead to drug resistance if tumor cells are exposed to antagonistic drug ratios. Consequently, the most efficacious drug combination may not occur at the typically employed maximum tolerated doses of the combined drugs if this leads to antagonistic ratios in vivo after administration and resistance to therapeutic effects of the drug combination. Our approach to systematically screen a wide range of drug ratios and concentrations and encapsulate the drug combination in a liposomal delivery vehicle at identified synergistic ratios represents a means to mitigate this drug ratio-dependent MDR mechanism. The in vivo efficacy of the improved agents (CombiPlex formulations) is demonstrated and contrasted with the decreased efficacy when drug combinations are exposed to tumor cells in vivo at antagonistic ratios.

  9. [Drug resistance reversal of HL-60/ADR cells by simultaneous suppression of XIAP and MRP].

    Science.gov (United States)

    Wang, Xiao-Fang; Wang, Chun; Qin, You-Wen; Yan, Shi-Ke; Gao, Yan-Rong

    2006-12-01

    This study was purposed to explore the mechanisms of drug resistance of HL-60/ADR cells and to compare the reversal drug-resistance effects of antisense oligonucleotides (AS ODN) of XIAP (X-linked inhibitor of apoptosis protein) and AS ODNs of MRP (multidrug resistance-associated protein) by use alone or in combination. Reverse transcription-PCR and Western blot were applied to detect the expression of XIAP, BCL-2, MRP and MDR1 in mRNA and protein levels of HL-60 cells and HL-60/ADR cells, respectively. Fully phosphorothioated AS ODN of XIAP and MRP was delivered into HL-60/ADR cells with Lipofectamine 2000 in the form of liposome-ODN complexes alone or in combination. CCK-8 cell viability assay was used to determine the effect of AS ODN of XIAP and MRP used alone or in combination on the chemotherapy sensitivity of HL-60/ADR cells to daunorubicin (DNR). Reverse transcription-PCR and Western blot were applied to examine the changes of XIAP, MRP in mRNA and protein levels respectively. The results showed that MRP and XIAP were both significantly higher in HL-60/ADR cells than those in HL-60 cells. AS ODN of XIAP and MRP down-regulated the expression of XIAP and MRP in HL-60/ADR cells and increased the sensitivity of HL-60/ADR cells to DNR, respectively. AS ODN of XIAP + MRP did not enhance the inhibition expression of XIAP in HL-60/ADR cells but increased the sensitivity of HL-60/ADR cells to DNR significantly as compared with AS ODN of XIAP (P MRP did not increase the concentration of DNR nor enhanced the inhibition expression of MRP in HL-60/ADR cells but increased the sensitivity of HL-60/ADR cells to DNR significantly (P MRP. It is concluded that both XIAP and MRP may be involved in the drug resistance mechanisms of HL-60/ADR cells. Drug-resistance of HL-60/ADR cells can be reversed significantly when antisense oligonucleotides of XIAP and MRP were used in combination.

  10. The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection

    OpenAIRE

    Huijben, Silvie; Sim, Derek G.; Nelson, William, A.; Read, Andrew F.

    2011-01-01

    Malaria infections normally consist of more than one clonally-replicating lineage. Within-host interactions between sensitive and resistant parasites can have profound effects on the evolution of drug resistance. Here, using the Plasmodium chabaudi mouse malaria model, we ask whether the costs and benefits of resistance are affected by the number of co-infecting strains competing with a resistant clone. We found strong competitive suppression of resistant parasites in untreated infections and...

  11. Arabidopsis YAK1 regulates abscisic acid response and drought resistance.

    Science.gov (United States)

    Kim, Dongjin; Ntui, Valentine Otang; Xiong, Liming

    2016-07-01

    Abscisic acid (ABA) is an important phytohormone that controls several plant processes such as seed germination, seedling growth, and abiotic stress response. Here, we report that AtYak1 plays an important role in ABA signaling and postgermination growth in Arabidopsis. AtYak1 knockout mutant plants were hyposensitive to ABA inhibition of seed germination, cotyledon greening, seedling growth, and stomatal movement. atyak1-1 mutant plants display reduced drought stress resistance, as evidenced by water loss rate and survival rate. Molecular genetic analysis revealed that AtYak1 deficiency led to elevated expression of stomatal-related gene, MYB60, and down-regulation of several stress-responsive genes. Altogether, these results indicate that AtYak1 plays a role as a positive regulator in ABA-mediated drought response in Arabidopsis. © 2016 Federation of European Biochemical Societies.

  12. Arabidopsis YAK1 regulates abscisic acid response and drought resistance

    KAUST Repository

    Kim, Dongjin

    2016-06-06

    Abscisic acid (ABA) is an important phytohormone that controls several plant processes such as seed germination, seedling growth, and abiotic stress response. Here, we report that AtYak1 plays an important role in ABA signaling and postgermination growth in Arabidopsis. AtYak1 knockout mutant plants were hyposensitive to ABA inhibition of seed germination, cotyledon greening, seedling growth, and stomatal movement. atyak1-1 mutant plants display reduced drought stress resistance, as evidenced by water loss rate and survival rate. Molecular genetic analysis revealed that AtYak1 deficiency led to elevated expression of stomatal-related gene, MYB60, and down-regulation of several stress-responsive genes. Altogether, these results indicate that AtYak1 plays a role as a positive regulator in ABA-mediated drought response in Arabidopsis. © 2016 Federation of European Biochemical Societies.

  13. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition

    Directory of Open Access Journals (Sweden)

    Morales Eva

    2012-05-01

    Full Text Available Abstract Background We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. Methods A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain. All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Results Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros. In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively. Conclusions P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact.

  14. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition.

    Science.gov (United States)

    Morales, Eva; Cots, Francesc; Sala, Maria; Comas, Mercè; Belvis, Francesc; Riu, Marta; Salvadó, Margarita; Grau, Santiago; Horcajada, Juan P; Montero, Maria Milagro; Castells, Xavier

    2012-05-23

    We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain). All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros). In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively). P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact.

  15. Transferable and non-transferable drug resistance in enteric bacteria from hospital and from general practice

    DEFF Research Database (Denmark)

    Møller, JK; Bak, AL; Bülow, P

    1976-01-01

    Drug resistance to 8 different antibiotics in Enterobacteriaceae isolated from different hospitals and two groups of general practitioners was studied. Escherichia coli dominated among the 632 strains investigated. Drug resistance was found in 62% of the 512 hospital strains and in 38% of the 120...

  16. Surveillance of extensively drug-resistant tuberculosis in Europe, 2003-2007.

    NARCIS (Netherlands)

    Devaux, I.; Manissero, D.; Fernandez de la Hoz, K.; Kremer, K.; Soolingen, D. van

    2010-01-01

    This paper describes the results of second-line drug (SLD) susceptibility tests among multidrug-resistant tuberculosis (MDR TB) cases reported in 20 European countries aiming to identify extensively drug-resistant tuberculosis (XDR TB) cases. A project on molecular surveillance of MDR TB cases was

  17. A study on demographic characteristics of drug resistant Mycobacterium tuberculosis isolates in Belarus

    Directory of Open Access Journals (Sweden)

    L Surkova

    2012-01-01

    Conclusion: As Belarus is a high-burden MDR-TB country and treatment of drug-resistant TB is long and complicated, the findings of this study provided useful information to deliver effective community-based disease control measures and a proposed plane for the effective management of drug-resistant TB at the national level.

  18. Exploring Culturally Specific Drug Resistance Strategies of Hawaiian Youth in Rural Communities

    Science.gov (United States)

    Okamoto, Scott K.; Po'a-Kekuawela, Ka'ohinani; Chin, Coralee I. H.; Nebre, La Risa H.; Helm, Susana

    2010-01-01

    This qualitative study examined the drug resistance strategies of Hawaiian youth residing in rural communities in Hawai'i. Forty seven youth participated in 14 focus groups which focused on the social and environmental context of drug use for these youth. The findings indicated that there were 47 references to resistance strategies used in drug…

  19. Antituberculosis drug resistance in the south of Vietnam: prevalence and trends

    NARCIS (Netherlands)

    Huong, Nguyen T.; Lan, Nguyen T. N.; Cobelens, Frank G. J.; Duong, Bui D.; Co, Nguyen V.; Bosman, Maarten C.; Kim, Sang-Jae; van Soolingen, Dick; Borgdorff, Martien W.

    2006-01-01

    BACKGROUND: There is limited evidence that the DOTS (directly observed therapy, short course) strategy for tuberculosis (TB) control can contain the emergence and spread of drug resistance in the absence of second-line treatment. We compared drug-resistance levels between 1996 and 2001 in the south

  20. Efficacy of verapamil as an adjunctive treatment in children with drug-resistant epilepsy

    DEFF Research Database (Denmark)

    Nicita, Francesco; Spalice, Alberto; Papetti, Laura

    2014-01-01

    Verapamil, a voltage-gated calcium channel blocker, has been occasionally reported to have some effect on reducing seizure frequency in drug-resistant epilepsy or status epilepticus. We aimed to investigate the efficacy of verapamil as add-on treatment in children with drug-resistant epilepsy....

  1. The Association between Mycobacterium Tuberculosis Genotype and Drug Resistance in Peru.

    Directory of Open Access Journals (Sweden)

    Louis Grandjean

    Full Text Available The comparison of Mycobacterium tuberculosis bacterial genotypes with phenotypic, demographic, geospatial and clinical data improves our understanding of how strain lineage influences the development of drug-resistance and the spread of tuberculosis.To investigate the association of Mycobacterium tuberculosis bacterial genotype with drug-resistance. Drug susceptibility testing together with genotyping using both 15-loci MIRU-typing and spoligotyping, was performed on 2,139 culture positive isolates, each from a different patient in Lima, Peru. Demographic, geospatial and socio-economic data were collected using questionnaires, global positioning equipment and the latest national census.The Latin American Mediterranean (LAM clade (OR 2.4, p<0.001 was significantly associated with drug-resistance and alone accounted for more than half of all drug resistance in the region. Previously treated patients, prisoners and genetically clustered cases were also significantly associated with drug-resistance (OR's 2.5, 2.4 and 1.8, p<0.001, p<0.05, p<0.001 respectively.Tuberculosis disease caused by the LAM clade was more likely to be drug resistant independent of important clinical, genetic and socio-economic confounding factors. Explanations for this include; the preferential co-evolution of LAM strains in a Latin American population, a LAM strain bacterial genetic background that favors drug-resistance or the "founder effect" from pre-existing LAM strains disproportionately exposed to drugs.

  2. A typology and analysis of drug resistance strategies of rural Native Hawaiian youth.

    Science.gov (United States)

    Okamoto, Scott K; Helm, Susana; Giroux, Danielle; Kaliades, Alexis; Kawano, Kaycee Nahe; Kulis, Stephen

    2010-12-01

    This study examines the drug resistance strategies described by Native Hawaiian youth residing in rural communities. Sixty-four youth from 7 middle and intermediate schools on the Island of Hawai'i participated in a series of gender-specific focus groups. Youth responded to 15 drug-related problem situations developed and validated from prior research. A total of 509 responses reflecting primary or secondary drug resistance strategies were identified by the youth, which were qualitatively collapsed into 16 different categories. Primary drug resistance strategies were those that participants listed as a single response, or the first part of a two-part response, while secondary drug resistance strategies were those that were used in tandem with primary drug resistance strategies. Over half of the responses reflecting primary drug resistance strategies fell into three different categories ("refuse," "explain," or "angry refusal"), whereas over half of the responses reflecting secondary drug resistance strategies represented one category ("explain"). Significant gender differences were found in the frequency of using different strategies as well as variations in the frequency of using different strategies based on the type of drug offerer (family versus friends/peers). Implications for prevention practice are discussed.

  3. Cigarette smoke promotes drug resistance and expansion of cancer stem cell-like side population.

    Directory of Open Access Journals (Sweden)

    Yi An

    Full Text Available It is well known that many patients continue to smoke cigarettes after being diagnosed with cancer. Although smoking cessation has typically been presumed to possess little therapeutic value for cancer, a growing body of evidence suggests that continued smoking is associated with reduced efficacy of treatment and a higher incidence of recurrence. We therefore investigated the effect of cigarette smoke condensate (CSC on drug resistance in the lung cancer and head and neck cancer cell lines A549 and UMSCC-10B, respectively. Our results showed that CSC significantly increased the cellular efflux of doxorubicin and mitoxantrone. This was accompanied by membrane localization and increased expression of the multi-drug transporter ABCG2. The induced efflux of doxorubicin was reversed upon addition of the specific ABCG2 inhibitor Fumitremorgin C, confirming the role of ABCG2. Treatment with CSC increased the concentration of phosphorylated Akt, while addition of the PI3K inhibitor LY294002 blocked doxorubicin extrusion, suggesting that Akt activation is required for CSC-induced drug efflux. In addition, CSC was found to promote resistance to doxorubicin as determined by MTS assays. This CSC-induced doxurbicin-resistance was mitigated by mecamylamine, a nicotinic acetylcholine receptor inhibitor, suggesting that nicotine is at least partially responsible for the effect of CSC. Lastly, CSC increased the size of the side population (SP, which has been linked to a cancer stem cell-like phenotype. In summary, CSC promotes chemoresistance via Akt-mediated regulation of ABCG2 activity, and may also increase the proportion of cancer stem-like cells, contributing to tumor resilience. These findings underscore the importance of smoking cessation following a diagnosis of cancer, and elucidate the mechanisms of continued smoking that may be detrimental to treatment.

  4. Reducing the Risk of Drug Involvement among Early Adolescents: An Evaluation of Drug Abuse Resistance Education (DARE).

    Science.gov (United States)

    Harmon, Michele Alicia

    1993-01-01

    DARE's effectiveness in Charleston County (South Carolina) was studied by comparing 341 DARE to 367 non-DARE fifth-grade students. DARE teaches students to recognize and resist social pressures to use drugs. DARE has positive impacts on anti-substance abuse attitudes, assertiveness, positive peer association, association with drug-using peers, and…

  5. Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins

    NARCIS (Netherlands)

    Cummings, Jeffrey; Zelcer, Noam; Allen, John D.; Yao, Denggao; Boyd, Gary; Maliepaard, Mark; Friedberg, Thomas H.; Smyth, John F.; Jodrell, Duncan I.

    2004-01-01

    We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in

  6. Within-host selection of drug resistance in a mouse model reveals dose-dependent selection of atovaquone resistance mutations

    NARCIS (Netherlands)

    Nuralitha, Suci; Murdiyarso, Lydia S.; Siregar, Josephine E.; Syafruddin, Din; Roelands, Jessica; Verhoef, Jan; Hoepelman, Andy I.M.; Marzuki, Sangkot

    2017-01-01

    The evolutionary selection of malaria parasites within an individual host plays a critical role in the emergence of drug resistance. We have compared the selection of atovaquone resistance mutants in mouse models reflecting two different causes of failure of malaria treatment, an inadequate

  7. Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children

    NARCIS (Netherlands)

    Kityo, Cissy; Boerma, Ragna S.; Sigaloff, Kim C. E.; Kaudha, Elizabeth; Calis, Job C. J.; Musiime, Victor; Balinda, Sheila; Nakanjako, Rita; Boender, T. Sonia; Mugyenyi, Peter N.; Rinke de Wit, Tobias F.

    2017-01-01

    Background: Pretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children. Methods: Children aged <12 years initiated first-line ART in Uganda during 2010-11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL.

  8. Transmission of Drug-Resistant Leprosy in Guinea-Conakry Detected Using Molecular Epidemiological Approaches.

    Science.gov (United States)

    Avanzi, Charlotte; Busso, Philippe; Benjak, Andrej; Loiseau, Chloé; Fomba, Abdoulaye; Doumbia, Glodia; Camara, Idrissa; Lamou, André; Sock, Gouressy; Drame, Tiguidanké; Kodio, Mamadou; Sakho, Fatoumata; Sow, Samba O; Cole, Stewart T; Johnson, Roch Christian

    2016-12-01

    Molecular drug susceptibility testing was performed on skin biopsies from 24 leprosy patients from Guinea-Conakry for the first time. We identified primary drug resistance in 4 cases and a dapsone-resistant cluster caused by the same strain. Primary transmission of drug-resistant Mycobacterium leprae, including a rifampicin-resistant strain, is reported. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  9. Drug Resistance and Population Structure of Mycobacterium tuberculosis Beijing Strains Isolated in Poland.

    Science.gov (United States)

    Kozińska, Monika; Augustynowicz-Kopeć, Ewa

    2015-01-01

    In total, 1095 Mycobacterium tuberculosis clinical isolates from 282 patients with drug-resistant and 813 with drug-sensitive tuberculosis (TB) in Poland during 2007-2011 were analysed. Seventy-one (6.5%) patients were found to have strains of Beijing genotype as defined by spoligotyping. The majority of patients were Polish-born; among foreign-born a large proportion came from Chechnya and Vietnam. Analysis showed strong associations between Beijing genotype infection and MDR, pre-XDR and XDR resistance, with a considerable relative risk among new patients, suggesting that this is due to increased spread of drug-resistant strains rather than acquisition of resistance during treatment.

  10. High prevalence of drug-resistant tuberculosis, Republic of Lithuania, 2002

    DEFF Research Database (Denmark)

    Dewan, P; Sosnovskaja, A; Thomsen, V

    2005-01-01

    BACKGROUND: Nations of the former Soviet Union have the world's highest reported levels of resistance to anti-tuberculosis drugs. We conducted the first national survey of anti-tuberculosis drug resistance in the Republic of Lithuania. METHODS: We tested Mycobacterium tuberculosis isolates from all...... isolates, 475 (41%) were resistant to at least one first-line drug, and 263 (23%) were resistant to at least INH and RMP (MDR); this included 76/818 (9.3%) from new patients and 187/345 (54%) from previously treated patients. Of 52 MDR isolates randomly selected for extended testing at an international...

  11. Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Marna S Costanzo

    Full Text Available Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness.We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine.Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.

  12. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a TBNET/RESIST-TB consensus statement

    NARCIS (Netherlands)

    Domínguez, J.; Boettger, E. C.; Cirillo, D.; Cobelens, F.; Eisenach, K. D.; Gagneux, S.; Hillemann, D.; Horsburgh, R.; Molina-Moya, B.; Niemann, S.; Tortoli, E.; Whitelaw, A.; Lange, C.

    2016-01-01

    The emergence of drug-resistant strains of Mycobacterium tuberculosis is a challenge to global tuberculosis (TB) control. Although culture-based methods have been regarded as the gold standard for drug susceptibility testing (DST), molecular methods provide rapid information on mutations in the M.

  13. Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway

    Directory of Open Access Journals (Sweden)

    He JL

    2014-12-01

    Full Text Available Jin-Lian He,1 Zhi-Wei Zhou,2,3 Juan-Juan Yin,2 Chang-Qiang He,1 Shu-Feng Zhou,2,3 Yang Yu1 1College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China Abstract: Drug metabolizing enzymes (DMEs and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2-like 2 (Nrf2 is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2 cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(PH: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate–cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant

  14. HIV drug resistance in infants increases with changing prevention of mother-to-child transmission regimens.

    Science.gov (United States)

    Poppe, Lisa K; Chunda-Liyoka, Catherine; Kwon, Eun H; Gondwe, Clement; West, John T; Kankasa, Chipepo; Ndongmo, Clement B; Wood, Charles

    2017-08-24

    The objectives of this study were to determine HIV drug resistance (HIVDR) prevalence in Zambian infants upon diagnosis, and to determine how changing prevention of mother-to-child transmission (PMTCT) drug regimens affect drug resistance. Dried blood spot (DBS) samples from infants in the Lusaka District of Zambia, obtained during routine diagnostic screening, were collected during four different years representing three different PMTCT drug treatment regimens. DNA extracted from dried blood spot samples was used to sequence a 1493 bp region of the reverse transcriptase gene. Sequences were analyzed via the Stanford HIVDRdatabase (http://hivdb.standford.edu) to screen for resistance mutations. HIVDR in infants increased from 21.5 in 2007/2009 to 40.2% in 2014. Nonnucleoside reverse transcriptase inhibitor resistance increased steadily over the sampling period, whereas nucleoside reverse transcriptase inhibitor resistance and dual class resistance both increased more than threefold in 2014. Analysis of drug resistance scores in each group revealed increasing strength of resistance over time. In 2014, children with reported PMTCT exposure, defined as infant prophylaxis and/or maternal treatment, showed a higher prevalence and strength of resistance compared to those with no reported exposure. HIVDR is on the rise in Zambia and presents a serious problem for the successful lifelong treatment of HIV-infected children. PMTCT affects both the prevalence and strength of resistance and further research is needed to determine how to mitigate its role leading to resistance.

  15. CHANGES IN THE PREVALENCE OF DRUG RESISTANT TUBERCULOSIS

    Directory of Open Access Journals (Sweden)

    V. B. Galkin

    2017-01-01

    Full Text Available The tendency of tuberculosis prevalence reduction observed in the Russian Federation is mostly related to the cases without multiple drug resistance (MDR. In general the number of MDR TB cases still tends to be increasing in the Russian Federation. Confident long-term reduction is registered only in the Central and North-Western Districts with relatively low level of MDR TB prevalence. From 2017 MDR TB patients are expected to prevail in the structure of the sputum positive cases which surely provides negative impact on the treatment efficiency and epidemic trends. The system of dispensary follow-up allows evaluating the annual number of MDT TB cases and following the ways of its increase and reduction. Taking MDR TB sources on and off the register is less intensive compared to the same flows of non-MDR infectious cases. The number of MDR TB sources is increasing mostly due new tuberculosis cases however acquired MDR TB makes significant contribution to the growth of MDR TB sources number. The increase in the ratio of respiratory MDR TB patients with sputum conversion to those died reflects the success in the improvement of the treatment strategy of MDR TB patients.

  16. Prevalence and patterns of HIV transmitted drug resistance in Guatemala.

    Science.gov (United States)

    Avila-Ríos, Santiago; Mejía-Villatoro, Carlos R; García-Morales, Claudia; Soto-Nava, Maribel; Escobar, Ingrid; Mendizabal, Ricardo; Girón, Amalia; García, Leticia; Reyes-Terán, Gustavo

    2011-12-01

    To assess human immunodeficiency virus (HIV) diversity and the prevalence of transmitted drug resistance (TDR) in Guatemala. One hundred forty-five antiretroviral treatment-naïve patients referred to the Roosevelt Hospital in Guatemala City were enrolled from October 2010 to March 2011. Plasma HIV pol sequences were obtained and TDR was assessed with the Stanford algorithm and the World Health Organization (WHO) TDR surveillance mutation list. HIV subtype B was highly prevalent in Guatemala (96.6%, 140/145), and a 2.8% (4/145) prevalence of BF1 recombinants and 0.7% (1/145) prevalence of subtype C viruses were found. TDR prevalence for the study period was 8.3% (12/145) with the Stanford database algorithm (score > 15) and the WHO TDR surveillance mutation list. Most TDR cases were associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (83.3%, 10/12); a low prevalence of nucleoside reverse transcriptase inhibitors and protease inhibitors was observed in the cohort (Guatemala. TDR prevalence in Guatemala was at the intermediate level. Most TDR cases were associated with NNRTIs. Further and continuous TDR surveillance is necessary to gain more indepth knowledge about TDR spread and trends in Guatemala and to optimize treatment outcomes in the country.

  17. Renal denervation for treatment of drug-resistant hypertension.

    Science.gov (United States)

    Esler, Murray

    2015-02-01

    At the seven-year anniversary of the first catheter-based renal denervation procedure for resistant hypertension, it is timely to reflect on the past, present, and future of the development and clinical application of this treatment. Unresolved procedural and technical questions are central: How much renal denervation is optimal? How can this level of denervation be achieved? What test for denervation can be applied in renal denervation trials? Will renal denervation show a "class effect," with the different energy forms now used for renal nerve ablation producing equivalent blood pressure lowering? When I have assessed renal denervation efficacy, using measurements of the spillover of norepinephrine from the renal sympathetic nerves to plasma, the only test validated to this point, denervation was found to be incomplete and non-uniform between patients. It is probable that the degree of denervation has commonly been suboptimal in renal denervation trials; this criticism applying with special force to the Symplicity HTN-3 trial, where the proceduralists, although expert interventional cardiologists, had no prior experience with the renal denervation technique. Recently presented results from the Symplicity HTN-3 trial confirm that renal denervation was not achieved effectively or consistently. Given this, and other difficulties in the execution of the trial relating to drug adherence, an idea mooted is that the US pivotal trial of the future may be in younger, untreated patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Mindfulness meditation improves emotion regulation and reduces drug abuse.

    Science.gov (United States)

    Tang, Yi-Yuan; Tang, Rongxiang; Posner, Michael I

    2016-06-01

    The core clinical symptoms of addiction include an enhanced incentive for drug taking (craving), impaired self-control (impulsivity and compulsivity), emotional dysregulation (negative mood) and increased stress reactivity. Symptoms related to impaired self-control involve reduced activity in anterior cingulate cortex (ACC), adjacent prefrontal cortex (mPFC) and other brain areas. Behavioral training such as mindfulness meditation can increase the function of control networks including those leading to improved emotion regulation and thus may be a promising approach for the treatment of addiction. In a series of randomized controlled trials (RCTs), we tested whether increased ACC/mPFC activity is related to better self-control abilities in executive functions, emotion regulation and stress response in healthy and addicted populations. After a brief mindfulness training (Integrative Body-Mind Training, IBMT), we used the Positive and Negative Affect Schedule (PANAS) and Profile of Mood States (POMS) to measure emotion regulation, salivary cortisol for the stress response and fMRI for brain functional and DTI structural changes. Relaxation training was used to serve as an active control. In both smokers and nonsmokers, improved self-control abilities in emotion regulation and stress reduction were found after training and these changes were related to increased ACC/mPFC activity following training. Compared with nonsmokers, smokers showed reduced ACC/mPFC activity in the self-control network before training, and these deficits were ameliorated after training. These results indicate that promoting emotion regulation and improving ACC/mPFC brain activity can help for addiction prevention and treatment. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  19. Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background.

    Directory of Open Access Journals (Sweden)

    Saskia Decuypere

    Full Text Available The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L. donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread

  20. Laboratory-Based Surveillance of Extensively Drug-Resistant Tuberculosis in Eastern China.

    Science.gov (United States)

    Huang, Yu; Wu, Qingqing; Xu, Shuiyang; Zhong, Jieming; Chen, Songhua; Xu, Jinghang; Zhu, Liping; He, Haibo; Wang, Xiaomeng

    2017-03-01

    With 25% of the global burden, China has the highest incidence of drug-resistant tuberculosis (TB) in the world. However, surveillance data on extensively drug-resistant TB (XDR-TB) from China are scant. To estimate the prevalence of XDR-TB in Zhejiang, Eastern China, 30 of 90 TB treatment centers in Zhejiang were recruited. Patients with suspected TB who reported to the clinics for diagnosis were requested to undergo a smear sputum test. Positive sputum samples were tested for drug susceptibility. Data on anti-TB drug resistance from 1999 to 2008 were also collected to assess drug resistance trends. A total of 931 cases were recruited for drug susceptibility testing (DST). Among these, 23.6% (95% confidence interval [CI], 18.8-24.4) were resistant to any of the following drugs: isoniazid, rifampin, streptomycin, and ethambutol. Multidrug resistant (MDR) strains were identified in 5.1% of all cases (95% CI, 3.61-6.49). Among MDR-TB cases, 6.4% were XDR (95% CI, 1.7-18.6) and 8.9% (95% CI, 7.0-10.8) of all cases were resistant to either isoniazid or rifampin (but not both). Among MDR-TB cases, 23.4% (95% CI, 12.8-38.4) were resistant to either fluoroquinolones or a second-line anti-TB injectable drug, but not both. From 1999 to 2014, the percentage of MDR cases decreased significantly, from 8.6% to 5.1% (p = 0.00). The Global Fund to Fight TB program showed signs of success in Eastern China. However, drug-resistant TB, MDR-TB, and XDR-TB still pose a challenge for TB control in Eastern China. High-quality directly observed treatment, short-course, and universal DST for TB cases to determine appropriate treatment regimens are urgently needed to prevent acquired drug resistance.

  1. Bone morphogenetic protein 4 is overexpressed in and promotes migration and invasion of drug-resistant cancer cells.

    Science.gov (United States)

    Zhou, Kairui; Shi, Xiaoli; Huo, Jinling; Liu, Weihua; Yang, Dongxiao; Yang, Tengjiao; Qin, Tiantian; Wang, Cong

    2017-08-01

    Drug resistance and metastasis significantly hinder chemotherapy and worsen prognoses in cancer. Bone morphogenetic protein 4 (BMP4) belongs to the TGF-β superfamily, has broad biological activities in cell proliferation and cartilage differentiation and is also able to induce migration and invasion. Herein, we investigated the role of BMP4 in the regulation of metastasis in paclitaxel-resistant human esophageal carcinoma EC109 cells (EC109/Taxol) and docetaxel-resistant human gastric cancer MGC803 cells (MGC/Doc). In these drug-resistant cell lines, we found the cell motility was enhanced and BMP4 was up-regulated relative to their respective parental cell lines. Consistent with in vitro assays, migration potential and BMP4 expression were increased in EC109/Taxol nude mice. Furthermore, to address whether BMP4 was required to enhance the metastatic in EC109/Taxol cells, the pharmacological inhibitor of BMP signaling dorsomorphin was used; meanwhile, we found that the migration and invasion abilities were inhibited. Moreover, the canonical Smad signaling pathway was investigated. Overall, our studies demonstrated that BMP4 participates in the regulation of invasion and migration by EC109/Taxol cells, and inhibition of BMP4 may be a novel strategy to interfere with metastasis in cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Consensus Statement on Research Definitions for Drug-Resistant Tuberculosis in Children

    OpenAIRE

    Seddon, James A.; Perez-Velez, Carlos M.; Schaaf, H. Simon; Furin, Jennifer J.; Marais, Ben J.; Tebruegge, Marc; Detjen, Anne; Hesseling, Anneke C.; Shah, Sarita; Adams, Lisa V.; Starke, Jeffrey R.; Swaminathan, Soumya; Becerra, Mercedes C.

    2013-01-01

    Few children with drug-resistant (DR) tuberculosis (TB) are identified, diagnosed, and given an appropriate treatment. The few studies that have described this vulnerable population have used inconsistent definitions. TheWorld Health Organization (WHO) definitions used for adults with DR-TB and for children with drug-susceptible TB are not always appropriate for children with DR-TB. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis was formed in 2011 as a network of experts and st...

  3. Antimicrobial Drug-Resistant Shiga Toxin-Producing Escherichia coli Infections, Michigan, USA.

    Science.gov (United States)

    Mukherjee, Sanjana; Mosci, Rebekah E; Anderson, Chase M; Snyder, Brian A; Collins, James; Rudrik, James T; Manning, Shannon D

    2017-09-01

    High frequencies of antimicrobial drug resistance were observed in O157 and non-O157 Shiga toxin-producing E. coli strains recovered from patients in Michigan during 2010-2014. Resistance was more common in non-O157 strains and independently associated with hospitalization, indicating that resistance could contribute to more severe disease outcomes.

  4. Passive flow regulators for drug delivery and hydrocephalus treatment

    Science.gov (United States)

    Chappel, E.; Dumont-Fillon, D.; Mefti, S.

    2014-03-01

    Passive flow regulators are usually intended to deliver or drain a fluid at a constant rate independently from pressure variations. New designs of passive flow regulators made of a stack of a silicon membrane anodically bonded to a Pyrex substrate are proposed. A first design has been built for the derivation of cerebrospinal fluid (CSF) towards peritoneum for hydrocephalus treatment. The device allows draining CSF at the patient production rate independently from postural changes. The flow rate is regulated at 20 ml/h in the range 10 to 40 mbar. Specific features to adjust in vivo the nominal flow rate are shown. A second design including high pressure shut-off feature has been made. The intended use is drug delivery with pressurized reservoir of typically 100 to 300 mbar. In both cases, the membrane comprises several holes facing pillars in the Pyrex substrate. These pillars are machined in a cavity which ensures a gap between the membrane and the pillars at rest. The fluid in the pressurized reservoir is directly in contact with the top surface of the membrane, inducing its deflection towards Pyrex substrate and closing progressively the fluidic pathway through each hole of the membrane. Since the membrane deflection is highly non-linear, FEM simulations have been performed to determine both radial position and diameter of the membrane holes that ensure a constant flow rate for a given range of pressure.

  5. [Tuberculosis and drug-resistance tuberculosis in prisoners. Colombia, 2010-2012].

    Science.gov (United States)

    Gómez, Ingrid T; Llerena, Claudia R; Zabaleta, Angie P

    2015-01-01

    To characterize tuberculosis drug-resistance using anti-tuberculosis drug-sensitivity tests in Colombian prisoners. Descriptive-retrospective analyses were performed on cases of tuberculosis in prisoners. Samples were evaluated by the National Reference Laboratory. Conditions like gender, TB/VIH co-infection and drug-resistance were evaluated. Anti-tuberculosis drug-sensitivity tests were carried out on 72 prisoners. Results showed a distribution of 90.7 % of cases in males and 9.3 % of cases in females. 12 % of cases were TB/VIH co-infections, 94 % of the cases had not received any anti-tuberculosis treatment before, six isolates were drug-resistant corresponding to 8.8 % of total cases, and two cases were multi drug-resistant representing 1.3 % of the cases. Of the drug-resistant cases, 83.3 % were TB/VIH co-infected. Previously treated cases corresponded to 5.6 % of the total cases analyzed. One case with TB/VIH co-infection and rifampicin resistance was observed, representing 1.3 % of the total cases. The government must create a clear policy for prisoners in Colombia, because a high rate of disease in prisoners was observed. In addition, the results showed an association between drug-resistance and TB/VIH co-infection. Overcrowding and low quality of life in penitentiaries could become an important public health problem.

  6. Engineered reversal of drug resistance in cancer cells--metastases suppressor factors as change agents.

    Science.gov (United States)

    Yadav, Vinod Kumar; Kumar, Akinchan; Mann, Anita; Aggarwal, Suruchi; Kumar, Maneesh; Roy, Sumitabho Deb; Pore, Subrata Kumar; Banerjee, Rajkumar; Mahesh Kumar, Jerald; Thakur, Ram Krishna; Chowdhury, Shantanu

    2014-01-01

    Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50-60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles.

  7. Clinical and Drug Resistance Characteristics of New Pediatric Tuberculosis Cases in Northern China.

    Science.gov (United States)

    Wang, Ting; Dong, Fang; Li, Qin-Jing; Yin, Qing-Qin; Song, Wen-Qi; Mokrousov, Igor; Jiao, Wei-Wei; Shen, A-Dong

    2018-05-09

    The aim of this study was to evaluate the clinical features and characteristics of drug resistance in newly diagnosed pediatric tuberculosis (TB) patients in northern China. Mycobacterium tuberculosis isolates were collected from September 2010 to October 2016 at the Beijing Children's Hospital. Patients were divided into two groups (resistant to at least one drug and pan-susceptible) according to drug susceptibility testing (DST) results. A total of 132 new cases, mainly from northern China (87.9%), were included in the study. The median age was 1.9 years (1 month-15 years). Resistance to at least one drug was detected in Mycobacterium tuberculosis isolates from 33 (25%) cases. Eight cases of multidrug-resistant TB (MDR-TB) (6.1%) were detected. The two groups did not differ in clinical presentations (disease site, fever >2 weeks, and cough >2 weeks) or in chest imaging (lesion location, lymphadenitis [mediastinal], and pleural effusion). The rate of Mycobacterium tuberculosis drug resistance in new pediatric TB cases was as high as in the new adult patients surveyed in the national drug resistance survey conducted in 2007. No significant difference was observed in clinical features between patients infected with drug-resistant and drug-susceptible strains. Routine DST is important for prescribing effective antituberculosis treatment regimens.

  8. MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4

    International Nuclear Information System (INIS)

    Wei, Xueju; Wang, Weibin; Wang, Lanlan; Zhang, Yuanyuan; Zhang, Xian; Chen, Mingtai; Wang, Fang; Yu, Jia; Ma, Yanni; Sun, Guotao

    2016-01-01

    Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21

  9. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya.

    Directory of Open Access Journals (Sweden)

    Julia Jezmir

    Full Text Available To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS methodology.The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance.This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains.Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints.

  10. A review of mechanisms of circumvention and modulation of chemotherapeutic drug resistance.

    Science.gov (United States)

    O'Connor, R

    2009-05-01

    Drug resistance is a serious limitation to the effective treatment of a number of common malignancies. Thirty years of laboratory and clinical research have greatly defined the molecular alterations underlying many drug resistance processes in cancer. Based on this knowledge, strategies to overcome the impact of resistance and increase the efficacy of cancer treatment have been translated from laboratory models to clinical trials. This article reviews laboratory and, in particular, clinical attempts at drug resistance circumvention from early forays in the inhibition of cellular efflux pump-mediated drug resistance through to more selective circumvention agent strategies and into inhibition of the other important mechanisms which can allow cancer cells to survive therapy, such as apoptosis resistance. Despite some promising results to date, resistance inhibition strategies have largely failed due to poor understanding of the pharmacology, dynamics and complexity of the resistance phenotype. With the realisation that new molecularly-targeted agents can also be rendered ineffectual by the actions of resistance mechanisms, a major focus is once again emerging on identifying new strategies/pharmaceuticals which can augment the activity of the arsenal of more conventional cytotoxics and newer targeted anti-cancer drugs. Future tactical directions where old and new resistance strategies may merge to overcome this challenge are discussed.

  11. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya.

    Science.gov (United States)

    Jezmir, Julia; Cohen, Ted; Zignol, Matteo; Nyakan, Edwin; Hedt-Gauthier, Bethany L; Gardner, Adrian; Kamle, Lydia; Injera, Wilfred; Carter, E Jane

    2016-01-01

    To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB) in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS) methodology. The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance. This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains. Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints.

  12. Different frequencies of drug resistance mutations among HIV-1 subtypes circulating in China: a comprehensive study.

    Directory of Open Access Journals (Sweden)

    Hongshuai Sui

    Full Text Available The rapid spreading of HIV drug resistance is threatening the overall success of free HAART in China. Much work has been done on drug-resistant mutations, however, most of which were based on subtype B. Due to different genetic background, subtypes difference would have an effect on the development of drug-resistant mutations, which has already been proved by more and more studies. In China, the main epidemic subtypes are CRF07_BC, CRF08_BC, Thai B and CRF01_AE. The depiction of drug resistance mutations in those subtypes will be helpful for the selection of regimens for Chinese. In this study, the distributions difference of amino acids at sites related to HIV drug resistance were compared among subtype B, CRF01_AE, CRF07_BC and CRF08_BC strains prevalent in China. The amino acid composition of sequences belonging to different subtypes, which were obtained from untreated and treated individuals separately, were also compared. The amino acids proportions of 19 sites in RT among subtype B, CRF01_AE and CRF08_BC have significant difference in drug resistance groups (chi-square test, p<0.05. Genetic barriers analysis revealed that sites 69, 138, 181, 215 and 238 were significantly different among subtypes (Kruskal Wallis test, p<0.05. All subtypes shared three highest prevalent drug resistance sites 103, 181 and 184 in common. Many drug resistant sites in protease show surprising high proportions in almost all subtypes in drug-naïve patients. This is the first comprehensive study in China on different development of drug resistance among different subtypes. The detailed data will lay a foundation for HIV treatment regimens design and improve HIV therapy in China.

  13. Interplay between Mutations and Efflux in Drug Resistant Clinical Isolates of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Miguel Viveiros

    2017-04-01

    Full Text Available Numerous studies show efflux as a universal bacterial mechanism contributing to antibiotic resistance and also that the activity of the antibiotics subject to efflux can be enhanced by the combined use of efflux inhibitors. Nevertheless, the contribution of efflux to the overall drug resistance levels of clinical isolates of Mycobacterium tuberculosis is poorly understood and still is ignored by many. Here, we evaluated the contribution of drug efflux plus target-gene mutations to the drug resistance levels in clinical isolates of M. tuberculosis. A panel of 17 M. tuberculosis clinical strains were characterized for drug resistance associated mutations and antibiotic profiles in the presence and absence of efflux inhibitors. The correlation between the effect of the efflux inhibitors and the resistance levels was assessed by quantitative drug susceptibility testing. The bacterial growth/survival vs. growth inhibition was analyzed through the comparison between the time of growth in the presence and absence of an inhibitor. For the same mutation conferring antibiotic resistance, different MICs were observed and the different resistance levels found could be reduced by efflux inhibitors. Although susceptibility was not restored, the results demonstrate the existence of a broad-spectrum synergistic interaction between antibiotics and efflux inhibitors. The existence of efflux activity was confirmed by real-time fluorometry. Moreover, the efflux pump genes mmr, mmpL7, Rv1258c, p55, and efpA were shown to be overexpressed in the presence of antibiotics, demonstrating the contribution of these efflux pumps to the overall resistance phenotype of the M. tuberculosis clinical isolates studied, independently of the genotype of the strains. These results showed that the drug resistance levels of multi- and extensively-drug resistant M. tuberculosis clinical strains are a combination between drug efflux and the presence of target-gene mutations, a reality

  14. Molecular approaches for detection of the multi-drug resistant tuberculosis (MDR-TB in Bangladesh.

    Directory of Open Access Journals (Sweden)

    Tafsina Haque Aurin

    Full Text Available The principal obstacles in the treatment of tuberculosis (TB are delayed and inaccurate diagnosis which often leads to the onset of the drug resistant TB cases. To avail the appropriate treatment of the patients and to hinder the transmission of drug-resistant TB, accurate and rapid detection of resistant isolates is critical. Present study was designed to demonstrate the efficacy of molecular techniques inclusive of line probe assay (LPA and GeneXpert MTB/RIF methods for the detection of multi-drug resistant (MDR TB. Sputum samples from 300 different categories of treated and new TB cases were tested for the detection of possible mutation in the resistance specific genes (rpoB, inhA and katG through Genotype MTBDRplus assay or LPA and GeneXpert MTB/RIF tests. Culture based conventional drug susceptibility test (DST was also carried out to measure the efficacy of the molecular methods employed. Among 300 samples, 191 (63.7% and 193 (64.3% cases were found to be resistant against rifampicin in LPA and GeneXpert methods, respectively; while 189 (63% cases of rifampicin resistance were detected by conventional DST methods. On the other hand, 196 (65.3% and 191 (63.7% isolates showed isoniazid resistance as detected by LPA and conventional drug susceptibility test (DST, respectively. Among the drug resistant isolates (collectively 198 in LPA and 193 in conventional DST, 189 (95.6% and 187 (96.9% were considered to be MDR as examined by LPA and conventional DST, respectively. Category-II and -IV patients encountered higher frequency of drug resistance compared to those from category-I and new cases. Considering the higher sensitivity, specificity and accuracy along with the required time to results significantly shorter, our study supports the adoption of LPA and GeneXpert assay as efficient tools in detecting drug resistant TB in Bangladesh.

  15. Radiation response of drug-resistant variants of a human breast cancer cell line

    International Nuclear Information System (INIS)

    Lehnert, S.; Greene, D.; Batist, G.

    1989-01-01

    The radiation response of drug-resistant variants of the human tumor breast cancer cell line MCF-7 has been investigated. Two sublines, one resistant to adriamycin (ADRR) and the other to melphalan (MLNR), have been selected by exposure to stepwise increasing concentrations of the respective drugs. ADRR cells are 200-fold resistant to adriamycin and cross-resistant to a number of other drugs and are characterized by the presence of elevated levels of selenium-dependent glutathione peroxidase and glutathione-S-transferase. MLNR cells are fourfold resistant to melphalan and cross-resistant to some other drugs. The only mechanism of drug resistance established for MLNR cells to date is an enhancement of DNA excision repair processes. While the spectrum of drug resistance and the underlying mechanisms differ for the two sublines, their response to radiation is qualitatively similar. Radiation survival curves for ADRR and MLNR cells differ from that for wild-type cells in a complex manner with, for the linear-quadratic model, a decrease in the size of alpha and an increase in the size of beta. There is a concomitant decrease in the size of the alpha/beta ratio which is greater for ADRR cells than for MLNR cells. Analysis of results using the multitarget model gave values of D0 of 1.48, 1.43, and 1.67 Gy for MCF-7 cells are not a consequence of cell kinetic differences between these sublines. Results of split-dose experiments indicated that for both drug-resistant sublines the extent of sublethal damage repair reflected the width of the shoulder on the single-dose survival curve. For MCF-7 cells in the stationary phase of growth, the drug-resistant sublines did not show cross-resistance to radiation; however, delayed subculture following irradiation of stationary-phase cultures increased survival to a greater extent for ADRR and MLNR cells than for wild-type cells

  16. Label-free recognition of drug resistance via impedimetric screening of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Bilge Eker

    Full Text Available We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX from their parental cells (MCF-7 WT via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra . Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

  17. Short history of regulations and approved indications of antimicrobial drugs for food animals in the USA.

    Science.gov (United States)

    Volkova, V V; DeMars, Z

    2017-06-01

    We review historical availability and regulation, and recent indications of antimicrobial drugs for food animals in the USA. We summarize the timeline of introduction of individual antimicrobial drug classes from the 1930s to present, history of regulation of antimicrobial drugs from the 1930s to present and indications of antimicrobial drugs in 1996-2014 for food animals in the USA. The history of antimicrobial drug regulation demonstrates a historical precedent for harmonized regulations of antimicrobials 'for human and other animals' in the USA. © 2016 John Wiley & Sons Ltd.

  18. Comparative Genomic Analysis of Rapid Evolution of an Extreme-Drug-Resistant Acinetobacter baumannii Clone

    Science.gov (United States)

    Tan, Sean Yang-Yi; Chua, Song Lin; Liu, Yang; Høiby, Niels; Andersen, Leif Percival; Givskov, Michael; Song, Zhijun; Yang, Liang

    2013-01-01

    The emergence of extreme-drug-resistant (EDR) bacterial strains in hospital and nonhospital clinical settings is a big and growing public health threat. Understanding the antibiotic resistance mechanisms at the genomic levels can facilitate the development of next-generation agents. Here, comparative genomics has been employed to analyze the rapid evolution of an EDR Acinetobacter baumannii clone from the intensive care unit (ICU) of Rigshospitalet at Copenhagen. Two resistant A. baumannii strains, 48055 and 53264, were sequentially isolated from two individuals who had been admitted to ICU within a 1-month interval. Multilocus sequence typing indicates that these two isolates belonged to ST208. The A. baumannii 53264 strain gained colistin resistance compared with the 48055 strain and became an EDR strain. Genome sequencing indicates that A. baumannii 53264 and 48055 have almost identical genomes—61 single-nucleotide polymorphisms (SNPs) were found between them. The A. baumannii 53264 strain was assembled into 130 contigs, with a total length of 3,976,592 bp with 38.93% GC content. The A. baumannii 48055 strain was assembled into 135 contigs, with a total length of 4,049,562 bp with 39.00% GC content. Genome comparisons showed that this A. baumannii clone is classified as an International clone II strain and has 94% synteny with the A. baumannii ACICU strain. The ResFinder server identified a total of 14 antibiotic resistance genes in the A. baumannii clone. Proteomic analyses revealed that a putative porin protein was down-regulated when A. baumannii 53264 was exposed to antimicrobials, which may reduce the entry of antibiotics into the bacterial cell. PMID:23538992

  19. A co-delivery nanosystem of chemotherapeutics and DNAzyme overcomes cancer drug resistance and metastasis

    Science.gov (United States)

    Sun, Shu-Pin; Liu, Ching-Ping; Huang, I.-Ping; Chu, Chia-Hui; Chung, Ming-Fang; Cheng, Shih-Hsun; Lin, Shu-Yi; Lo, Leu-Wei

    2017-12-01

    Multidrug resistance (MDR) constitutes a major problem in the management of cancer and cancer metastasized from primary-source tumor causes cancer-related deaths. Our new approach is the co-delivery of chemotherapy drugs with a transcription-factor-targeting genetic agent to simultaneously inhibit the growth and metastasis of cancer cells. C-Jun is a transcription factor that regulates multidrug resistance-associated protein 1 (MRP1) pump efflux transcription and tumor metastasis. In this work, we reported that mesoporous silica nanoparticles (MSNs) can be functionalized to co-deliver doxorubicin (Dox) and DNAzyme (Dz) to increase cancer cell killing in an additive fashion. The MSNs were sequentially conjugated with Dox into the MSNs’ nanochannels and Dz onto the MSNs’ outermost surface to target c-Jun as the Dox@MSN-Dz co-delivery system. The Dox-resistant PC-3 cells treated with Dox@MSN-Dz efficiently enhanced the intracellular Dox concentration due to the abrogation of Dox-induced MRP1 expression through the downregulation of c-Jun expression by Dz. Additionally, significant reductions in invasion and migration related to metastasis were also observed in cells treated with Dox@MSN-Dz. Therefore, our results contribute new insight to the treatment of MDR combined metastatic cancer cells, worthwhile for studying its potential for development in clinical translation.

  20. Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa.

    Science.gov (United States)

    Slater, Hannah C; Griffin, Jamie T; Ghani, Azra C; Okell, Lucy C

    2016-01-06

    Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7% increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.

  1. Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

    NARCIS (Netherlands)

    Hofstra, L. Marije; Sauvageot, Nicolas; Albert, Jan; Alexiev, Ivailo; Garcia, Federico; Struck, Daniel; Van De Vijver, David A M C; Åsjö, Birgitta; Beshkov, Danail; Coughlan, Suzie; Descamps, Diane; Griskevicius, Algirdas; Hamouda, Osamah; Horban, Andrzej; Van Kasteren, Marjo; Kolupajeva, Tatjana; Kostrikis, Leontios G.; Liitsola, Kirsi; Linka, Marek; Mor, Orna; Nielsen, Claus; Otelea, Dan; Paraskevis, Dimitrios; Paredes, Roger; Poljak, Mario; Puchhammer-Stöckl, Elisabeth; Sönnerborg, Anders; Staneková, Danica; Stanojevic, Maja; Van Laethem, Kristel; Zazzi, Maurizio; Lepej, Snjezana Zidovec; Boucher, Charles A B; Schmit, Jean Claude; Wensing, Annemarie M J; Puchhammer-Stockl, E.; Sarcletti, M.; Schmied, B.; Geit, M.; Balluch, G.; Vandamme, A. M.; Vercauteren, J.; Derdelinckx, I.; Sasse, A.; Bogaert, M.; Ceunen, H.; De Roo, A.; De Wit, S.; Echahidi, F.; Fransen, K.; Goffard, J. C.; Goubau, P.; Goudeseune, E.; Yombi, J. C.; Lacor, P.; Liesnard, C.; Moutschen, M.; Pierard, D.; Rens, R.; Schrooten, Y.; Vaira, D.; Vandekerckhove, L. P R; Van Den Heuvel, A.; Van Der Gucht, B.; Van Ranst, M.; Van Wijngaerden, E.; Vandercam, B.; Vekemans, M.; Verhofstede, C.; Clumeck, N.; Van Laethem, K.; Beshkov, D.; Alexiev, I.; Lepej, S. Zidovec; Begovac, J.; Kostrikis, Leontios G.; Demetriades, I.; Kousiappa, I.; Demetriou, V.; Hezka, J.; Linka, M.; Maly, M.; Machala, L.; Nielsen, C.; Jørgensen, L. B.; Gerstoft, J.; Mathiesen, L.; Pedersen, C.; Nielsen, H.; Laursen, A.; Kvinesdal, B.; Liitsola, K.; Ristola, M.; Suni, J.; Sutinen, J.; Descamps, D.; Assoumou, L.; Castor, G.; Grude, M.; Flandre, P.; Storto, A.; Hamouda, O.; Kücherer, C.; Berg, T.; Braun, P.; Poggensee, G.; Däumer, M.; Eberle, J.; Heiken, H.; Kaiser, R.; Knechten, H.; Korn, K.; Müller, H.; Neifer, S.; Schmidt, B.; Walter, H.; Gunsenheimer-Bartmeyer, B.; Harrer, T.; Paraskevis, D.; Hatzakis, A.; Zavitsanou, A.; Vassilakis, A.; Lazanas, M.; Chini, M.; Lioni, A.; Sakka, V.; Kourkounti, S.; Paparizos, V.; Antoniadou, A.; Papadopoulos, A.; Poulakou, G.; Katsarolis, I.; Protopapas, K.; Chryssos, G.; Drimis, S.; Gargalianos, P.; Xylomenos, G.; Lourida, G.; Psichogiou, M.; Daikos, G. L.; Sipsas, N. V.; Kontos, A.; Gamaletsou, M. N.; Koratzanis, G.; Sambatakou, E.; Mariolis, H.; Skoutelis, A.; Papastamopoulos, V.; Georgiou, O.; Panagopoulos, P.; Maltezos, E.; Coughlan, S.; De Gascun, C.; Byrne, C.; Duffy, M.; Bergin, C.; Reidy, D.; Farrell, G.; Lambert, J.; O'Connor, E.; Rochford, A.; Low, J.; Coakely, P.; O'Dea, S.; Hall, W.; Mor, O.; Levi, I.; Chemtob, D.; Grossman, Z.; Zazzi, M.; De Luca, A.; Balotta, C.; Riva, C.; Mussini, C.; Caramma, I.; Capetti, A.; Colombo, M. C.; Rossi, C.; Prati, F.; Tramuto, F.; Vitale, F.; Ciccozzi, M.; Angarano, G.; Rezza, G.; Kolupajeva, T.; Kolupajeva, T.; Vasins, O.; Griskevicius, A.; Lipnickiene, V.; Schmit, J. C.; Struck, D.; Sauvageot, N.; Hemmer, R.; Arendt, V.; Michaux, C.; Staub, T.; Sequin-Devaux, C.; Wensing, A. M J; Boucher, C. A B; Van Kessel, A.; Van Bentum, P. H M; Brinkman, K.; Connell, B. J.; Van Der Ende, M. E.; Hoepelman, I. M.; Van Kasteren, M.; Kuipers, M.; Langebeek, N.; Richter, C.; Santegoets, R. M W J; Schrijnders-Gudde, L.; Schuurman, R.; Van De Ven, B. J M; Åsjö, B.; Kran, A. M Bakken; Ormaasen, V.; Aavitsland, P.; Horban, A.; Stanczak, J. J.; Stanczak, G. P.; Firlag-Burkacka, E.; Wiercinska-Drapalo, A.; Jablonowska, E.; Maolepsza, E.; Leszczyszyn-Pynka, M.; Szata, W.; Camacho, R.; Palma, C.; Borges, F.; Paixão, T.; Duque, V.; Araújo, F.; Otelea, D.; Paraschiv, S.; Tudor, A. M.; Cernat, R.; Chiriac, C.; Dumitrescu, F.; Prisecariu, L. J.; Stanojevic, M.; Jevtovic, Dj; Salemovic, D.; Stanekova, D.; Habekova, M.; Chabadová, Z.; Drobkova, T.; Bukovinova, P.; Shunnar, A.; Truska, P.; Poljak, M.; Lunar, M.; Babic, D.; Tomazic, J.; Vidmar, L.; Vovko, T.; Karner, P.; Garcia, F.; Paredes, R.; Monge, S.; Moreno, S.; Del Amo, J.; Asensi, V.; Sirvent, J. L.; De Mendoza, C.; Delgado, R.; Gutiérrez, F.; Berenguer, J.; Garcia-Bujalance, S.; Stella, N.; De Los Santos, I.; Blanco, J. R.; Dalmau, D.; Rivero, M.; Segura, F.; Elías, M. J Pérez; Alvarez, M.; Chueca, N.; Rodríguez-Martín, C.; Vidal, C.; Palomares, J. C.; Viciana, I.; Viciana, P.; Cordoba, J.; Aguilera, A.; Domingo, P.; Galindo, M. J.; Miralles, C.; Del Pozo, M. A.; Ribera, E.; Iribarren, J. A.; Ruiz, L.; De La Torre, J.; Vidal, F.; Clotet, B.; Albert, J.; Heidarian, A.; Aperia-Peipke, K.; Axelsson, M.; Mild, M.; Karlsson, A.; Sönnerborg, A.; Thalme, A.; Navér, L.; Bratt, G.; Karlsson, A.; Blaxhult, A.; Gisslén, M.; Svennerholm, B.; Bergbrant, I.; Björkman, P.; Säll, C.; Lindholm, A.; Kuylenstierna, N.; Montelius, R.; Azimi, F.; Johansson, B.; Carlsson, M.; Johansson, E.; Ljungberg, B.; Ekvall, H.; Strand, A.; Mäkitalo, S.; Öberg, S.; Holmblad, P.; Höfer, M.; Holmberg, H.; Josefson, P.; Ryding, U.

    2016-01-01

    Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline

  2. Supplementary Material for: Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance

    KAUST Repository

    Phelan, Jody; Coll, Francesc; McNerney, Ruth; Ascher, David; Pires, Douglas; Furnham, Nick; Coeck, Nele; Hill-Cawthorne, Grant; Nair, Mridul; Mallard, Kim; Ramsay, Andrew; Campino, Susana; Hibberd, Martin; Pain, Arnab; Rigouts, Leen; Clark, Taane

    2016-01-01

    Abstract Background Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure

  3. Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer.

    Science.gov (United States)

    Yang, Wanli; Ma, Jiaojiao; Zhou, Wei; Cao, Bo; Zhou, Xin; Yang, Zhiping; Zhang, Hongwei; Zhao, Qingchuan; Fan, Daiming; Hong, Liu

    2017-11-01

    Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer. Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications. Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.

  4. European recommendations for the clinical use of HIV drug resistance testing: 2011 update

    DEFF Research Database (Denmark)

    Vandamme, Anne-Mieke; Camacho, Ricardo J; Ceccherini-Silberstein, Francesca

    2011-01-01

    , and other drug targets (integrase and envelope) if such drugs were part of the failing regimen; (iii) consider testing for CCR5 tropism at virologic failure or when a change of therapy has to be made in absence of detectable viral load, and in the latter case test DNA or last detectable plasma RNA; (iv...... the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure...... is needed after treatment failure. The Panel recommends genotyping in most situations, using updated and clinically evaluated interpretation systems. It is mandatory that laboratories performing HIV resistance tests take part regularly in external quality assurance programs, and that they consider storing...

  5. Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac ▿

    Science.gov (United States)

    van Leeuwen, Jolanda S.; Vermeulen, Nico P. E.; Vos, J. Chris

    2011-01-01

    Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as a model eukaryote with which to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during the initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. In particular, pleiotropic drug resistance (PDR) genes and genes under the control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. We tested if these processes or pathways were directly involved in diclofenac toxicity or resistance. Of the pleiotropic drug resistance gene products, the multidrug transporter Pdr5p was crucially important for diclofenac tolerance. Furthermore, deletion of components of the cell wall stress-responsive PKC pathway increased diclofenac toxicity, whereas incubation of cells with the cell wall stressor calcofluor white before the addition of diclofenac decreased its toxicity. Also, diclofenac induced flocculation, which might trigger the cell wall alterations. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as were zinc-responsive genes. Paradoxically, deletion of the zinc-responsive transcription factor Zap1p or addition of the zinc chelator 1,10-phenanthroline significantly increased diclofenac toxicity, establishing a regulatory role for zinc in diclofenac resistance. In conclusion, we have identified three new pathways involved in diclofenac tolerance in yeast, namely, Pdr5p as the main contributor to the PDR response, cell wall signaling via the PKC pathway, and zinc homeostasis, regulated by Zap1p. PMID:21724882

  6. Genotypic diversity of multidrug-, quinolone- and extensively drug-resistant Mycobacterium tuberculosis isolates in Thailand.

    Science.gov (United States)

    Disratthakit, Areeya; Meada, Shinji; Prammananan, Therdsak; Thaipisuttikul, Iyarit; Doi, Norio; Chaiprasert, Angkana

    2015-06-01

    Drug-resistant tuberculosis (TB), which includes multidrug-resistant (MDR-TB), quinolone-resistant (QR-TB) and extensively drug-resistant tuberculosis (XDR-TB), is a serious threat to TB control. We aimed to characterize the genotypic diversity of drug-resistant TB clinical isolates collected in Thailand to establish whether the emergence of drug-resistant TB is attributable to transmitted resistance or acquired resistance. We constructed the first molecular phylogeny of MDR-TB (n=95), QR-TB (n=69) and XDR-TB (n=28) in Thailand based on spoligotyping and proposed 24-locus multilocus variable-number of tandem repeat analysis (MLVA). Clustering analysis was performed using the unweighted pair group method with arithmetic mean. Spoligotyping identified the Beijing strain (SIT1) as the most predominant genotype (n=139; 72.4%). The discriminatory power of 0.9235 Hunter-Gaston Discriminatory Index (HGDI) with the 15-locus variable-number tandem repeats of mycobacterial interspersed repetitive units typing was improved to a 0.9574 HGDI with proposed 24-locus MLVA, thereby resulting in the subdivision of a large cluster of Beijing strains (SIT1) into 17 subclusters. We identified the spread of drug-resistant TB clones caused by three different MLVA types in the Beijing strain (SIT1) and a specific clone of XDR-TB caused by a rare genotype, the Manu-ancestor strain (SIT523). Overall, 49.5% of all isolates were clustered. These findings suggest that a remarkable transmission of drug-resistant TB occurred in Thailand. The remaining 50% of drug-resistant TB isolates were unique genotypes, which may have arisen from the individual acquisition of drug resistance. Our results suggest that transmitted and acquired resistance have played an equal role in the emergence of drug-resistant TB. Further characterization of whole genome sequences of clonal strains could help to elucidate the mycobacterial genetic factors relevant for drug resistance, transmissibility and virulence

  7. Antimicrobial drug resistance of Salmonella isolates from meat and humans, Denmark

    DEFF Research Database (Denmark)

    Skov, Marianne Nielsine; Andersen, Jens Strodl; Aabo, Søren

    2007-01-01

    We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from...... humans showed resistance rates lower than those found in imported meat but higher than in domestic meat. These findings indicate that programs for controlling resistant Salmonella spp. are a global issue...

  8. Antimicrobial drug resistance of Salmonella isolates from meat and humans, Denmark

    DEFF Research Database (Denmark)

    Skov, Marianne; Andersen, Jens Strodl; Aabo, Søren

    2007-01-01

    We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from...... humans showed resistance rates lower than those found in imported meat but higher than in domestic meat. These findings indicate that programs for controlling resistant Salmonella spp. are a global issue....

  9. Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study

    NARCIS (Netherlands)

    Hamers, Raph L.; Schuurman, Rob; Sigaloff, Kim C. E.; Wallis, Carole L.; Kityo, Cissy; Siwale, Margaret; Mandaliya, Kishor; Ive, Prudence; Botes, Mariette E.; Wellington, Maureen; Osibogun, Akin; Wit, Ferdinand W.; van Vugt, Michèle; Stevens, Wendy S.; de Wit, Tobias F. Rinke

    2012-01-01

    Background The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large

  10. HIV-1 evolution, drug resistance, and host genetics: The Indian scenario

    Directory of Open Access Journals (Sweden)

    U Shankarkumar

    2009-03-01

    Full Text Available U Shankarkumar, A Pawar, K GhoshNational Institute of Immunohaematology (ICMR, KEM Hospital, Parel, Mumbai, Maharashtra, IndiaAbstract: A regimen with varied side effects and compliance is of paramount importance to prevent viral drug resistance. Most of the drug-resistance studies, as well as interpretation algorithms, are based on sequence data from HIV-1 subtype B viruses. Increased resistance to antiretroviral drugs leads to poor prognosis by restricting treatment options. Due to suboptimal adherence to antiretroviral therapy there is an emergence of drug-resistant HIV-1 strains. The other factors responsible for this viral evolution are antiretroviral drug types and host genetics, especially major histocompatibility complex (MHC. Both primary and secondary drug resistances occur due to mutations in specific epitopes of viral protein regions which may influence the T cell recognition by immune system through MHC Class I and class II alleles. Mutations in viral epitopes enable the virus to escape the immune system. New drugs under clinical trials are being added but their exorbitant costs limit their access in developing countries. Thus the environmental consequences and, the impact of both viral and host genetic variations on the therapy in persons infected with HIV-1 clade C from India need to be determined.Keywords: HIV-1 C drug resistance, virus adaptation, HARRT, India

  11. Clinical characteristics, drug resistance, and treatment outcomes among tuberculosis patients with diabetes in Peru.

    Science.gov (United States)

    Magee, M J; Bloss, E; Shin, S S; Contreras, C; Huaman, H Arbanil; Ticona, J Calderon; Bayona, J; Bonilla, C; Yagui, M; Jave, O; Cegielski, J P

    2013-06-01

    Diabetes is a risk factor for active tuberculosis (TB). Data are limited regarding the association between diabetes and TB drug resistance and treatment outcomes. We examined characteristics of TB patients with and without diabetes in a Peruvian cohort at high risk for drug-resistant TB. Among TB patients with diabetes (TB-DM), we studied the association between diabetes clinical/management characteristics and TB drug resistance and treatment outcomes. During 2005-2008, adults with suspected TB with respiratory symptoms in Lima, Peru, who received rapid drug susceptibility testing (DST), were prospectively enrolled and followed during treatment. Bivariate and Kaplan-Meier analyses were used to examine the relationships of diabetes characteristics with drug-resistant TB and TB outcomes. Of 1671 adult TB patients enrolled, 186 (11.1%) had diabetes. TB-DM patients were significantly more likely than TB patients without diabetes to be older, have had no previous TB treatment, and to have a body mass index (BMI) >18.5 kg/m(2) (pdiabetes, and 12% and 28%, respectively, among TB-DM patients. Among 149 TB-DM patients with DST results, 104 (69.8%) had drug-susceptible TB and 45 (30.2%) had drug-resistant TB, of whom 29 had multidrug-resistant TB. There was no association between diabetes characteristics and drug-resistant TB. Of 136 TB-DM patients with outcome information, 107 (78.7%) had a favorable TB outcome; active diabetes management was associated with a favorable outcome. Diabetes was common in a cohort of TB patients at high risk for drug-resistant TB. Despite prevalent multidrug-resistant TB among TB-DM patients, the majority had a favorable TB treatment outcome. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  12. Alteration of gene expression and DNA methylation in drug-resistant gastric cancer.

    Science.gov (United States)

    Maeda, Osamu; Ando, Takafumi; Ohmiya, Naoki; Ishiguro, Kazuhiro; Watanabe, Osamu; Miyahara, Ryoji; Hibi, Yoko; Nagai, Taku; Yamada, Kiyofumi; Goto, Hidemi

    2014-04-01

    The mechanisms of drug resistance in cancer are not fully elucidated. To study the drug resistance of gastric cancer, we analyzed gene expression and DNA methylation profiles of 5-fluorouracil (5-FU)- and cisplatin (CDDP)-resistant gastric cancer cells and biopsy specimens. Drug-resistant gastric cancer cells were established with culture for >10 months in a medium containing 5-FU or CDDP. Endoscopic biopsy specimens were obtained from gastric cancer patients who underwent chemotherapy with oral fluoropyrimidine S-1 and CDDP. Gene expression and DNA methylation analyses were performed using microarray, and validated using real-time PCR and pyrosequencing, respectively. Out of 17,933 genes, 541 genes commonly increased and 569 genes decreased in both 5-FU- and CDDP-resistant AGS cells. Genes with expression changed by drugs were related to GO term 'extracellular region' and 'p53 signaling pathway' in both 5-FU- and CDDP-treated cells. Expression of 15 genes including KLK13 increased and 12 genes including ETV7 decreased, in both drug-resistant cells and biopsy specimens of two patients after chemotherapy. Out of 10,365 genes evaluated with both expression microarray and methylation microarray, 74 genes were hypermethylated and downregulated, or hypomethylated and upregulated in either 5-FU-resistant or CDDP-resistant cells. Of these genes, expression of 21 genes including FSCN1, CPT1C and NOTCH3, increased from treatment with a demethylating agent. There are alterations of gene expression and DNA methylation in drug-resistant gastric cancer; they may be related to mechanisms of drug resistance and may be useful as biomarkers of gastric cancer drug sensitivity.

  13. The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria.

    Science.gov (United States)

    Walsh, Fiona; Duffy, Brion

    2013-01-01

    Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR) mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16-23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR) resistance genes) were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family.

  14. The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria.

    Directory of Open Access Journals (Sweden)

    Fiona Walsh

    Full Text Available Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16-23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR resistance genes were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family.

  15. Changing patterns of drug-resistant Shigella isolates in egypt.

    Science.gov (United States)

    Abd-Elmeged, Ghada M; Khairy, Rasha M; Abo-Eloyoon, Sahar M; Abdelwahab, Sayed F

    2015-06-01

    The emergence of multidrug resistance (MDR) is a serious problem in treating shigellosis. There are limited existing data examining the change in the antimicrobial resistance profile of Shigella in Egypt. We previously reported that 58% of the Shigella isolates in Egypt were resistant to at least one member of the three different antimicrobial groups. This study was performed to determine the antimicrobial resistance profile of Shigella, determine their possible mechanisms of resistance, and compare their resistance profile to those reported 20 years ago. Stool samples were collected from 500 subjects and processed for the isolation and identification of Shigella. The susceptibility of the isolates to 11 different antimicrobials was determined using the disc diffusion method. Of 500 stool cultures, 24 (4.8%) samples were positive for Shigella. There was a high percentage of resistance to ampicillin (88%), tetracycline (83%), and sulfamethoxazole-trimethoprim (75%). Also, there was a moderate percentage of resistance to chloramphenicol (46%), streptomycin (42%), ceftazidime (33%), and cefotaxime (25%). A lower percentage of resistance was recorded for amikacin, nalidixic acid (17% each), and ofloxacin (7%), while no resistance was found to ciprofloxacin (0%). Twenty-one of the isolates (88%) were resistant to at least three different antimicrobial groups (indicating MDR). The average number of antimicrobial agents to which the Shigella isolates were resistant was 4.3±1.4, while it was 3.4±1.5 in the same locality in 1994. These data demonstrate that there is a marked increase in MDR and change in the resistance patterns of Shigella over the past 20 years.

  16. Genotypic drug resistance and long-term mortality in patients with triple-class antiretroviral drug failure

    DEFF Research Database (Denmark)

    Lohse, Nicolai; Jørgensen, LB; Kronborg, G

    2007-01-01

    OBJECTIVE: To examine the prevalence of drug-resistance-associated mutations in HIV patients with triple-drug class virological failure (TCF) and their association with long-term mortality. DESIGN: Population-based study from the Danish HIV Cohort Study (DHCS). METHODS: We included all patients...... range 2-10), and 81 (61%) patients had mutations conferring resistance towards all three major drug classes. In a regression model adjusted for CD4+ T-cell count, HIV RNA, year of TCF, age, gender and previous inferior antiretroviral therapy, harbouring > or =9 versus ... in the DHCS who experienced TCF between January 1995 and November 2004, and we performed genotypic resistance tests for International AIDS Society (IAS)-USA primary mutations on virus from plasma samples taken around the date of TCF. We computed time to all-cause death from date of TCF. The relative risk...

  17. Shifts in Mycobacterial Populations and Emerging Drug-Resistance in West and Central Africa.

    Directory of Open Access Journals (Sweden)

    Florian Gehre

    Full Text Available In this study, we retrospectively analysed a total of 605 clinical isolates from six West or Central African countries (Benin, Cameroon, Central African Republic, Guinea-Conakry, Niger and Senegal. Besides spoligotyping to assign isolates to ancient and modern mycobacterial lineages, we conducted phenotypic drug-susceptibility-testing for each isolate for the four first-line drugs. We showed that phylogenetically modern Mycobacterium tuberculosis strains are more likely associated with drug resistance than ancient strains and predict that the currently ongoing replacement of the endemic ancient by a modern mycobacterial population in West/Central Africa might result in increased drug resistance in the sub-region.

  18. ZK DrugResist 2.0: A TextMiner to extract semantic relations of drug resistance from PubMed.

    Science.gov (United States)

    Khalid, Zoya; Sezerman, Osman Ugur

    2017-05-01

    Extracting useful knowledge from an unstructured textual data is a challenging task for biologists, since biomedical literature is growing exponentially on a daily basis. Building an automated method for such tasks is gaining much attention of researchers. ZK DrugResist is an online tool that automatically extracts mutations and expression changes associated with drug resistance from PubMed. In this study we have extended our tool to include semantic relations extracted from biomedical text covering drug resistance and established a server including both of these features. Our system was tested for three relations, Resistance (R), Intermediate (I) and Susceptible (S) by applying hybrid feature set. From the last few decades the focus has changed to hybrid approaches as it provides better results. In our case this approach combines rule-based methods with machine learning techniques. The results showed 97.67% accuracy with 96% precision, recall and F-measure. The results have outperformed the previously existing relation extraction systems thus can facilitate computational analysis of drug resistance against complex diseases and further can be implemented on other areas of biomedicine. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

  20. Antimicrobial drug resistance in Staphylococcus aureus isolated from cattle in Brazil.

    Science.gov (United States)

    Pereira, M S; Siqueira-Júnior, J P

    1995-06-01

    Isolates of Staphylococcus aureus obtained from apparently healthy cattle in the State of Paraiba, Brazil were characterized in relation to resistance to 21 antimicrobial agents. Among the 46 isolates obtained, resistance to penicillin was most frequent, followed by resistance to cadmium, streptomycin, arsenate, tetracycline, mercury, erythromycin and kanamycin/neomycin. All isolates were susceptible to fusidic acid, ethidium bromide, cetrimide, chloramphenicol, benzalkonium chloride, doxycycline, gentamicin, methicillin, minocycline, novobiocin, rifamycin, tylosin and vancomycin. Only six isolates were susceptible to all the drugs tested. With respect to the antibiotics, multi-resistant isolates were uncommon. These results are probably a consequence of the peculiarities of local drug usage pressures. In relation to metal ions, resistance to mercury was rare while resistance to arsenate was relatively frequent, which contrasts with the situation for human Staph. aureus strains. After treatment with ethidium bromide, elimination of resistance to penicillin, tetracycline, streptomycin, erythromycin and cadmium was observed, which was consistent with the genetic determinants being plasmid-borne.

  1. Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases.

    Science.gov (United States)

    Sarafianos, Stefan G; Das, Kalyan; Hughes, Stephen H; Arnold, Eddy

    2004-12-01

    HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.

  2. Efflux drug transporters at the forefront of antimicrobial resistance

    OpenAIRE

    Rahman, Tahmina; Yarnall, Benjamin; Doyle, Declan A.

    2017-01-01

    Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence mechanisms that existed long before man’s discovery of antibiotics. Bacteria utilise levels of protection that range from gene upregulation, mutations, adaptive resistance, and production of resistant phenotypes (persisters) to communal behaviour, as in swarming and the ultimate defence of a biofilm. A major part of all of these respon...

  3. [Detection of CRISPR and its relationship to drug resistance in Shigella].

    Science.gov (United States)

    Wang, Linlin; Wang, Yingfang; Duan, Guangcai; Xue, Zerun; Guo, Xiangjiao; Wang, Pengfei; Xi, Yuanlin; Yang, Haiyan

    2015-04-04

    To detect clustered regularly interspaced short palindromic repeats (CRISPR) in Shigella, and to analyze its relationship to drug resistance. Four pairs of primers were used for the detection of convincing CRISPR structures CRISPR-S2 and CRISPR-S4, questionable CRISPR structures CRISPR-S1 and CRISPR-S3 in 60 Shigella strains. All primers were designed using sequences in CRISPR database. CRISPR Finder was used to analyze CRISPR and susceptibilities of Shigella strains were tested by agar diffusion method. Furthermore, we analyzed the relationship between drug resistance and CRISPR-S4. The positive rate of convincing CRISPR structures was 95%. The four CRISPR loci formed 12 spectral patterns (A-L), all of which contained convincing CRISPR structures except type K. We found one new repeat and 12 new spacers. The multi-drug resistance rate was 53. 33% . We found no significant difference between CRISPR-S4 and drug resistant. However, the repeat sequence of CRISPR-S4 in multi- or TE-resistance strains was mainly R4.1 with AC deletions in the 3' end, and the spacer sequences of CRISPR-S4 in multi-drug resistance strains were mainly Sp5.1, Sp6.1 and Sp7. CRISPR was common in Shigella. Variations df repeat sequences and diversities of spacer sequences might be related to drug resistance in Shigella.

  4. Drug resistance pattern of M. tuberculosis in category II treatment failure pulmonary tuberculosis patients

    Directory of Open Access Journals (Sweden)

    Fahmida Rahman

    2013-01-01

    Full Text Available This study was designed to determine the extent of drug resistance of M. tuberculosis (MTB isolated from category II treatment failure pulmonary tuberculosis (PTB patients. A total of 100 Ziehl-Neelsen (Z-N smear positive category II failure PTB patients were included in this study. Sputum culture was done in Lowenstein-Jensen (L-J media. Conventional proportion method on Lowenstein-Jensen (L-J media was used to determine the drug susceptibility of M. tuberculosis to isoniazid (INH, rifampicin (RMP, ofloxacin (OFX and kanamycin (KA. Out of 100 sputum samples, a total of 87 samples were positive by culture. Drug susceptibility test (DST revealed that 82 (94.25% isolates were resistant to one or more anti -TB drugs. Resistance to isoniazide (INH, rifampicin (RMP, ofloxacin (OFX and kanamycin (KA was 94.25%, 82.75%, 29.90% and 3.45% respectively. Among these isolates, 79.31% and 3.45% isolates were multi-drug resistant (MDR and extended drug resistant (XDR M. tuberculosis respectively. High rate of anti-tubercular drug resistance was observed among the category II treatment failure TB patients. Ibrahim Med. Coll. J. 2013; 7(1: 9-11

  5. Setting priorities for a research agenda to combat drug-resistant tuberculosis in children.

    Science.gov (United States)

    Velayutham, B; Nair, D; Ramalingam, S; Perez-Velez, C M; Becerra, M C; Swaminathan, S

    2015-12-21

    Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculosis (TB). Identifying research priorities is vital to inform and develop strategies to address this neglected problem. To systematically identify and rank research priorities in childhood drug-resistant TB. Adapting the Child Health and Nutrition Research Initiative (CHNRI) methodology, we compiled 53 research questions in four research areas, then classified the questions into three research types. We invited experts in childhood drug-resistant TB to score these questions through an online survey. A total of 81 respondents participated in the survey. The top-ranked research question was to identify the best combination of existing diagnostic tools for early diagnosis. Highly ranked treatment-related questions centred on the reasons for and interventions to improve treatment outcomes, adverse effects of drugs and optimal treatment duration. The prevalence of drug-resistant TB was the highest-ranked question in the epidemiology area. The development type questions that ranked highest focused on interventions for optimal diagnosis, treatment and modalities for treatment delivery. This is the first effort to identify and rank research priorities for childhood drug-resistant TB. The result is a resource to guide research to improve prevention and treatment of drug-resistant TB in children.

  6. Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Rajmohan Rajamuthiah

    Full Text Available Staphylococcus aureus, the leading cause of hospital-acquired infections in the United States, is also pathogenic to the model nematode Caenorhabditis elegans. The C. elegans-S. aureus infection model was previously carried out on solid agar plates where the bacteriovorous C. elegans feeds on a lawn of S. aureus. However, agar-based assays are not amenable to large scale screens for antibacterial compounds. We have developed a high throughput liquid screening assay that uses robotic instrumentation to dispense a precise amount of methicillin resistant S. aureus (MRSA and worms in 384-well assay plates, followed by automated microscopy and image analysis. In validation of the liquid assay, an MRSA cell wall defective mutant, MW2ΔtarO, which is attenuated for killing in the agar-based assay, was found to be less virulent in the liquid assay. This robust assay with a Z'-factor consistently greater than 0.5 was utilized to screen the Biomol 4 compound library consisting of 640 small molecules with well characterized bioactivities. As proof of principle, 27 of the 30 clinically used antibiotics present in the library conferred increased C. elegans survival and were identified as hits in the screen. Surprisingly, the antihelminthic drug closantel was also identified as a hit in the screen. In further studies, we confirmed the anti-staphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. The liquid C. elegans-S. aureus assay described here allows screening for anti-staphylococcal compounds that are not toxic to the host.

  7. Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus.

    Science.gov (United States)

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Jayamani, Elamparithi; Kim, Younghoon; Larkins-Ford, Jonah; Conery, Annie; Ausubel, Frederick M; Mylonakis, Eleftherios

    2014-01-01

    Staphylococcus aureus, the leading cause of hospital-acquired infections in the United States, is also pathogenic to the model nematode Caenorhabditis elegans. The C. elegans-S. aureus infection model was previously carried out on solid agar plates where the bacteriovorous C. elegans feeds on a lawn of S. aureus. However, agar-based assays are not amenable to large scale screens for antibacterial compounds. We have developed a high throughput liquid screening assay that uses robotic instrumentation to dispense a precise amount of methicillin resistant S. aureus (MRSA) and worms in 384-well assay plates, followed by automated microscopy and image analysis. In validation of the liquid assay, an MRSA cell wall defective mutant, MW2ΔtarO, which is attenuated for killing in the agar-based assay, was found to be less virulent in the liquid assay. This robust assay with a Z'-factor consistently greater than 0.5 was utilized to screen the Biomol 4 compound library consisting of 640 small molecules with well characterized bioactivities. As proof of principle, 27 of the 30 clinically used antibiotics present in the library conferred increased C. elegans survival and were identified as hits in the screen. Surprisingly, the antihelminthic drug closantel was also identified as a hit in the screen. In further studies, we confirmed the anti-staphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. The liquid C. elegans-S. aureus assay described here allows screening for anti-staphylococcal compounds that are not toxic to the host.

  8. Re-sensitizing drug-resistant bacteria to antibiotics by designing Antisense Therapeutics

    Science.gov (United States)

    Courtney, Colleen; Chatterjee, Anushree

    2014-03-01

    ``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.

  9. Drug resistance in Mycobacterium leprae from patients with leprosy in China.

    Science.gov (United States)

    Liu, D; Zhang, Q; Sun, Y; Wang, C; Zhang, Y; Fu, X; Chen, M; Zhou, G; Yu, X; Wang, J; Liu, H; Zhang, F

    2015-12-01

    Previous studies of drug resistance have shown that mutations in the drug resistance-determining region (DRDR) in the Folp1, RpoB and GyrA genes of Mycobacterium leprae are responsible for resistance to dapsone, rifampin and ofloxacin, respectively. To investigate the prevalence of mutations in genes associated with drug resistance in M. leprae isolates from patients with leprosy in Shandong Province. The DRDR in the FolP1, RpoB and GyrA genes was analysed by direct sequencing of the PCR product from 85 isolates of M. leprae sampled from patients with leprosy in Shandong, China. Sequencing results were obtained for FolP1, RpoB and GyrA in 67, 57 and 81 of the 85 samples, with mutation rates of 1.5% (1/67), 8.8% 5/57 and 25.9% (21/81). Three multidrug-resistant samples were found among the new cases: one had a mutation in both Folp1 and RpoB, while the other two had a mutation in both RpoB and GyrA. Primary resistance appears to be to either single drugs or combinations of two drugs. The resistance rate to dapsone seems to be low. To our knowledge, this is the first case of multidrug-resistant M. leprae from China. © 2015 British Association of Dermatologists.

  10. Managing anthelmintic resistance-Variability in the dose of drug reaching the target worms influences selection for resistance?

    Science.gov (United States)

    Leathwick, Dave M; Luo, Dongwen

    2017-08-30

    The concentration profile of anthelmintic reaching the target worms in the host can vary between animals even when administered doses are tailored to individual liveweight at the manufacturer's recommended rate. Factors contributing to variation in drug concentration include weather, breed of animal, formulation and the route by which drugs are administered. The implications of this variability for the development of anthelmintic resistance was investigated using Monte-Carlo simulation. A model framework was established where 100 animals each received a single drug treatment. The 'dose' of drug allocated to each animal (i.e. the concentration-time profile of drug reaching the target worms) was sampled at random from a distribution of doses with mean m and standard deviation s. For each animal the dose of drug was used in conjunction with pre-determined dose-response relationships, representing single and poly-genetic inheritance, to calculate efficacy against susceptible and resistant genotypes. These data were then used to calculate the overall change in resistance gene frequency for the worm population as a result of the treatment. Values for m and s were varied to reflect differences in both mean dose and the variability in dose, and for each combination of these 100,000 simulations were run. The resistance gene frequency in the population after treatment increased as m decreased and as s increased. This occurred for both single and poly-gene models and for different levels of dominance (survival under treatment) of the heterozygote genotype(s). The results indicate that factors which result in lower and/or more variable concentrations of active reaching the target worms are more likely to select for resistance. The potential of different routes of anthelmintic administration to play a role in the development of anthelmintic resistance is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells.

    Science.gov (United States)

    Yan, Chen; Luo, Lan; Guo, Chang-Ying; Goto, Shinji; Urata, Yoshishige; Shao, Jiang-Hua; Li, Tao-Sheng

    2017-03-01

    Cancer stem cells (CSCs) are known to be drug resistant. Mitophagy selectively degrades unnecessary or damaged mitochondria by autophagy during cellular stress. To investigate the potential role of mitophagy in drug resistance in CSCs, we purified CD133 + /CD44 + CSCs from HCT8 human colorectal cancer cells and then exposed to doxorubicin (DXR). Compared with parental cells, CSCs were more resistant to DXR treatment. Although DXR treatment enhanced autophagy levels in both cell types, the inhibition of autophagy by ATG7 silencing significantly increased the toxicity of DXR only in parental cells, not in CSCs. Interestingly, the level of mitochondrial superoxide was detected to be significantly lower in CSCs than in parental cells after DXR treatment. Furthermore, the mitophagy level and expression of BNIP3L, a mitophagy regulator, were significantly higher in CSCs than in parental cells after DXR treatment. Silencing BNIP3L significantly halted mitophagy and enhanced the sensitivity to DXR in CSCs. Our data suggested that mitophagy, but not non-selective autophagy, likely contributes to drug resistance in CSCs isolated from HCT8 cells. Further studies in other cancer cell lines will be needed to confirm our findings. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells

    Directory of Open Access Journals (Sweden)

    Mark E. Issa

    2017-09-01

    Full Text Available In spite of recent therapeutic advances, multiple myeloma (MM remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs. MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND, a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.

  13. Monitoring of drug resistance amplification and attenuation with the use of tetracycline-resistant bacteria during wastewater treatment

    Science.gov (United States)

    Harnisz, Monika; Korzeniewska, Ewa; Niestępski, Sebastian; Osińska, Adriana; Nalepa, Beata

    2017-11-01

    The objective of this study was to monitor changes (amplification or attenuation) in antibiotic resistance during wastewater treatment based on the ecology of tetracycline-resistant bacteria. The untreated and treated wastewater were collected in four seasons. Number of tetracycline-(TETR) and oxytetracycline-resistant (OTCR) bacteria, their qualitative composition, minimum inhibitory concentrations (MICs), sensitivity to other antibiotics, and the presence of tet (A, B, C, D, E) resistance genes were determined. TETR and OTCR counts in untreated wastewater were 100 to 1000 higher than in treated effluent. OTCR bacterial counts were higher than TETR populations in both untreated and treated wastewater. TETR isolates were not dominated by a single bacterial genus or species, whereas Aeromonas hydrophila and Aeromonas sobria were the most common in OTCR isolates. The treatment process attenuated the drug resistance of TETR bacteria and amplified the resistance of OTCR bacteria. In both microbial groups, the frequency of tet(A) gene increased in effluent in comparison with untreated wastewater. Our results also indicate that treated wastewater is a reservoir of multiple drug-resistant bacteria as well as resistance determinants which may pose a health hazard for humans and animals when released to the natural environment.

  14. 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.

  15. 75 FR 16001 - New Animal Drugs; Removal of Obsolete and Redundant Regulations

    Science.gov (United States)

    2010-03-31

    ... drug-resistant bacteria associated with these animals, was obsolete as FDA had a new strategy and... on any approved new animal drugs, or to cause any approved new animal drug to lose its marketing ability or experience a loss of sales. C. Regulatory Flexibility Analysis The Regulatory Flexibility Act...

  16. Protease Inhibitors Drug Resistance Mutations in Turkish Patients with Chronic Hepatitis C.

    Science.gov (United States)

    Sargin Altunok, Elif; Sayan, Murat; Akhan, Sila; Aygen, Bilgehan; Yildiz, Orhan; Tekin Koruk, Suda; Mistik, Resit; Demirturk, Nese; Ural, Onur; Kose, Şükran; Aynioglu, Aynur; Korkmaz, Fatime; Ersoz, Gülden; Tuna, Nazan; Ayaz, Celal; Karakecili, Faruk; Keten, Derya; Inan, Dilara; Yazici, Saadet; Koculu, Safiye; Yildirmak, Taner

    2016-09-01

    Drug resistance development is an expected problem during treatment with protease inhibitors (PIs), this is largely due to the fact that Pls are low-genetic barrier drugs. Resistance-associated variants (RAVs) however may also occur naturally, and prior to treatment with Pls, the clinical impact of this basal resistance remains unknown. In Turkey, there is yet to be an investigation into the hepatitis C (HCV) drug associated resistance to oral antivirals. 178 antiviral-naïve patients infected with HCV genotype 1 were selected from 27 clinical centers of various geographical regions in Turkey and included in the current study. The basal NS3 Pls resistance mutations of these patients were analyzed. In 33 (18.5%) of the patients included in the study, at least one mutation pattern that can cause drug resistance was identified. The most frequently detected mutation pattern was T54S while R109K was the second most frequently detected. Following a more general examination of the patients studied, telaprevir (TVR) resistance in 27 patients (15.2%), boceprevir (BOC) resistance in 26 (14.6%) patients, simeprevir (SMV) resistance in 11 (6.2%) patients and faldaprevir resistance in 13 (7.3%) patients were detected. Our investigation also revealed that rebound developed in the presence of a Q80K mutation and amongst two V55A mutations following treatment with TVR, while no response to treatment was detected in a patient with a R55K mutation. We are of the opinion that drug resistance analyses can be beneficial and necessary in revealing which variants are responsible for pre-treatment natural resistance and which mutations are responsible for the viral breakthrough that may develop during the treatment. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Molecular detection of drug resistance in microbes by isotopic techniques: The IAEA experience

    International Nuclear Information System (INIS)

    Dar, L.; Boussaha, A.; Padhy, A.K.; Khan, B.

    2003-01-01

    The International Atomic Energy Agency (IAEA) supports various programmes on the uses of radionuclide techniques in the management of human communicable diseases. An important issue, being addressed through several technology transfer projects, is the detection of drug resistance in microbes by radioisotope based molecular-biology diagnostic procedures. The techniques employed include dot blot hybridisation with P-32 labelled oligonucleotide probes to detect point mutations, associated with drug resistance, in microbial genes amplified by the polymerase chain reaction (PCR). Molecular methods have been used for the detection of drug resistance in the malarial parasite, Plasmodium falciparum, and in Mycobacterium tuberculosis. Radioisotope based molecular-biology methods have been demonstrated to have comparative advantages in being sensitive, specific, cost-effective, and suitable for application to large-scale molecular surveillance for drug resistance. (author)

  18. Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index.

    Science.gov (United States)

    Wasserman, Sean; Meintjes, Graeme; Maartens, Gary

    2016-10-01

    Linezolid is an oxazolidinone with potent activity against M tuberculosis, and improves culture conversion and cure rates when added to treatment regimens for drug resistant tuberculosis. However, linezolid has a narrow therapeutic window, and the optimal dosing strategy that minimizes the substantial toxicity associated with linezolid's prolonged use in tuberculosis treatment has not been determined, limiting the potential impact of this anti-mycobacterial agent. This paper aims to review and summarize the current knowledge on linezolid for the treatment of drug-resistant tuberculosis. The focus is on the pharmacokinetic-pharmacodynamic determinants of linezolid's efficacy and toxicity in tuberculosis, and how this relates to defining an optimal dose. Mechanisms of linezolid toxicity and resistance, and the potential role of therapeutic drug monitoring are also covered. Expert commentary: Prospective pharmacokinetic-pharmacodynamic studies are required to define optimal therapeutic targets and to inform improved linezolid dosing strategies for drug-resistant tuberculosis.

  19. Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value

    NARCIS (Netherlands)

    Farhat, M.R.; Sultana, R.; Iartchouk, O.; Bozeman, S.; Galagan, J.; Sisk, P.; Stolte, C.; Nebenzahl-Guimaraes, H.; Jacobson, K.; Sloutsky, A.; Kaur, D.; Posey, J.; Kreiswirth, B.N.; Kurepina, N.; Rigouts, L.; Streicher, E.M.; Victor, T.C.; Warren, R.M.; Soolingen, D. van; Murray, M.

    2016-01-01

    RATIONALE: The development of molecular diagnostics that detect both the presence of Mycobacterium tuberculosis in clinical samples and drug resistance-conferring mutations promises to revolutionize patient care and interrupt transmission by ensuring early diagnosis. However, these tools require the

  20. Early Warning Indicators for Population-Based Monitoring of HIV Drug Resistance in 6 African Countries

    NARCIS (Netherlands)

    Sigaloff, Kim C. E.; Hamers, Raph L.; Menke, Jack; Labib, Moheb; Siwale, Margaret; Ive, Prudence; Botes, Mariette E.; Kityo, Cissy; Mandaliya, Kishor; Wellington, Maureen; Osibogun, Akin; Geskus, Ronald B.; Stevens, Wendy S.; van Vugt, Michèle; Rinke de Wit, Tobias F.

    2012-01-01

    Human immunodeficiency virus (HIV) RNA testing and HIV drug resistance (HIVDR) testing are not routinely available for therapeutic monitoring of patients receiving antiretroviral therapy (ART) in resource-limited settings. World Health Organization HIVDR early warning indicators (EWIs) assess ART

  1. Primary drug resistance in a region with high burden of tuberculosis. A critical problem

    Directory of Open Access Journals (Sweden)

    Cecilia Villa-Rosas

    2015-03-01

    Full Text Available Objective. To determine rates of drug resistance in new cases of pulmonary tuberculosis in a region with a high burden of the disease. Materials and methods. New case suspects were referred for drug susceptibility testing. Results. 28.9% of new cases were resistant to at least one first line drug; 3.9% had a multidrug-resistant strain, 15.6% a monoresistant strain and 9.4% a polyresistant strain. Conclusion. Our rate of drug resistant tuberculosis in new cases is very high; this has important clinical implications, since even monoresistance can have a negative impact on the outcome of new cases treated empirically with a six month regimen.

  2. Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis

    KAUST Repository

    Coll, Francesc; Phelan, Jody; Hill-Cawthorne, Grant A.; Nair, Mridul; Mallard, Kim; Ali, Shahjahan; Abdallah, Abdallah; Alghamdi, Saad; Alsomali, Mona; Ahmed, Abdallah O.; Portelli, Stephanie; Oppong, Yaa; Alves, Adriana; Bessa, Theolis Barbosa; Campino, Susana; Caws, Maxine; Chatterjee, Anirvan; Crampin, Amelia C.; Dheda, Keertan; Furnham, Nicholas; Glynn, Judith R.; Grandjean, Louis; Minh Ha, Dang; Hasan, Rumina; Hasan, Zahra; Hibberd, Martin L.; Joloba, Moses; Jones-Ló pez, Edward C.; Matsumoto, Tomoshige; Miranda, Anabela; Moore, David J.; Mocillo, Nora; Panaiotov, Stefan; Parkhill, Julian; Penha, Carlos; Perdigã o, Joã o; Portugal, Isabel; Rchiad, ‍ Zineb; Robledo, Jaime; Sheen, Patricia; Shesha, Nashwa Talaat; Sirgel, Frik A.; Sola, Christophe; Oliveira Sousa, Erivelton; Streicher, Elizabeth M.; Helden, Paul Van; Viveiros, Miguel; Warren, Robert M.; McNerney, Ruth; Pain, Arnab; Clark, Taane G.

    2018-01-01

    To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed

  3. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences

    KAUST Repository

    Coll, Francesc; McNerney, Ruth; Preston, Mark D; Guerra-Assunç ã o, José Afonso; Warry, Andrew; Hill-Cawthorne, Grant A.; Mallard, Kim; Nair, Mridul; Miranda, Anabela; Alves, Adriana; Perdigã o, Joã o; Viveiros, Miguel; Portugal, Isabel; Hasan, Zahra; Hasan, Rumina; Glynn, Judith R; Martin, Nigel; Pain, Arnab; Clark, Taane G

    2015-01-01

    Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data

  4. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Juan D Unciti-Broceta

    2015-06-01

    Full Text Available African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

  5. Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids

    Directory of Open Access Journals (Sweden)

    Susu He

    2016-12-01

    Full Text Available The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance.

  6. Cooperative Antibiotic Resistance in a Multi-Drug Environment

    Science.gov (United States)

    Yurtsev, Eugene; Dai, Lei; Gore, Jeff

    2013-03-01

    The emergence of antibiotic resistance in bacteria is a significant health concern. A frequent mechanism of antibiotic resistance involves the production of an enzyme which inactivates the antibiotic. By inactivating the antibiotic, resistant cells can ``share'' their resistance with other cells in the bacterial population, suggesting that it may be possible to observe cooperation between strains that inactivate different antibiotics. Here, we experimentally track the population dynamics of two E. coli strains in the presence of two different antibiotics. We find that together the strains are able to grow in antibiotic concentrations that inhibit growth of either of the strains individually. We observe that even when there is stable coexistence between the two strains, the population size of each strain can undergo large oscillations. We expect that our results will provide insight into the evolution of antibiotic resistance and the evolutionary origin of phenotypic diversity and cooperative behaviors.

  7. Genome Analysis of the First Extensively Drug-Resistant (XDR Mycobacterium tuberculosis in Malaysia Provides Insights into the Genetic Basis of Its Biology and Drug Resistance.

    Directory of Open Access Journals (Sweden)

    Chee Sian Kuan

    Full Text Available The outbreak of extensively drug-resistant tuberculosis (XDR-TB has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia.

  8. Alarming levels of drug-resistant tuberculosis in HIV-infected patients in metropolitan Mumbai, India.

    Science.gov (United States)

    Isaakidis, Petros; Das, Mrinalini; Kumar, Ajay M V; Peskett, Christopher; Khetarpal, Minni; Bamne, Arun; Adsul, Balkrishna; Manglani, Mamta; Sachdeva, Kuldeep Singh; Parmar, Malik; Kanchar, Avinash; Rewari, B B; Deshpande, Alaka; Rodrigues, Camilla; Shetty, Anjali; Rebello, Lorraine; Saranchuk, Peter

    2014-01-01

    Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India. A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases. Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%-40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models. The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and

  9. Alarming levels of drug-resistant tuberculosis in HIV-infected patients in metropolitan Mumbai, India.

    Directory of Open Access Journals (Sweden)

    Petros Isaakidis

    Full Text Available BACKGROUND: Drug-resistant tuberculosis (DR-TB is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug in patients attending public antiretroviral treatment (ART centers in greater metropolitan Mumbai, India. METHODS: A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST against all first and second-line TB-drugs using phenotypic liquid culture (MGIT were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases. RESULTS: Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4% were smear-positive and 202 (12% had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%-40% TB-patients. The proportions of DR-TB were 25% (29/114 and 44% (39/88 among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB, 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable, 6% extensively drug-resistant (XDR-TB and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug. Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models. CONCLUSION: The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing

  10. The Role of ABC Proteins in Drug Resistant Breast Cancer Cells

    Science.gov (United States)

    2008-04-01

    called the Plasmodium falciparum Chloroquine Transporter (PfCRT). While PfCRT is known to be the main molecular determinant of chloroquine resistance...proteins (such as human P-glycoprotein) and labeled PfCRT with a photoaffinity drug analogue . A manuscript is currently in preparation detailing my results...directly responsible for drug response, the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) (Fidock et al 2000). While not a member of

  11. Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0600 TITLE: Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers PRINCIPAL INVESTIGATOR: Dr...2017 4. TITLE AND SUBTITLE Dissecting the Mechanisms of Drug Resistance in BRCA1/2- Mutant Breast Cancers 5a. CONTRACT NUMBER W81XWH-16-1-0600 5b...therapeutic modality for targeting homologous recombination (HR) deficient tumors such as BRCA1 and BRCA2-mutated triple negative breast cancers

  12. Fluorometric assay for phenotypic differentiation of drug-resistant HIV mutants

    OpenAIRE

    Zhu, Qinchang; Yu, Zhiqiang; Kabashima, Tsutomu; Yin, Sheng; Dragusha, Shpend; El-Mahdy, Ahmed F. M.; Ejupi, Valon; Shibata, Takayuki; Kai, Masaaki

    2015-01-01

    Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates f...

  13. Decreasing prevalence of multi-drugs resistant Mycobacterium tuberculosis in Nashik City, India

    Directory of Open Access Journals (Sweden)

    Arun P. More

    2013-03-01

    Full Text Available Objective: In India, increasing prevalence of multi-drug resistant tuberculosis (MDR has aggravated the control oftuberculosis problem. In many urban and semi-urban regions of India, no surveillance data of multidrug resistance inMycobacterium tuberculosisis available.Methods: A surveillance study on multidrug resistance was carried out in semi-urban and rural regions in and aroundNashik City of Maharashtra, India. The surveillance study was conducted in this region found that the prevalence ofcombined resistance to first and second-line anti-tuberculosis drugs is remarkably high. The isolates of M. tuberculosiswas identified and subjected to drug susceptibility testing. The patterns of drug susceptibility of isolates of M. tuberculosisduring the periods 2000 and 2004 were compared with drug susceptibility patterns of the organisms during theperiod 2008 to 2011.Results: The 260 isolates identified as M. tuberculosis show mean drug resistance prevalence of 45.6% for more than anytwo drugs and the MDR rate as 37% in the years 2000 to 2004 whereas 305 isolates of the organism show mean drugresistance prevalence of 30.2% and the MDR rate as 25% in the years 2008 to 2011.Conclusion: The researcher found that, though the prevalence of multidrug resistance to the drugs tested is remarkablyhigh, it has come down noticeably during the past seven years due to efforts of State Government and strict implementationof treatment guidelines of WHO by the physicians. J Microbiol Infect Dis 2013; 3(1: 12-17Key words: MDR-TB, XDR-TB, DOTS, drug-resistance prevalence rate.

  14. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro.

    Science.gov (United States)

    Khdair, Ayman; Handa, Hitesh; Mao, Guangzhao; Panyam, Jayanth

    2009-02-01

    Drug resistance limits the success of many anticancer drugs. Reduced accumulation of the drug at its intracellular site of action because of overexpression of efflux transporters such as P-glycoprotein (P-gp) is a major mechanism of drug resistance. In this study, we investigated whether photodynamic therapy (PDT) using methylene blue, also a P-gp inhibitor, can be used to enhance doxorubicin-induced cytotoxicity in drug-resistant tumor cells. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier for the simultaneous cellular delivery of doxorubicin and methylene blue. Methylene blue was photoactivated using light of 665 nm wavelength. Induction of apoptosis and necrosis following treatment with combination chemotherapy and PDT was investigated in drug-resistant NCI/ADR-RES cells using flow cytometry and fluorescence microscopy. Effect of encapsulation in nanoparticles on the intracellular accumulation of doxorubicin and methylene blue was investigated qualitatively using fluorescence microscopy and was quantitated using HPLC. Encapsulation in AOT-alginate nanoparticles significantly enhanced the cytotoxicity of combination therapy in resistant tumor cells. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs. Further, nanoparticle-mediated combination therapy resulted in significantly elevated reactive oxygen species (ROS) production compared to single drug treatment. In conclusion, nanoparticle-mediated combination chemotherapy and PDT using doxorubicin and methylene blue was able to overcome resistance mechanisms and resulted in improved cytotoxicity in drug-resistant tumor cells.

  15. Clinical and molecular surveillance of drug resistant vivax malaria in Myanmar (2009-2016).

    Science.gov (United States)

    Nyunt, Myat Htut; Han, Jin-Hee; Wang, Bo; Aye, Khin Myo; Aye, Kyin Hla; Lee, Seong-Kyun; Htut, Ye; Kyaw, Myat Phone; Han, Kay Thwe; Han, Eun-Taek

    2017-03-16

    One of the major challenges for control and elimination of malaria is ongoing spread and emergence of drug resistance. While epidemiology and surveillance of the drug resistance in falciparum malaria is being explored globally, there are few studies on drug resistance vivax malaria. To assess the spread of drug-resistant vivax malaria in Myanmar, a multisite, prospective, longitudinal study with retrospective analysis of previous therapeutic efficacy studies, was conducted. A total of 906 from nine study sites were included in retrospective analysis and 208 from three study sites in prospective study. Uncomplicated vivax mono-infected patients were recruited and monitored with longitudinal follow-up until day 28 after treatment with chloroquine. Amplification and sequence analysis of molecular markers, such as mutations in pvcrt-O, pvmdr1, pvdhps and pvdhfr, were done in day-0 samples in prospective study. Clinical failure cases were found only in Kawthaung, southern Myanmar and western Myanmar sites within 2009-2016. Chloroquine resistance markers, pvcrt-O 'AAG' insertion and pvmdr1 mutation (Y976F) showed higher mutant rate in southern and central Myanmar than western site: 66.7, 72.7 vs 48.3% and 26.7, 17.0 vs 1.7%, respectively. A similar pattern of significantly higher mutant rate of antifolate resistance markers, pvdhps (S382A, K512M, A553G) and pvdhfr (F57L/I, S58R, T61M, S117T/N) were noted. Although clinical failure rate was low, widespread distribution of chloroquine and antifolate resistance molecular makers alert to the emergence and spread of drug resistance vivax malaria in Myanmar. Proper strategy and action plan to eliminate and contain the resistant strain strengthened together with clinical and molecular surveillance on drug resistance vivax is recommended.

  16. Comparison of the pharmacokinetics of two dosage regimens of linezolid in multidrug-resistant and extensively drug-resistant tuberculosis patients.

    NARCIS (Netherlands)

    Alffenaar, J.W.C.; Altena, R. van; Harmelink, I.M.; Filguera, P.; Molenaar, E.; Wessels, A.M.; Soolingen, D. van; Kosterink, J.G.W.; Uges, D.R.A.; Werf, T.S. van der

    2010-01-01

    BACKGROUND AND OBJECTIVES: For the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), potent new drugs are urgently needed. Linezolid is a promising drug, but its use is limited by adverse effects with prolonged administration of 600 mg twice daily. In

  17. Comparison of the Pharmacokinetics of Two Dosage Regimens of Linezolid in Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Patients

    NARCIS (Netherlands)

    Alffenaar, Jan-Willem C.; van Altena, Richard; Harmelink, Ilse M.; Filguera, Patricia; Molenaar, Esther; Wessels, A. Mireille A.; van Soolingen, Dick; Kosterink, Jos G. W.; Uges, Donald R. A.; van der Werf, Tjip S.

    2010-01-01

    Background and Objectives: For the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), potent new drugs are urgently needed. Linezolid is a promising drug, but its use is limited by adverse effects with prolonged administration of 600 mg twice daily. In

  18. Acid-fast bacilli culture positivity and drug resistance in abdominal tuberculosis in Mumbai, India.

    Science.gov (United States)

    Samant, Hrishikesh; Desai, Devendra; Abraham, Philip; Joshi, Anand; Gupta, Tarun; Rodrigues, Camilla; George, Siji

    2014-09-01

    Culture positivity for Mycobacterium tuberculosis complex (MTB) in abdominal tuberculosis (TB) using Lowenstein Jensen medium and Bactec system varies from 25 % to 36 %. Data on the prevalence of drug resistance in primary abdominal TB is scant. Our aim was to study the acid-fast bacilli (AFB) culture positivity rate in primary abdominal TB using Bactec Mycobacterial Growth Indicator Tubes (MGIT) system and the prevalence of drug resistance in these patients. Records of patients with abdominal TB (diagnosed on clinical features, endoscopy, histology, microbiology) seen during the period 2008 to 2013 were retrieved from the Gastroenterology and Microbiology departments. Patients with extra-abdominal TB (five pulmonary, two nodal), adnexal (one), and HIV (one) were excluded from analysis. Of 61 patients, 31 (50.8 %) had a positive AFB culture. In the 30 culture-negative patients, histology showed non-caseating granulomas in 25 patients. Drug sensitivity pattern was analyzed in 18 patients; resistance was detected in eight (14.3 % of all patients and 44.4 % of patients in whom drug sensitivity was done) including three (5.4 % of all subjects and 16.6 % in whom drug sensitivity was available) who were multidrug-resistant. The rate of AFB culture positivity in primary abdominal TB was 50.8 % using Bactec MGIT. Likelihood of drug resistance was seen in 14.3 %, of whom 5.4 % were multidrug-resistant.

  19. Treatment of a solid tumor using engineered drug-resistant immunocompetent cells and cytotoxic chemotherapy.

    Science.gov (United States)

    Dasgupta, Anindya; Shields, Jordan E; Spencer, H Trent

    2012-07-01

    Multimodal therapy approaches, such as combining chemotherapy agents with cellular immunotherapy, suffers from potential drug-mediated toxicity to immune effector cells. Overcoming such toxic effects of anticancer cellular products is a potential critical barrier to the development of combined therapeutic approaches. We are evaluating an anticancer strategy that focuses on overcoming such a barrier by genetically engineering drug-resistant variants of immunocompetent cells, thereby allowing for the coadministration of cellular therapy with cytotoxic chemotherapy, a method we refer to as drug-resistant immunotherapy (DRI). The strategy relies on the use of cDNA sequences that confer drug resistance and recombinant lentiviral vectors to transfer nucleic acid sequences into immunocompetent cells. In the present study, we evaluated a DRI-based strategy that incorporates the immunocompetent cell line NK-92, which has intrinsic antitumor properties, genetically engineered to be resistant to both temozolomide and trimetrexate. These immune effector cells efficiently lysed neuroblastoma cell lines, which we show are also sensitive to both chemotherapy agents. The antitumor efficacy of the DRI strategy was demonstrated in vivo, whereby neuroblastoma-bearing NOD/SCID/γ-chain knockout (NSG) mice treated with dual drug-resistant NK-92 cell therapy followed by dual cytotoxic chemotherapy showed tumor regression and significantly enhanced survival compared with animals receiving either nonengineered cell-based therapy and chemotherapy, immunotherapy alone, or chemotherapy alone. These data show there is a benefit to using drug-resistant cellular therapy when combined with cytotoxic chemotherapy approaches.

  20. PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

    Science.gov (United States)

    Burke, Amy C; Dron, Jacqueline S; Hegele, Robert A; Huff, Murray W

    2017-01-06

    Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

  1. Infection control, genetic assessment of drug resistance and drug susceptibility testing in the current management of multidrug/extensively-resistant tuberculosis (M/XDR-TB) in Europe

    DEFF Research Database (Denmark)

    Bothamley, Graham H.; Lange, Christoph; Albrecht, Dirk

    2017-01-01

    AIM: Europe has the highest documented caseload and greatest increase in multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) of all World Health Organization (WHO) regions. This survey examines how recommendations for M/XDR-TB management are being implemented. METHODS: TBNET is a pan...

  2. Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture

    Directory of Open Access Journals (Sweden)

    Tatsuya Usui

    2018-04-01

    Full Text Available Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air–liquid interface (ALI method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU and Irinotecan. Here, we investigate which inhibitor for stem cell-related signal improves the sensitivity for anti-cancer drug treatment in tumor ALI organoids. Treatment with Hedgehog signal inhibitors (AY9944, GANT61 decreases the cell viability of organoids compared with Notch (YO-01027, DAPT and Wnt (WAV939, Wnt-C59 signal inhibitors. Combination treatment of AY9944 or GANT61 with 5-FU, Irinotecan or Oxaliplatin decreases the cell viability of tumor organoids compared with each anti-cancer drug alone treatment. Treatment with AY9944 or GANT61 inhibits expression of stem cell markers c-Myc, CD44 and Nanog, likely through the decrease of their transcription factor, GLI-1 expression. Combination treatment of AY9944 or GANT61 with 5-FU or Irinotecan also prevents colony formation of colorectal cancer cell lines HCT116 and SW480. These findings suggest that Hedgehog signals mediate anti-cancer drug resistance in colorectal tumor patient-derived ALI organoids and that the inhibitors are useful as a combinational therapeutic strategy against colorectal cancer.

  3. [From the discovery of antibiotics to emerging highly drug-resistant bacteria].

    Science.gov (United States)

    Meunier, Olivier

    2015-01-01

    The discovery of antibiotics has enabled serious infections to be treated. However, bacteria resistant to several families of antibiotics and the emergence of new highly drug-resistant bacteria constitute a public health issue in France and across the world. Actions to prevent their transmission are being put in place. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  4. 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

  5. Plasmid Conjugation in E. coli and Drug Resistance

    African Journals Online (AJOL)

    Prof. Ogunji

    2Department of Pharmaceutics and Pharmaceutical Microbiology, Ahmadu Bello University, Zaria ... decreasing the emergence of resistant bacteria strains within our environment. ..... Cowan and Steel's Manual for the Identification of Medical.

  6. Rapid detection of drug resistance and mutational patterns of extensively drug-resistant strains by a novel GenoType® MTBDRsl assay

    Directory of Open Access Journals (Sweden)

    A K Singh

    2013-01-01

    Full Text Available Background: The emergence of extensively drug-resistant tuberculosis (XDR-TB is a major concern in the India. The burden of XDR-TB is increasing due to inadequate monitoring, lack of proper diagnosis, and treatment. The GenoType ® Mycobacterium tuberculosis drug resistance second line (MTBDRsl assay is a novel line probe assay used for the rapid detection of mutational patterns conferring resistance to XDR-TB. Aim: The aim of this study was to study the rapid detection of drug resistance and mutational patterns of the XDR-TB by a novel GenoType ® MTBDRsl assay. Materials and Methods: We evaluated 98 multidrug-resistant (MDR M. tuberculosis isolates for second line drugs susceptibility testing by 1% proportion method (BacT/ALERT 3D system and GenoType ® MTBDRsl assay for rapid detection of conferring drug resistance to XDR-TB. Results: A total of seven (17.4% were identified as XDR-TB by using standard phenotypic method. The concordance between phenotypic and GenoType ® MTBDRsl assay was 91.7-100% for different antibiotics. The sensitivity and specificity of the MTBDRsl assay were 100% and 100% for aminoglycosides; 100% and 100% for fluoroquinolones; 91.7% and 100% for ethambutol. The most frequent mutations and patterns were gyrA MUT1 (A90V in seven (41.2% and gyrA + WT1-3 + MUT1 in four (23.5%; rrs MUT1 (A1401G in 11 (64.7%, and rrs WT1-2 + MUT1 in eight (47.1%; and embB MUT1B (M306V in 11 (64.7% strains. Conclusions: These data suggest that the GenoType ® MTBDRsl assay is rapid, novel test for detection of resistance to second line anti-tubercular drugs. This assay provides additional information about the frequency and mutational patterns responsible for XDR-TB resistance.

  7. Drug resistance plasmids in Lactobacillus acidophilus and Lactobacillus reuteri.

    OpenAIRE

    Vescovo, M; Morelli, L; Bottazzi, V

    1982-01-01

    Sixteen strains of Lactobacillus reuteri and 20 strains of Lactobacillus acidophilus were tested for resistance to 22 antibiotics by using commercially available sensitivity disks. Evidence suggesting linkage of these resistances to plasmids was obtained by "curing" experiments with acridine dyes and high growth temperatures. Examination of plasmid patterns of agarose gel electrophoresis provided further evidence of loss in plasmid DNA under curing conditions in some of the strains examined.

  8. Signaling to P-glycoprotein-A new therapeutic target to treat drug-resistant epilepsy?

    NARCIS (Netherlands)

    Hartz, A.M.; Notenboom, S.; Bauer, B.

    2009-01-01

    Epilepsy affects more than 60 million people worldwide. While most patients can be treated with antiepileptic drugs, up to 40% of patients respond poorly to pharmacotherapy. This drug resistance is not well understood and presents a major clinical problem. In this short review we provide background

  9. Resistance to anticoccidial drugs : Alternative strategies to control coccidiosis in broilers

    NARCIS (Netherlands)

    Peek, H.W.

    2010-01-01

    Manuscripts documenting the occurrence of resistance against all commonly used anticoccidial drugs abroad, together with the high incidence of clinical coccidiosis in the field (60-90% of flocks) in the Netherlands, were the reasons to start investigations on the occurrence of anticoccidial drug

  10. Drug resistance in vectorborne parasites: multiple actors and scenarios for an evolutionary arms race.

    Science.gov (United States)

    Vanaerschot, Manu; Huijben, Silvie; Van den Broeck, Frederik; Dujardin, Jean-Claude

    2014-01-01

    Drug-resistant pathogens emerge faster than new drugs come out of drug discovery pipelines. Current and future drug options should therefore be better protected, requiring a clear understanding of the factors that contribute to the natural history of drug resistance. Although many of these factors are relatively well understood for most bacteria, this proves to be more complex for vectorborne parasites. In this review, we discuss considering three key models (Plasmodium, Leishmania and Schistosoma) how drug resistance can emerge, spread and persist. We demonstrate a multiplicity of scenarios, clearly resulting from the biological diversity of the different organisms, but also from the different modes of action of the drugs used, the specific within- and between-host ecology of the parasites, and environmental factors that may have direct or indirect effects. We conclude that integrated control of drug-resistant vectorborne parasites is not dependent upon chemotherapy only, but also requires a better insight into the ecology of these parasites and how their transmission can be impaired. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

  11. Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance

    NARCIS (Netherlands)

    Moreno-Gamez, Stefany; Hill, Alison L.; Rosenbloom, Daniel I. S.; Petrov, Dmitri A.; Nowak, Martin A.; Pennings, Pleuni S.

    2015-01-01

    Infections with rapidly evolving pathogens are often treated using combinations of drugs with different mechanisms of action. One of the major goal of combination therapy is to reduce the risk of drug resistance emerging during a patient's treatment. Although this strategy generally has significant

  12. Towards appropriate design solutions for drug-resistant TB facilities in SA

    CSIR Research Space (South Africa)

    Parsons, SA

    2010-07-01

    Full Text Available South Africa has a high and increasing burden of both drugs-susceptible and drug-resistant tuberculosis. This disease has been declared an emergency in Africa. South Africa has committed itself to addressing this national crises by designing...

  13. a meta-analysis of drug resistant tuberculosis in sub-saharan africa

    African Journals Online (AJOL)

    GB

    2013-11-03

    Nov 3, 2013 ... challenge because of the emergence of drug resistant TB strains and the high prevalence of HIV ... The risk ratios for each included study and for the pooled ... treatment warrants special emphasis, and screening for anti-TB drugs sensitivity .... the titles and abstracts. •. 92 were not directly related to our topic.

  14. Decreasing prevalence of multi-drugs resistant Mycobacterium tuberculosis in Nashik City, India

    OpenAIRE

    More, Arun Punaji; Nagdawane, Ramkrishna Panchamrao; Gangurde, Aniket K

    2013-01-01

    Objective: In India, increasing prevalence of multi-drug resistant tuberculosis (MDR) has aggravated the control oftuberculosis problem. In many urban and semi-urban regions of India, no surveillance data of multidrug resistance inMycobacterium tuberculosisis available.Methods: A surveillance study on multidrug resistance was carried out in semi-urban and rural regions in and aroundNashik City of Maharashtra, India. The surveillance study was conducted in this region found that the prevalence...

  15. Drug Resistance Patterns of Escherichia coli in Ethiopia: A Meta-Analysis.

    Science.gov (United States)

    Tuem, Kald Beshir; Gebre, Abadi Kahsu; Atey, Tesfay Mehari; Bitew, Helen; Yimer, Ebrahim M; Berhe, Derbew Fikadu

    2018-01-01

    Antimicrobial drug resistance is a global threat for treatment of infectious diseases and costs life and money and threatens health delivery system's effectiveness. The resistance of E. coli to frequently utilized antimicrobial drugs is becoming a major challenge in Ethiopia. However, there is no inclusive countrywide study. Therefore, this study intended to assess the prevalence of E. coli resistance and antimicrobial-specific resistance pattern among E. coli clinical isolates in Ethiopia. Articles were retrieved from PubMed, Embase, and grey literature from 2007 to 2017. The main outcome measures were overall E. coli and drug-specific resistance patterns. A random-effects model was used to determine pooled prevalence with 95% confidence interval (CI), using DerSimonian and Laird method. In addition, subgroup analysis was conducted to improve the outcome. The study bias was assessed by Begg's funnel plot. This study was registered in PROSPERO as follows: PROSPERO 2017: CRD42017070106. Of 164 articles retrieved, 35 articles were included. A total of 19,235 study samples participated in the studies and 2,635 E. coli strains were isolated. Overall, E. coli antibacterial resistance was 45.38% (95% confidence interval (CI): 33.50 to 57.27). The resistance pattern ranges from 62.55% in Addis Ababa to 27.51% in Tigray region. The highest resistance of E. coli reported was to ampicillin (83.81%) and amoxicillin (75.79%), whereas only 13.55% of E. coli isolates showed resistance to nitrofurantoin. E. coli antimicrobial resistance remains high with disparities observed among regions. The bacterium was found to be highly resistant to aminopenicillins. The finding implies the need for effective prevention strategies for the E. coli drug resistance and calls for multifaceted approaches with full involvement of all stakeholders.

  16. MRP- and BCL-2-mediated drug resistance in human SCLC: effects of apoptotic sphingolipids in vitro.

    Science.gov (United States)

    Khodadadian, M; Leroux, M E; Auzenne, E; Ghosh, S C; Farquhar, D; Evans, R; Spohn, W; Zou, Y; Klostergaard, J

    2009-10-01

    Multidrug-resistance-associated protein (MRP) and BCL-2 contribute to drug resistance expressed in SCLC. To establish whether MRP-mediated drug resistance affects sphingolipid (SL)-induced apoptosis in SCLC, we first examined the human SCLC cell line, UMCC-1, and its MRP over-expressing, drug-resistant subline, UMCC-1/VP. Despite significantly decreased sensitivity to doxorubicin (Dox) and to the etoposide, VP-16, the drug-selected line was essentially equally as sensitive to treatment with exogenous ceramide (Cer), sphingosine (Sp) or dimethyl-sphingosine (DMSP) as the parental line. Next, we observed that high BCL-2-expressing human H69 SCLC cells, that were approximately 160-fold more sensitive to Dox than their combined BCL-2 and MRP-over-expressing (H69AR) counterparts, were only approximately 5-fold more resistant to DMSP. Time-lapse fluorescence microscopy of either UMCC cell line treated with DMSP-Coumarin revealed comparable extents and kinetics of SL uptake, further ruling out MRP-mediated effects on drug uptake. DMSP potentiated the cytotoxic activity of VP-16 and Taxol, but not Dox, in drug-resistant UMCC-1/VP cells. However, this sensitization did not appear to involve DMSP-mediated effects on the function of MRP in drug export; nor did DMSP strongly shift the balance of pro-apoptotic Sps and anti-apoptotic Sp-1-Ps in these cells. We conclude that SL-induced apoptosis markedly overcomes or bypasses MRP-mediated drug resistance relevant to SCLC and may suggest a novel therapeutic approach to chemotherapy for these tumors.

  17. Drug-resistant tuberculosis among HIV-infected patients starting antiretroviral therapy in Durban, South Africa.

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    Jeffrey K Hom

    Full Text Available To estimate the prevalence of drug-resistant tuberculosis (TB and describe the resistance patterns in patients commencing antiretroviral therapy (ART in an HIV clinic in Durban, South Africa.Cross-sectional cohort study.Consecutive HIV-infected adults (≥ 18y/o initiating HIV care were enrolled from May 2007-May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium. Positive cultures were tested for susceptibility to first- and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed.1,035 subjects had complete culture results. Median CD4 count was 92/µl (IQR 42-150/µl. 267 subjects (26% reported a prior history of TB and 210 (20% were receiving TB treatment at enrollment; 191 (18% subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0-12.4. Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9-30.5 compared to 5.2% (95% CI 2.1-8.9 among those with no prior TB. 5.1% (95% CI 2.4-9.5 had rifampin or rifampin plus INH resistance.The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence.

  18. Antiretroviral drug resistance in HIV-1 therapy-naive patients in Cuba.

    Science.gov (United States)

    Pérez, Lissette; Kourí, Vivian; Alemán, Yoan; Abrahantes, Yeisel; Correa, Consuelo; Aragonés, Carlos; Martínez, Orlando; Pérez, Jorge; Fonseca, Carlos; Campos, Jorge; Álvarez, Delmis; Schrooten, Yoeri; Dekeersmaeker, Nathalie; Imbrechts, Stijn; Beheydt, Gertjan; Vinken, Lore; Soto, Yudira; Álvarez, Alina; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2013-06-01

    In Cuba, antiretroviral therapy rollout started in 2001 and antiretroviral therapy coverage has reached almost 40% since then. The objectives of this study were therefore to analyze subtype distribution, and level and patterns of drug resistance in therapy-naive HIV-1 patients. Four hundred and one plasma samples were collected from HIV-1 therapy-naive patients in 2003 and in 2007-2011. HIV-1 drug resistance genotyping was performed in the pol gene and drug resistance was interpreted according to the WHO surveillance drug-resistance mutations list, version 2009. Potential impact on first-line therapy response was estimated using genotypic drug resistance interpretation systems HIVdb version 6.2.0 and Rega version 8.0.2. Phylogenetic analysis was performed using Neighbor-Joining. The majority of patients were male (84.5%), men who have sex with men (78.1%) and from Havana City (73.6%). Subtype B was the most prevalent subtype (39.3%), followed by CRF20-23-24_BG (19.5%), CRF19_cpx (18.0%) and CRF18_cpx (10.3%). Overall, 29 patients (7.2%) had evidence of drug resistance, with 4.0% (CI 1.6%-4.8%) in 2003 versus 12.5% (CI 7.2%-14.5%) in 2007-2011. A significant increase in drug resistance was observed in recently HIV-1 diagnosed patients, i.e. 14.8% (CI 8.0%-17.0%) in 2007-2011 versus 3.8% (CI 0.9%-4.7%) in 2003 (OR 3.9, CI 1.5-17.0, p=0.02). The majority of drug resistance was restricted to a single drug class (75.8%), with 55.2% patients displaying nucleoside reverse transcriptase inhibitor (NRTI), 10.3% non-NRTI (NNRTI) and 10.3% protease inhibitor (PI) resistance mutations. Respectively, 20.7% and 3.4% patients carried viruses containing drug resistance mutations against NRTI+NNRTI and NRTI+NNRTI+PI. The first cases of resistance towards other drug classes than NRTI were only detected from 2008 onwards. The most frequent resistance mutations were T215Y/rev (44.8%), M41L (31.0%), M184V (17.2%) and K103N (13.8%). The median genotypic susceptibility score for the

  19. Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and long-term outcome

    Directory of Open Access Journals (Sweden)

    Dollfus Catherine

    2009-09-01

    Full Text Available Abstract Background Primary-HIV-1-infection in newborns that occurs under antiretroviral prophylaxis that is a high risk of drug-resistance acquisition. We examine the frequency and the mechanisms of resistance acquisition at the time of infection in newborns. Patients and Methods We studied HIV-1-infected infants born between 01 January 1997 and 31 December 2004 and enrolled in the ANRS-EPF cohort. HIV-1-RNA and HIV-1-DNA samples obtained perinatally from the newborn and mother were subjected to population-based and clonal analyses of drug resistance. If positive, serial samples were obtained from the child for resistance testing. Results Ninety-two HIV-1-infected infants were born during the study period. Samples were obtained from 32 mother-child pairs and from another 28 newborns. Drug resistance was detected in 12 newborns (20%: drug resistance to nucleoside reverse transcriptase inhibitors was seen in 10 cases, non-nucleoside reverse transcriptase inhibitors in two cases, and protease inhibitors in one case. For 9 children, the detection of the same resistance mutations in mothers' samples (6 among 10 available and in newborn lymphocytes (6/8 suggests that the newborn was initially infected by a drug-resistant strain. Resistance variants were either transmitted from mother-to-child or selected during subsequent temporal exposure under suboptimal perinatal prophylaxis. Follow-up studies of the infants showed that the resistance pattern remained stable over time, regardless of antiretroviral therapy, suggesting the early cellular archiving of resistant viruses. The absence of resistance in the mother of the other three children (3/10 and neonatal lymphocytes (2/8 suggests that the newborns were infected by a wild-type strain without long-term persistence of resistance when suboptimal prophylaxis was stopped. Conclusion This study confirms the importance of early resistance genotyping of HIV-1-infected newborns. In most cases (75%, drug

  20. Metabolomics As a Tool for the Characterization of Drug-Resistant Epilepsy

    OpenAIRE

    Federica Murgia; Antonella Muroni; Monica Puligheddu; Lorenzo Polizzi; Luigi Barberini; Gianni Orofino; Paolo Solla; Simone Poddighe; Simone Poddighe; Francesco Del Carratore; Francesco Del Carratore; Julian L. Griffin; Luigi Atzori; Francesco Marrosu

    2017-01-01

    PurposeDrug resistance is a critical issue in the treatment of epilepsy, contributing to clinical emergencies and increasing both serious social and economic burdens on the health system. The wide variety of potential drug combinations followed by often failed consecutive attempts to match drugs to an individual patient may mean that this treatment stage may last for years with suboptimal benefit to the patient. Given these challenges, it is valuable to explore the availability of new methodo...

  1. Metabolomics as a Tool for the characterization of Drug-resistant epilepsy

    OpenAIRE

    Murgia, Federica; Muroni, Antonella; Puligheddu, Monica; Polizzi, Lorenzo; Barberini, Luigi; Orofino, Gianni; Solla, Paolo; Poddighe, Simone; Carratore, Francesco Del; Griffin, Julian L.; Atzori, Luigi; Marrosu, Francesco

    2017-01-01

    Purpose: Drug resistance is a critical issue in the treatment of epilepsy, contributing to clinical emergencies and increasing both serious social and economic burdens on the health system. The wide variety of potential drug combinations followed by often failed consecutive attempts to match drugs to an individual patient may mean that this treatment stage may last for years with suboptimal benefit to the patient. Given these challenges, it is valuable to explore the availability of new metho...

  2. New Treatments for Drug-Resistant Epilepsy that Target Presynaptic Transmitter Release

    Science.gov (United States)

    2015-07-01

    may become a key piece in the arsenal of antiepileptic drugs in mesial temporal lobe epilepsy . Thereby, screening for a presynaptic action site may be...neuronal damage, mesial temporal lobe epilepsy (MTLE) in ~30% of patients, and resistance to available anticonvulsant drugs. Therefore, it is of... temporal lobe epilepsy (MTLE) (months 1-12). Working hypothesis: Drugs acting on presynaptic Ca 2+ channels, autoreceptors, and SV2a will be more

  3. MiR-285 targets P450 (CYP6N23) to regulate pyrethroid resistance in Culex pipiens pallens.

    Science.gov (United States)

    Tian, Mengmeng; Liu, Bingqian; Hu, Hongxia; Li, Xixi; Guo, Qin; Zou, Feifei; Liu, Xianmiao; Hu, Mengxue; Guo, Juxin; Ma, Lei; Zhou, Dan; Sun, Yan; Shen, Bo; Zhu, Changliang

    2016-12-01

    MicroRNAs play critical roles in post-transcriptional regulation of gene expression, which participate in the modulation of almost all of the cellular processes. Although emerging evidence indicates that microRNAs are related with antineoplastic drugs resistance, whether microRNAs are responsible for insecticide resistance in mosquitos is poorly understood. In this paper, we found that miR-285 was significantly upregulated in the deltamethrin-resistant strain of Culex pipiens pallens, and overexpression miR-285 through microinjection increased mosquito survival rate against deltamethrin treatement. Using bioinformatic software, quantitative reverse transcription PCR, luciferase reporter assay and microinjection approaches, we conformed that CYP6N23 was the target of miR-285. Lower expression of CYP6N23 was observed in the deltamethrin-resistant strain. While, mosquito mortality rate was decreased after downregulating expression of CYP6N23 by dsRNA against CYP6N23 or miR-285 mimic microinjection. These findings revealed that miR-285 could target CYP6N23 to regulate pyrethroid resistance, providing new insights into mosquito insecticide resistance surveillance and control.

  4. [Morphological signs of inflammatory activity in different clinical forms of drug-resistant pulmonary tuberculosis].

    Science.gov (United States)

    Elipashev, A A; Nikolsky, V O; Shprykov, A S

    to determine whether the activity of tuberculous inflammation is associated with different clinical forms of drug-resistant pulmonary tuberculosis. The material taken from 310 patients operated on in 2010-2015 were retrospectively examined. The patients underwent economical lung resections of limited extent (typical and atypical ones of up to 3 segments) for circumscribed forms of tuberculosis with bacterial excretion. A study group consisted of 161 (51.9%) patients with drug-resistant variants of pulmonary tuberculosis. A control group included 149 (48.1%) patients with preserved susceptibility of Mycobacterium tuberculosis to anti-TB drugs. The activity of specific changes in tuberculosis was morphologically evaluated in accordance with the classification proposed by B.M. Ariel in 1998. The highest activity of fourth-to-fifth degree specific inflammation, including that outside the primary involvement focus, was obtained in the drug-resistant pulmonary tuberculosis group due to the predominance of patients with cavernous and fibrous-cavernous tuberculosis versus those in whom the susceptibility to chemotherapeutic agents was preserved. A macroscopic study showed that the primary lesion focus had a median size in one-half of the all the examinees; but large tuberculomas, caverns, and fibrous caverns over 4 cm in diameter were multiple and detected in the drug-resistant pulmonary tuberculosis group. Multidrug resistance was observed in more than 60% of the patients with fibrous-cavernous pulmonary tuberculosis, extensive drug resistance was seen in those with cavernous tuberculosis, which is an aggravating factor. The data obtained from the morphological study of the intraoperative material can specify the clinical form of tuberculosis and evaluate the efficiency of preoperative specific therapy. The highest activity of specific inflammation was observed in patients with multiple drug-resistant pulmonary tuberculosis, the prevalence of third-to-fourth degree

  5. Genetic Indicators of Drug Resistance in the Highly Repetitive Genome of Trichomonas vaginalis.

    Science.gov (United States)

    Bradic, Martina; Warring, Sally D; Tooley, Grace E; Scheid, Paul; Secor, William E; Land, Kirkwood M; Huang, Po-Jung; Chen, Ting-Wen; Lee, Chi-Ching; Tang, Petrus; Sullivan, Steven A; Carlton, Jane M

    2017-06-01

    Trichomonas vaginalis, the most common nonviral sexually transmitted parasite, causes ∼283 million trichomoniasis infections annually and is associated with pregnancy complications and increased risk of HIV-1 acquisition. The antimicrobial drug metronidazole is used for treatment, but in a fraction of clinical cases, the parasites can become resistant to this drug. We undertook sequencing of multiple clinical isolates and lab derived lines to identify genetic markers and mechanisms of metronidazole resistance. Reduced representation genome sequencing of ∼100 T. vaginalis clinical isolates identified 3,923 SNP markers and presence of a bipartite population structure. Linkage disequilibrium was found to decay rapidly, suggesting genome-wide recombination and the feasibility of genetic association studies in the parasite. We identified 72 SNPs associated with metronidazole resistance, and a comparison of SNPs within several lab-derived resistant lines revealed an overlap with the clinically resistant isolates. We identified SNPs in genes for which no function has yet been assigned, as well as in functionally-characterized genes relevant to drug resistance (e.g., pyruvate:ferredoxin oxidoreductase). Transcription profiles of resistant strains showed common changes in genes involved in drug activation (e.g., flavin reductase), accumulation (e.g., multidrug resistance pump), and detoxification (e.g., nitroreductase). Finally, we identified convergent genetic changes in lab-derived resistant lines of Tritrichomonas foetus, a distantly related species that causes venereal disease in cattle. Shared genetic changes within and between T. vaginalis and Tr. foetus parasites suggest conservation of the pathways through which adaptation has occurred. These findings extend our knowledge of drug resistance in the parasite, providing a panel of markers that can be used as a diagnostic tool. © The Author 2017. Published by Oxford University Press on behalf of the Society for

  6. What is the mechanism for persistent coexistence of drug-susceptible and drug-resistant strains of Streptococcus pneumoniae?

    Science.gov (United States)

    Colijn, Caroline; Cohen, Ted; Fraser, Christophe; Hanage, William; Goldstein, Edward; Givon-Lavi, Noga; Dagan, Ron; Lipsitch, Marc

    2010-01-01

    The rise of antimicrobial resistance in many pathogens presents a major challenge to the treatment and control of infectious diseases. Furthermore, the observation that drug-resistant strains have risen to substantial prevalence but have not replaced drug-susceptible strains despite continuing (and even growing) selective pressure by antimicrobial use presents an important problem for those who study the dynamics of infectious diseases. While simple competition models predict the exclusion of one strain in favour of whichever is ‘fitter’, or has a higher reproduction number, we argue that in the case of Streptococcus pneumoniae there has been persistent coexistence of drug-sensitive and drug-resistant strains, with neither approaching 100 per cent prevalence. We have previously proposed that models seeking to understand the origins of coexistence should not incorporate implicit mechanisms that build in stable coexistence ‘for free’. Here, we construct a series of such ‘structurally neutral’ models that incorporate various features of bacterial spread and host heterogeneity that have been proposed as mechanisms that may promote coexistence. We ask to what extent coexistence is a typical outcome in each. We find that while coexistence is possible in each of the models we consider, it is relatively rare, with two exceptions: (i) allowing simultaneous dual transmission of sensitive and resistant strains lets coexistence become a typical outcome, as does (ii) modelling each strain as competing more strongly with itself than with the other strain, i.e. self-immunity greater than cross-immunity. We conclude that while treatment and contact heterogeneity can promote coexistence to some extent, the in-host interactions between strains, particularly the interplay between coinfection, multiple infection and immunity, play a crucial role in the long-term population dynamics of pathogens with drug resistance. PMID:19940002

  7. Stability Analysis of an HIV/AIDS Dynamics Model with Drug Resistance

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    Qianqian Li

    2012-01-01

    Full Text Available A mathematical model of HIV/AIDS transmission incorporating treatment and drug resistance was built in this study. We firstly calculated the threshold value of the basic reproductive number (R0 by the next generation matrix and then analyzed stability of two equilibriums by constructing Lyapunov function. When R0<1, the system was globally asymptotically stable and converged to the disease-free equilibrium. Otherwise, the system had a unique endemic equilibrium which was also globally asymptotically stable. While an antiretroviral drug tried to reduce the infection rate and prolong the patients’ survival, drug resistance was neutralizing the effects of treatment in fact.

  8. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

    Science.gov (United States)

    Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

    2016-05-01

    The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Primary drug-resistant tuberculosis in Hanoi, Viet Nam: present status and risk factors.

    Directory of Open Access Journals (Sweden)

    Nguyen Thi Le Hang

    Full Text Available INTRODUCTION: Resistance of Mycobacterium tuberculosis (MTB to anti-tuberculosis (TB drugs presents a serious challenge to TB control worldwide. We investigated the status of drug resistance, including multidrug-resistant (MDR TB, and possible risk factors among newly diagnosed TB patients in Hanoi, the capital of Viet Nam. METHODS: Clinical and epidemiological information was collected from 506 newly diagnosed patients with sputum smear- and culture-positive TB, and 489 (96.6% MTB isolates were subjected to conventional drug susceptibility testing, spoligotyping, and 15-locus variable numbers of tandem repeats typing. Adjusted odds ratios (aORs were calculated to analyze the risk factors for primary drug resistance. RESULTS: Of 489 isolates, 298 (60.9% were sensitive to all drugs tested. Resistance to isoniazid, rifampicin, streptomycin, ethambutol, and MDR accounted for 28.2%, 4.9%, 28.2%, 2.9%, and 4.5%, respectively. Of 24 isolates with rifampicin resistance, 22 (91.7% were MDR and also resistant to streptomycin, except one case. Factors associated with isoniazid resistance included living in old urban areas, presence of the Beijing genotype, and clustered strains [aOR = 2.23, 95% confidence interval (CI 1.15-4.35; 1.91, 1.18-3.10; and 1.69, 1.06-2.69, respectively. The Beijing genotype was also associated with streptomycin resistance (aOR = 2.10, 95% CI 1.29-3.40. Human immunodeficiency virus (HIV coinfection was associated with rifampicin resistance and MDR (aOR = 5.42, 95% CI 2.07-14.14; 6.23, 2.34-16.58, respectively. CONCLUSION: Isoniazid and streptomycin resistance was observed in more than a quarter of TB patients without treatment history in Hanoi. Transmission of isoniazid-resistant TB among younger people should be carefully monitored in urban areas, where Beijing strains and HIV coinfection are prevalent. Choosing an optimal treatment regimen on the basis of the results of drug susceptibility tests and monitoring of treatment

  10. HIV-1 drug resistance mutations among antiretroviral-naive HIV-1-infected patients in Asia: results from the TREAT Asia Studies to Evaluate Resistance-Monitoring Study.

    Science.gov (United States)

    Sungkanuparph, Somnuek; Oyomopito, Rebecca; Sirivichayakul, Sunee; Sirisanthana, Thira; Li, Patrick C K; Kantipong, Pacharee; Lee, Christopher K C; Kamarulzaman, Adeeba; Messerschmidt, Liesl; Law, Matthew G; Phanuphak, Praphan

    2011-04-15

    Of 682 antiretroviral-naïve patients initiating antiretroviral therapy in a prospective, multicenter human immunodeficiency virus type 1 (HIV-1) drug resistance monitoring study involving 8 sites in Hong Kong, Malaysia, and Thailand, the prevalence of patients with ≥1 drug resistance mutation was 13.8%. Primary HIV drug resistance is emerging after rapid scaling-up of antiretroviral therapy use in Asia.

  11. Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes

    NARCIS (Netherlands)

    Falzon, Dennis; Gandhi, Neel; Migliori, Giovanni B.; Sotgiu, Giovanni; Cox, Helen S.; Holtz, Timothy H.; Hollm-Delgado, Maria-Graciela; Keshavjee, Salmaan; Deriemer, Kathryn; Centis, Rosella; D'Ambrosio, Lia; Lange, Christoph G.; Bauer, Melissa; Menzies, Dick; Ahuja, S. D.; Ashkin, D.; Avendaño, M.; Banerjee, R.; Bauer, M.; Becerra, M. C.; Benedetti, A.; Burgos, M.; Centis, R.; Chan, E. D.; Chiang, C. Y.; Cobelens, F.; Cox, H.; D'Ambrosio, L.; de Lange, W. C. M.; DeRiemer, K.; Enarson, D.; Falzon, D.; Flanagan, K. L.; Flood, J.; Gandhi, N.; Garcia-Garcia, M. L.; Granich, R. M.; Hollm-Delgado, M. G.; Holtz, T. H.; Hopewell, P.; Iseman, M. D.; Jarlsberg, L. G.; Keshavjee, S.; Kim, H. R.; Koh, W. J.; Lancaster, J. L.; Lange, C.; Leimane, V.; Leung, C. C.; Li, J.

    2013-01-01

    A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable

  12. The fourth national anti-tuberculosis drug resistance survey in Viet Nam.

    Science.gov (United States)

    Nhung, N V; Hoa, N B; Sy, D N; Hennig, C M; Dean, A S

    2015-06-01

    Viet Nam's Fourth National Anti-Tuberculosis Drug Resistance Survey was conducted in 2011. To determine the prevalence of resistance to the four main first-line anti-tuberculosis drugs in Viet Nam. Eighty clusters were selected using a probability proportion to size approach. Drug susceptibility testing (DST) against the four main first-line anti-tuberculosis drugs was performed. A total of 1629 smear-positive tuberculosis (TB) patients were eligible for culture. Of these, DST results were available for 1312 patients, including 1105 new TB cases, 195 previously treated TB cases and 12 cases with an unknown treatment history. The proportion of cases with resistance to any drug was 32.7% (95%CI 29.1-36.5) among new cases and 54.2% (95%CI 44.3-63.7) among previously treated cases. The proportion of multidrug-resistant TB (MDR-TB) cases was 4.0% (95%CI 2.5-5.4) in new cases and 23.3 (95%CI 16.7-29.9) in previously treated cases. The fourth drug resistance survey in Viet Nam found that the proportion of MDR-TB among new and previously treated cases was not significantly different from that in the 2005 survey. The National TB Programme should prioritise the detection and treatment of MDR-TB to reduce transmission of MDR-TB in the community.

  13. Targeting oncoprotein stability overcomes drug resistance caused by FLT3 kinase domain mutations.

    Directory of Open Access Journals (Sweden)

    Chuanjiang Yu

    Full Text Available FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML. Internal tandem duplications (ITDs in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.

  14. The influence of the European paediatric regulation on marketing authorisation of orphan drugs for children

    NARCIS (Netherlands)

    Kreeftmeijer-Vegter, Annemarie Rosan; de Boer, Anthonius; van der Vlugt-Meijer, Roselinda H.; de Vries, Peter J.

    2014-01-01

    Background: Drug development for rare diseases is challenging, especially when these orphan drugs (OD) are intended for children. In 2007 the EU Paediatric Drug Regulation was enacted to improve the development of high quality and ethically researched medicines for children through the establishment

  15. Direct-to-consumer prescription drug advertising: history, regulation, and issues.

    Science.gov (United States)

    Huh, Jisu; DeLorme, Denise E; Reid, Leonard N; An, Soontae

    2010-03-01

    Direct-to-consumer advertising has changed the way prescription drugs are marketed in the United States. This article traces the history of direct-to-consumer advertising of prescription and over-the-counter medications and describes how drug advertising is regulated and by whom. It also discusses the controversies that surround direct-to-consumer marketing of prescription drugs.

  16. The influence of the European paediatric regulation on marketing authorisation of orphan drugs for children

    NARCIS (Netherlands)

    Kreeftmeijer-Vegter, Annemarie Rosan; de Boer, Anthonius; van der Vlugt-Meijer, Roselinda H; de Vries, Peter J

    2014-01-01

    BACKGROUND: Drug development for rare diseases is challenging, especially when these orphan drugs (OD) are intended for children. In 2007 the EU Paediatric Drug Regulation was enacted to improve the development of high quality and ethically researched medicines for children through the establishment

  17. Fluorometric assay for phenotypic differentiation of drug-resistant HIV mutants

    Science.gov (United States)

    Zhu, Qinchang; Yu, Zhiqiang; Kabashima, Tsutomu; Yin, Sheng; Dragusha, Shpend; El-Mahdy, Ahmed F. M.; Ejupi, Valon; Shibata, Takayuki; Kai, Masaaki

    2015-01-01

    Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates for the enzymatic reaction. In this study, susceptibility of HIV mutations to drugs was evaluated by selective formation of three FL products after the enzymatic HIV-PR reaction. This proof-of-concept study indicates that the present HPLC-FL method could be an alternative to current phenotypic assays for the evaluation of HIV drug resistance. PMID:25988960

  18. Knockdown of UbcH10 Enhances the Chemosensitivity of Dual Drug Resistant Breast Cancer Cells to Epirubicin and Docetaxel

    Directory of Open Access Journals (Sweden)

    Cheng Wang

    2015-03-01

    Full Text Available Breast cancer is one of the most common and lethal cancers in women. As a hub gene involved in a diversity of tumors, the ubiquitin-conjugating enzyme H10 (UbcH10, may also play some roles in the genesis and development of breast cancer. In the current study, we found that the expression of UbcH10 was up-regulated in some breast cancer tissues and five cell lines. We established a dual drug resistant cell line MCF-7/EPB (epirubicin/TXT (docetaxel and a lentiviral system expressing UbcH10 shRNA to investigate the effects of UbcH10 knockdown on the chemosensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel. The knockdown of UbcH10 inhibited the proliferation of both MCF-7 and MCF-7/EPB/TXT cells, due to the G1 phase arrest in cell cycle. Furthermore, UbcH10 knockdown increased the sensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel and promoted the apoptosis induced by these two drugs. Protein detection showed that, in addition to inhibiting the expression of Ki67 and cyclin D1, UbcH10 RNAi also impaired the increased BCL-2 and MDR-1 expression levels in MCF-7/EPB/TXT cells, which may contribute to abating the drug resistance in the breast cancer cells. Our research in the current study demonstrated that up-regulation of UbcH10 was involved in breast cancer and its knockdown can inhibit the growth of cancer cells and increase the chemosensitivity of the dual drug resistant breast cancer cells to epirubicin and docetaxel, suggesting that UbcH10 may be a promising target for the therapy of breast cancer.

  19. Involvement of CD147 on multidrug resistance through the regulation of P-glycoprotein expression in K562/ADR leukemic cell line

    Directory of Open Access Journals (Sweden)

    Aoranit Somno

    2016-01-01

    Full Text Available The relationship between P-gp and CD147 in the regulation of MDR in leukemic cells has not been reported. This study aimed to investigate the correlation between CD147 and P-gp in the regulation of drug resistance in the K562/ADR leukemic cell line. The results showed that drug-resistant K562/ADR cells expressed significantly higher P-gp and CD147 levels than drug-free K562/ADR cells. To determine the regulatory effect of CD147 on P-gp expression, anti-CD147 antibody MEM-M6/6 significantly decreased P-gp and CD147 mRNA and protein levels. This is the first report to show that CD147 mediates MDR in leukemia through the regulation of P-gp expression.

  20. Vaccination of chickens against coccidiosis ameliorates drug resistance in commercial poultry production

    Directory of Open Access Journals (Sweden)

    H. David Chapman

    2014-12-01

    Full Text Available Drug resistance is a problem wherever livestock are raised under intensive conditions and drugs are used to combat parasitic infections. This is particularly true for the anticoccidial agents used for the prevention of coccidiosis caused by protozoa of the apicomplexan genus Eimeria in poultry. Resistance has been documented for all the dozen or so drugs approved for use in chickens and varying levels of resistance is present for those currently employed. A possible solution may be the introduction of drug-sensitive parasites into the houses where poultry are raised so that they may replace such drug-resistant organisms. This can be achieved by utilizing live vaccines that contain strains of Eimeria that were isolated before most anticoccidial compounds were introduced. Such strains are inherently drug-sensitive. Practical proposals to achieve this objective involve the alternation of vaccination with medication (known as rotation programs in successive flocks reared in the same poultry house. A proposal for a yearly broiler production cycle involving chemotherapy and vaccination is presented. There are few, if any, examples in veterinary parasitology where it has proved possible to restore sensitivity to drugs used to control a widespread parasite. Further research is necessary to ascertain whether this can result in sustainable and long-term control of Eimeria infections in poultry.

  1. Vaccination of chickens against coccidiosis ameliorates drug resistance in commercial poultry production

    Science.gov (United States)

    Chapman, H. David; Jeffers, Thomas K.

    2014-01-01

    Drug resistance is a problem wherever livestock are raised under intensive conditions and drugs are used to combat parasitic infections. This is particularly true for the anticoccidial agents used for the prevention of coccidiosis caused by protozoa of the apicomplexan genus Eimeria in poultry. Resistance has been documented for all the dozen or so drugs approved for use in chickens and varying levels of resistance is present for those currently employed. A possible solution may be the introduction of drug-sensitive parasites into the houses where poultry are raised so that they may replace such drug-resistant organisms. This can be achieved by utilizing live vaccines that contain strains of Eimeria that were isolated before most anticoccidial compounds were introduced. Such strains are inherently drug-sensitive. Practical proposals to achieve this objective involve the alternation of vaccination with medication (known as rotation programs) in successive flocks reared in the same poultry house. A proposal for a yearly broiler production cycle involving chemotherapy and vaccination is presented. There are few, if any, examples in veterinary parasitology where it has proved possible to restore sensitivity to drugs used to control a widespread parasite. Further research is necessary to ascertain whether this can result in sustainable and long-term control of Eimeria infections in poultry. PMID:25516830

  2. Selection of antibiotics for meticillin-resistant Staphylococcus pseudintermedius: time to revisit some old drugs?

    Science.gov (United States)

    Papich, Mark G

    2012-08-01

    The aim of this review is to consider systemic therapy options for meticillin-resistant Staphylococcus pseudintermedius (MRSP). Infections caused by MRSP in small animals--particularly dogs--have been frustrating veterinarians in recent years. After a susceptibility test is performed, veterinarians are left to select from drugs that have not been frequently encountered on a susceptibility report. Some of these are old drugs that have not been used regularly by veterinary dermatologists. As MRSP is, by definition, resistant to all β-lactam antibiotics, including cephalosporins, penicillins and amoxicillin-clavulanate combinations, the β-lactam drugs are not an option for systemic treatment. As most MRSPs are multidrug resistant, familiar drugs, such as trimethoprim-sulfonamides, fluoroquinolones, macrolides and lincosamides (clindamycin), are also not usually an option for treatment. Therefore, veterinarians are left with drugs such as rifampicin, chloramphenicol, tetracyclines, aminoglycosides and vancomycin to choose from on the basis of an in vitro susceptibility test. Some of these drugs were originally approved over 50 years ago and may not be familiar to some veterinarians. Each of these drugs possesses unique properties and has particular advantages and disadvantages. Veterinarians should be particularly aware of the adverse effects, limitations and precautions when using these drugs. New drugs also have been developed for meticillin-resistant Staphylococcus aureus in humans. These include linezolid, ceftaroline, daptomycin and tigecycline. Although these drugs are very infrequently--if ever--considered for veterinary use, the properties of these drugs should also be known to veterinary dermatologists. © 2012 The Author. Veterinary Dermatology. © 2012 ESVD and ACVD.

  3. Phenotypic and genotypic analysis of anti-tuberculosis drug resistance in Mycobacterium tuberculosis isolates in Myanmar.

    Science.gov (United States)

    Aung, Wah Wah; Ei, Phyu Win; Nyunt, Wint Wint; Swe, Thyn Lei; Lwin, Thandar; Htwe, Mi Mi; Kim, Kyung Jun; Lee, Jong Seok; Kim, Chang Ki; Cho, Sang Nae; Song, Sun Dae; Chang, Chulhun L

    2015-09-01

    Tuberculosis (TB) is one of the most serious health problems in Myanmar. Because TB drug resistance is associated with genetic mutation(s) relevant to responses to each drug, genotypic methods for detecting these mutations have been proposed to overcome the limitations of classic phenotypic drug susceptibility testing (DST). We explored the current estimates of drug-resistant TB and evaluated the usefulness of genotypic DST in Myanmar. We determined the drug susceptibility of Mycobacterium tuberculosis isolated from sputum smear-positive patients with newly diagnosed pulmonary TB at two main TB centers in Myanmar during 2013 by using conventional phenotypic DST and the GenoType MTBDRplus assay (Hain Lifescience, Germany). Discrepant results were confirmed by sequencing the genes relevant to each type of resistance (rpoB for rifampicin; katG and inhA for isoniazid). Of 191 isolates, phenotypic DST showed that 27.7% (n=53) were resistant to at least one first-line drug and 20.9% (n=40) were resistant to two or more, including 18.3% (n=35) multidrug-resistant TB (MDR-TB) strains. Monoresistant strains accounted for 6.8% (n=13) of the samples. Genotypic assay of 189 isolates showed 17.5% (n=33) MDR-TB and 5.3% (n=10) isoniazid-monoresistant strains. Genotypic susceptibility results were 99.5% (n=188) concordant and agreed almost perfectly with phenotypic DST (kappa=0.99; 95% confidence interval 0.96-1.01). The results highlight the burden of TB drug resistance and prove the usefulness of the genotypic DST in Myanmar.

  4. Drug-resistant tuberculosis--current dilemmas, unanswered questions, challenges, and priority needs.

    Science.gov (United States)

    Zumla, Alimuddin; Abubakar, Ibrahim; Raviglione, Mario; Hoelscher, Michael; Ditiu, Lucica; McHugh, Timothy D; Squire, S Bertel; Cox, Helen; Ford, Nathan; McNerney, Ruth; Marais, Ben; Grobusch, Martin; Lawn, Stephen D; Migliori, Giovanni-Battista; Mwaba, Peter; O'Grady, Justin; Pletschette, Michel; Ramsay, Andrew; Chakaya, Jeremiah; Schito, Marco; Swaminathan, Soumya; Memish, Ziad; Maeurer, Markus; Atun, Rifat

    2012-05-15

    Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis-specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR

  5. A primer of drug safety surveillance: an industry perspective. Part I: Information flow, new drug development, and federal regulations.

    Science.gov (United States)

    Allan, M C

    1992-01-01

    To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part I of this series provides a background for the discussion of drug safety by defining the basic terms and showing the flow of safety information through a pharmaceutical company. The customers for adverse drug event data are identified to provide a basis for providing quality service. The development of a drug product is briefly reviewed to show the evolution of safety data. Drug development and safety are defined by federal regulations. These regulations are developed by the FDA with information from pharmaceutical manufacturers. The intent of the regulations and the accompanying guidelines is described. An illustration from the news media is cited to show an alternative, positive approach to handling an adverse event report. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are presented in an appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction ;of the components

  6. In vivo selection of resistant E. coli after ingestion of milk with added drug residues.

    Directory of Open Access Journals (Sweden)

    Richard Van Vleck Pereira

    Full Text Available Antimicrobial resistance represents a major global threat to modern medicine. In vitro studies have shown that very low concentrations of drugs, as frequently identified in the environment, and in foods and water for human and animal consumption, can select for resistant bacteria. However, limited information is currently available on the in vivo impact of ingested drug residues. The objective of our study was to evaluate the effect of feeding preweaned calves milk containing antimicrobial drug residues (below the minimum inhibitory concentration, similar to concentrations detected in milk commonly fed to dairy calves, on selection of resistant fecal E. coli in calves from birth to weaning. At birth, thirty calves were randomly assigned to a controlled feeding trial where: 15 calves were fed raw milk with no drug residues (NR, and 15 calves were fed raw milk with drug residues (DR by adding ceftiofur, penicillin, ampicillin, and oxytetracycline at final concentrations in the milk of 0.1, 0.005, 0.01, and 0.3 µg/ml, respectively. Fecal samples were rectally collected from each calf once a week starting at birth prior to the first feeding in the trial (pre-treatment until 6 weeks of age. A significantly greater proportion of E. coli resistant to ampicillin, cefoxitin, ceftiofur, streptomycin and tetracycline was observed in DR calves when compared to NR calves. Additionally, isolates from DR calves had a significant decrease in susceptibility to ceftriaxone and ceftiofur when compared to isolates from NR calves. A greater proportion of E. coli isolates from calves in the DR group were resistant to 3 or more antimicrobial drugs when compared to calves in the ND group. These findings highlight the role that low concentrations of antimicrobial drugs have on the evolution and selection of resistance to multiple antimicrobial drugs in vivo.

  7. Assessment of clinical risk factors for drug-resistant epilepsy in children and teenagers

    Directory of Open Access Journals (Sweden)

    Marta Kasprzyk

    2014-09-01

    Full Text Available Introduction: Epilepsy is one of the most common neurological illnesses occurring in children. In approximately 20–30% of cases it is drug-resistant. Aim of the research: To assess the already-known risk factors, analyse the rarely described ones, and find new causes of epilepsy drug resistance in children, taking into account the level of impact of each factor. Material and methods : The study comprised 152 of all 383 children hospitalised in 2012 at the Neurology Department of the Polish Mother’s Memorial Hospital in Lodz due to epilepsy. Based on medical documentation, neurological examination, and our own questionnaire, we divided patients into two groups: drug-resistant epilepsy or drug-sensitive epilepsy. We compared the type, level of influence, and prevalence of different factors. For statistical analysis, the 2 test was used. Statistical significance was set at p < 0.05. Results: Drug-resistant epilepsy was found in 64 patients (42.1%, and drug-sensitive epilepsy was found in 88 patients (57.9%. Factors that were most probable to cause drug resistance included: high prevalence of seizures (Cramer’s V = 0.66, type of epileptic syndrome (V = 0.62, psychomotor developmental delay (V = 0.62, and occurrence of status epilepticus (V = 0.6. Factors such as infections of CNS in early childhood, repeated severe infections of airways in childhood, and mother’s infectious diseases with high fever during pregnancy were rare or non occurring (Cramer’s V = 0.41, 0.32, and 0.31, respectively. Conclusions : The study confirmed the previously known causes of drug resistance and indicated the significance of underestimated inflammatory and infectious factors involving pyrexia, in children and also in mothers during pregnancy.

  8. Calcineurin signaling and membrane lipid homeostasis regulates iron mediated multidrug resistance mechanisms in Candida albicans.

    Directory of Open Access Journals (Sweden)

    Saif Hameed

    2011-04-01

    Full Text Available We previously demonstrated that iron deprivation enhances drug susceptibility of Candida albicans by increasing membrane fluidity which correlated with the lower expression of ERG11 transcript and ergosterol levels. The iron restriction dependent membrane perturbations led to an increase in passive diffusion and drug susceptibility. The mechanisms underlying iron homeostasis and multidrug resistance (MDR, however, are not yet resolved. To evaluate the potential mechanisms, we used whole genome transcriptome and electrospray ionization tandem mass spectrometry (ESI-MS/MS based lipidome analyses of iron deprived Candida cells to examine the new cellular circuitry of the MDR of this pathogen. Our transcriptome data revealed a link between calcineurin signaling and iron homeostasis. Among the several categories of iron deprivation responsive genes, the down regulation of calcineurin signaling genes including HSP90, CMP1 and CRZ1 was noteworthy. Interestingly, iron deprived Candida cells as well as iron acquisition defective mutants phenocopied molecular chaperone HSP90 and calcineurin mutants and thus were sensitive to alkaline pH, salinity and membrane perturbations. In contrast, sensitivity to above stresses did not change in iron deprived DSY2146 strain with a hyperactive allele of calcineurin. Although, iron deprivation phenocopied compromised HSP90 and calcineurin, it was independent of protein kinase C signaling cascade. Notably, the phenotypes associated with iron deprivation in genetically impaired calcineurin and HSP90 could be reversed with iron supplementation. The observed down regulation of ergosterol (ERG1, ERG2, ERG11 and ERG25 and sphingolipid biosynthesis (AUR1 and SCS7 genes followed by lipidome analysis confirmed that iron deprivation not only disrupted ergosterol biosynthesis, but it also affected sphingolipid homeostasis in Candida cells. These lipid compositional changes suggested extensive remodeling of the membranes in iron

  9. Lack of cross-resistance to fostriecin in a human small-cell lung carcinoma cell line showing topoisomerase II-related drug resistance

    NARCIS (Netherlands)

    de Jong, Steven; Zijlstra, J G; Mulder, Nanno; de Vries, Liesbeth

    1991-01-01

    Cells exhibiting decreased topoisomerase II (Topo II) activity are resistant to several drugs that require Topo II as an intermediate. These drugs are cytotoxic due to the formation of a cleavable complex between the drug, Topo II and DNA. Fostriecin belongs to a new class of drugs that inhibit Topo

  10. Mechanistic and Structural Insights Into the Unique TetR-Dependent Regulation of a Drug Efflux Pump in Mycobacterium abscessus.

    Science.gov (United States)

    Richard, Matthias; Gutiérrez, Ana Victoria; Viljoen, Albertus J; Ghigo, Eric; Blaise, Mickael; Kremer, Laurent

    2018-01-01

    Mycobacterium abscessus is an emerging human pathogen causing severe pulmonary infections and is refractory to standard antibiotherapy, yet few drug resistance mechanisms have been reported in this organism. Recently, mutations in MAB_4384 leading to up-regulation of the MmpS5/MmpL5 efflux pump were linked to increased resistance to thiacetazone derivatives. Herein, the DNA-binding activity of MAB_4384 was investigated by electrophoretic mobility shift assays using the palindromic sequence IR S5/L5 located upstream of mmpS5/mmpL5 . Introduction of point mutations within IR S5/L5 identified the sequence requirements for optimal binding of the regulator. Moreover, formation of the protein/IR S5/L5 complex was severely impaired for MAB_4384 harboring D14N or F57L substitutions. IR S5/L5 /lacZ reporter fusions in M. abscessus demonstrated increased β-galactosidase activity either in strains lacking a functional MAB_4384 or in cultures treated with the TAC analogs. In addition, X-ray crystallography confirmed a typical TetR homodimeric structure of MAB_4384 and unraveled a putative ligand binding site in which the analogs could be docked. Overall, these results support drug recognition of the MAB_4384 TetR regulator, alleviating its binding to IR S5/L5 and steering up-regulation of MmpS5/MmpL5. This study provides new mechanistic and structural details of TetR-dependent regulatory mechanisms of efflux pumps and drug resistance in mycobacteria.

  11. Parallel screening of wild-type and drug-resistant targets for anti-resistance neuraminidase inhibitors.

    Directory of Open Access Journals (Sweden)

    Kai-Cheng Hsu

    Full Text Available Infection with influenza virus is a major public health problem, causing serious illness and death each year. Emergence of drug-resistant influenza virus strains limits the effectiveness of drug treatment. Importantly, a dual H275Y/I223R mutation detected in the pandemic influenza A 2009 virus strain results in multidrug resistance to current neuraminidase (NA drugs. Therefore, discovery of new agents for treating multiple drug-resistant (MDR influenza virus infections is important. Here, we propose a parallel screening strategy that simultaneously screens wild-type (WT and MDR NAs, and identifies inhibitors matching the subsite characteristics of both NA-binding sites. These may maintain their potency when drug-resistant mutations arise. Initially, we analyzed the subsite of the dual H275Y/I223R NA mutant. Analysis of the site-moiety maps of NA protein structures show that the mutant subsite has a relatively small volume and is highly polar compared with the WT subsite. Moreover, the mutant subsite has a high preference for forming hydrogen-bonding interactions with polar moieties. These changes may drive multidrug resistance. Using this strategy, we identified a new inhibitor, Remazol Brilliant Blue R (RB19, an anthraquinone dye, which inhibited WT NA and MDR NA with IC(50 values of 3.4 and 4.5 µM, respectively. RB19 comprises a rigid core scaffold and a flexible chain with a large polar moiety. The former interacts with highly conserved residues, decreasing the probability of resistance. The latter forms van der Waals contacts with the WT subsite and yields hydrogen bonds with the mutant subsite by switching the orientation of its flexible side chain. Both scaffolds of RB19 are good starting points for lead optimization. The results reveal a parallel screening strategy for identifying resistance mechanisms and discovering anti-resistance neuraminidase inhibitors. We believe that this strategy may be applied to other diseases with high

  12. Extent and origin of resistance to antituberculosis drugs in the Netherlands, 1993 to 2011.

    Science.gov (United States)

    Ruesen, C; van Gageldonk-Lafeber, A B; de Vries, G; Erkens, C G; van Rest, J; Korthals Altes, H; de Neeling, H; Kamst, M; van Soolingen, D

    2014-03-20

    The elimination of tuberculosis (TB) is threatened by an apparent increase in the level of resistance in Mycobacterium tuberculosis. In the Netherlands, where the majority of TB patients are migrants, resistance may also be increasing. We conducted a retrospective study, using 18,294 M. tuberculosis isolates from TB cases notified between 1993 and 2011. We investigated the trends in antituberculosis drug resistance, focusing on the country of birth of the patients and whether resistance had developed during treatment or was the result of transmission of resistant M. tuberculosis strains. For both scenarios, we determined whether this had happened in or outside the Netherlands. Antituberculosis drug resistance was found in 13% of all cases analysed and showed an increasing trend among patients who had been born in the Netherlands (pNetherlands or before 1993 (when DNA fingerprinting was not systematically performed), in some cases (n=45), resistance was acquired in the Netherlands. We conclude that antituberculosis drug resistance is increasing in the Netherlands, mostly related to migration from high TB-incidence countries, but also to domestic acquisition.

  13. Increased multi-drug resistant Escherichia coli from hospitals in ...

    African Journals Online (AJOL)

    Background: Multidrug-resistant Escherichia coli (MDR E. coli) has become a major public health concern in Sudan and many countries, causing failure in treatment with consequent huge health burden. Objectives: To determine the prevalence and susceptibility of MDR E. coli isolated from patients in hospitals at Khartoum ...

  14. Nasal carriage of multi-drug resistant Staphylococcus aureus in ...

    African Journals Online (AJOL)

    Background: Nasal Staphylococcus aureus is a major source of community and hospital associated staphylococcal infections. This study determined the prevalence of nasal S. aureus isolates and investigated their antimicrobial resistance profile in healthy volunteers. Methods: Nasal specimens of healthy volunteers in ...

  15. Multi-drug resistant Staphylococcus aureus isolated from emergency ...

    African Journals Online (AJOL)

    Purpose: To study the prevalence of resistant strains of S. aureus isolated from surfaces, beds and various equipment of an Iranian hospital emergency ward. Methods: Two hundred swab samples were collected from the surfaces, beds, trolleys, surgical equipment and diagnostic medical devices in emergency ward.

  16. Drug resistance patterns of bacterial isolates from infected wounds ...

    African Journals Online (AJOL)

    unhcc

    The resistance rate of S. aureus for penicillin was at 69.7%. Conclusions: High ... January 2013 to 30 December 2015 was conducted. BRHRLC is one of ... Wound infection, bacterial isolates, culture and antimicrobial susceptibility 113. Ethiop. J. Health ... Socio-demographic characteristic of patients and types of bacterial ...

  17. Prevalence and drug resistance in bacteria of the urinary tract ...

    African Journals Online (AJOL)

    Objective: To obtain data on the prevalence of antibiotic resistance in bacteria isolated from patients with suspected urinary tract infection in Bulawayo province, Zimbabwe. Method: Over a period of one year, 257 urine samples were analyzed for bacteria by standard procedures. Antimicrobial susceptibility testing of isolated ...

  18. Efflux drug transporters at the forefront of antimicrobial resistance.

    Science.gov (United States)

    Rahman, Tahmina; Yarnall, Benjamin; Doyle, Declan A

    2017-10-01

    Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence mechanisms that existed long before man's discovery of antibiotics. Bacteria utilise levels of protection that range from gene upregulation, mutations, adaptive resistance, and production of resistant phenotypes (persisters) to communal behaviour, as in swarming and the ultimate defence of a biofilm. A major part of all of these responses involves the use of antibiotic efflux transporters. At the single cell level, it is becoming apparent that the use of efflux pumps is the first line of defence against an antibiotic, as these pumps decrease the intracellular level of antibiotic while the cell activates the various other levels of protection. This frontline of defence involves a coordinated network of efflux transporters. In the future, inhibition of this efflux transporter network, as a target for novel antibiotic therapy, will require the isolation and then biochemical/biophysical characterisation of each pump against all known and new antibiotics. This depth of knowledge is required so that we can fully understand and tackle the mechanisms of developing antimicrobial resistance.

  19. [Markers of antimicrobial drug resistance in the most common bacteria of normal facultative anaerobic intestinal flora].

    Science.gov (United States)

    Plavsić, Teodora

    2011-01-01

    Bacteria of normal intestinal flora are frequent carriers of markers of antimicrobial drug resistance. Resistance genes may be exchanged with other bacteria of normal flora as well as with pathogenic bacteria. The increase in the number of markers of resistance is one of the major global health problems, which induces the emergence of multi-resistant strains. The aim of this study is to confirm the presence of markers of resistance in bacteria of normal facultative anaerobic intestinal flora in our region. The experiment included a hundred fecal specimens obtained from a hundred healthy donors. A hundred bacterial strains were isolated (the most numerous representatives of the normal facultative-anaerobic intestinal flora) by standard bacteriological methods. The bacteria were cultivated on Endo agar and SS agar for 24 hours at 37 degrees C. Having been incubated, the selected characteristic colonies were submitted to the biochemical analysis. The susceptibility to antimicrobial drugs was tested by standard disc diffusion method, and the results were interpreted according to the Standard of Clinical and Laboratory Standards Institute 2010. The marker of resistance were found in 42% of the isolated bacteria. The resistance was the most common to ampicillin (42% of isolates), amoxicillin with clavulanic acid (14% of isolates), cephalexin (14%) and cotrimoxazole (8%). The finding of 12 multiresistant strains (12% of isolates) and resistance to ciprofloxacin were significant. The frequency of resistance markers was statistically higher in Klebsiella pneumoniae compared to Escherichia coli of normal flora. The finding of a large number of markers of antimicrobial drug resistance among bacteria of normal intestinal flora shows that it is necessary to begin with systematic monitoring of their antimicrobial resistance because it is an indicator of resistance in the population.

  20. miR-133b down-regulates ABCC1 and enhances the sensitivity of CRC to anti-tumor drugs.

    Science.gov (United States)

    Chen, Miao; Li, Daojiang; Gong, Ni; Wu, Hao; Su, Chen; Xie, Canbin; Xiang, Hong; Lin, Changwei; Li, Xiaorong

    2017-08-08

    Multidrug resistance (MDR) is the main cause of failed chemotherapy treatments. Therefore, preventing MDR is pivotal in treating colorectal cancer (CRC). In a previous study miR-133b was shown to be a tumor suppressor. Additionally, in CRC cells transfected with miR-133b, ATP-binding cassette (ABC) subfamily C member 1(ABCC1) was shown to be significantly down regulated. Whether miR-133b also enhances the chemosensitivity of drugs used to treat CRC by targeting ABCC1 is still unclear. Here, we utilized flow cytometry and high-performance liquid chromatography (HPLC) analysis to identify the ability of miR-133b to reserve MDR in CRC. We then used a dual-luciferase reporter assay to validate that miR-133b targets ABCC1. Further in vivo experiments were designed to validate the method in which miR-133b reversed MDR in CRC cells. The results demonstrated that the level of miR-133b was down-regulated and the expression of ABCC1 was up-regulated in drug-resistant CRC cells compared to non-drug-resistant CRC cells. The restoration of miR-133b expression in CRC drug-resistant cells in vitro resulted in reduced IC50s to chemotherapeutic drugs, significantly induced G1 accumulation, inhibited growth and promoted necrosis in combination with either 5-fluorouracil (5-FU) or vincristine (VCR), and decreased the expression of ABCC1. The dual-luciferase assay demonstrated that miR-133b directly targets ABCC1. The combination of agomiRNA-133b with chemotherapeutic drugs in vivo inhibited tumor growth induced by CRC drug-resistant cells. A xenograft from the in vivo model resulted in up-regulated levels of miR-133b and down-regulated levels of ABCC1. Therefore, miR-133b enhances the chemosensitivity of CRC cells to anti-tumor drugs by directly down-regulating ABCC1. This discovery provides a therapeutic strategy in which miR-133b is used as a potential sensitizer for drug-resistant CRC.

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

    Science.gov (United States)

    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.

  2. Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria.

    NARCIS (Netherlands)

    Ingen, J. van; Boeree, M.J.; Soolingen, D. van; Mouton, J.W.

    2012-01-01

    Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans. For most NTM infections the therapy of choice is drug treatment, but treatment regimens differ by species, in particular between slow (e.g. Mycobacterium avium complex,

  3. MicroRNA Expression Profiles Associated with Development of Drug Resistance in Ehrlich Ascites Tumor Cells

    DEFF Research Database (Denmark)

    Husted, Susanne; Søkilde, Rolf; Rask, Lene

    2011-01-01

    Multidrug resistance (MDR) poses a major obstacle to successful chemotherapeutic treatment of cancer, and often involves multiple genes, which may be regulated post-transcriptionally by microRNAs (miRNAs). The purpose of the present study was therefore to identify any resistance-associated change...

  4. Estimating prevalence of accumulated HIV-1 drug resistance in a cohort of patients on antiretroviral therapy

    DEFF Research Database (Denmark)

    Bannister, Wendy P; Cozzi-Lepri, Alessandro; Kjær, Jesper

    2011-01-01

    Estimating the prevalence of accumulated HIV drug resistance in patients receiving antiretroviral therapy (ART) is difficult due to lack of resistance testing at all occasions of virological failure and in patients with undetectable viral load. A method to estimate this for 6498 EuroSIDA patients...... who were under follow-up on ART at 1 July 2008 was therefore developed by imputing data on patients with no prior resistance test results, based on the probability of detecting resistance in tested patients with similar profiles....

  5. Pathogen infection distribution and drug resistance analysis of patients with severe liver disease

    Directory of Open Access Journals (Sweden)

    Xi CHEN

    2018-04-01

    Full Text Available Objective To explore the infection distribution and drug resistance of pathogens in patients with severe liver disease, and provide reference for clinical medication. Methods Retrospective analysis of the microbiological specimens from patients with severe liver disease in Department of Infection of our hospital from August 2014 to November 2016 and the drug susceptibility testing were carried out by means of K-B disc diffusion method after bacterial culturing, and the distribution and drug resistance of pathogens were analyzed. Results Totally 17 of 73 patients with severe liver disease developed hospital infection (23.3%. 104 strains of bacteria were isolated and 78 strains out of them were multidrug-resistant bacteria (75.0%. Among them, 28(26.9% strains were gram-positive coccus, mainly consisting of Staphylococcus aureus and Staphylococcus epidermidis, and 58(55.8% were gram-negative coccus, mainly composed of Escherichia coli, Klebsiella pneumonia and Acinetobacter baumannii, and 18(17.3% strains fungi. S.aureus and enterococci were resistant to penicillin, erythromycin and levofloxacin, the resistance rates were above 80.0%, but had low resistance rates to vancomycin, teicoplanin and tigecycline. The resistance rates of E.coli and K.pneumoniae to piperacillin, cefazolin and cefuroxime sodium were above 85.0%, but they had lower resistance rates to tigecycline and amikacin. Acinetobacter baumannii was 100% resistant to piperacillin and tazobactam, ceftazidime, imipenem and amikacin, but had low resistance to tigecycline and minocycline. Conclusions Multi-drug resistant bacteria are the main bacterial pathogens in patients with severe liver disease and have a high resistance rate to commonly used antibiotics, empirical treatment in the population at high risk of multidrug-resistant bacteria infections requires the use of broad-spectrum or high-grade antibiotics (e.g. carbapenems or tigecycline and drugs against specific pathogenic

  6. Quadruple-first line drug resistance in Mycobacterium tuberculosis in Vietnam: What can we learn from genes?

    Science.gov (United States)

    Nguyen, Huy Quang; Nguyen, Nhung Viet; Contamin, Lucie; Tran, Thanh Hoa Thi; Vu, Thuong Thi; Nguyen, Hung Van; Nguyen, Ngoc Lan Thi; Nguyen, Son Thai; Dang, Anh Duc; Bañuls, Anne-Laure; Nguyen, Van Anh Thi

    2017-06-01

    In Vietnam, a country with high tuberculosis (137/100.000 population) and multidrug-resistant (MDR)-TB burdens (7.8/100.000 population), little is known about the molecular signatures of drug resistance in general and more particularly of second line drug (SLD) resistance. This study is specifically focused on Mycobacterium tuberculosis isolates resistant to four first-line drugs (FLDs) that make TB much more difficult to treat. The aim is to determine the proportion of SLD resistance in these quadruple drug resistant isolates and the genetic determinants linked to drug resistance to better understand the genetic processes leading to quadruple and extremely drug resistance (XDR). 91 quadruple (rifampicin, isoniazid, ethambutol and streptomycin) FLD resistant and 55 susceptible isolates were included. Spoligotyping and 24-locus MIRU-VNTR techniques were performed and 9 genes and promoters linked to FLD and SLD resistance were sequenced. SLD susceptibility testing was carried out on a subsample of isolates. High proportion of quadruple-FLD resistant isolates was resistant to fluoroquinolones (27%) and second-line injectable drugs (30.2%) by drug susceptibility testing. The sequencing revealed high mutation diversity with prevailing mutations at positions katG315, inhA-15, rpoB531, embB306, rrs1401, rpsL43 and gyrA94. The sensitivity and specificity were high for most drug resistances (>86%), but the sensitivity was lower for injectable drug resistances (resistance. Ne