scholarly journals The de novo selection of drug–resistant malaria parasites

2003 ◽  
Vol 270 (1514) ◽  
pp. 545-554 ◽  
Author(s):  
N. J. White ◽  
W. Pongtavornpinyo
2021 ◽  
Author(s):  
Santosh Kumar ◽  
Valid Gahramanov ◽  
Julia Yaglom ◽  
Shivani Patel ◽  
Lukasz Kaczmarczyk ◽  
...  

The selection of drug-resistant mammalian cell mutants requires multiple drug exposures. When cloned genetically identical cells are exposed to the drug, resistance is unlikely to result from the selection of pre-existent mutations. Therefore, adaptation must involve the generation of drug-resistant mutations de-novo. Understanding how adaptive mutations are generated and protect cells is important for our knowledge of cancer biology and evolution. Here, we studied the adaptation of cancer cells to topoisomerase (Top1) inhibitor irinotecan, which triggers DNA breaks, resulting in cytotoxicity. The resistance mechanism was based on the gradual accumulation of hundreds of thousands of recurrent mutations in non-coding DNA at sequence-specific Top1 cleavage sites. Repair of DSBs at these sites following initial irinotecan exposures created mutant sequences that were resistant to further Top1 cleavage. Therefore, by creating DNA breaks Top1 increases the rate of highly protective mutations specifically at such spots, thus explaining a puzzling need of dose escalation in resistance development.


2016 ◽  
Vol 04 (01) ◽  
pp. 4-10

AbstractImmunosuppression permits graft survival after transplantation and consequently a longer and better life. On the other hand, it increases the risk of infection, for instance with cytomegalovirus (CMV). However, the various available immunosuppressive therapies differ in this regard. One of the first clinical trials using de novo everolimus after kidney transplantation [1] already revealed a considerably lower incidence of CMV infection in the everolimus arms than in the mycophenolate mofetil (MMF) arm. This result was repeatedly confirmed in later studies [2–4]. Everolimus is now considered a substance with antiviral properties. This article is based on the expert meeting “Posttransplant CMV infection and the role of immunosuppression”. The expert panel called for a paradigm shift: In a CMV prevention strategy the targeted selection of the immunosuppressive therapy is also a key element. For patients with elevated risk of CMV, mTOR inhibitor-based immunosuppression is advantageous as it is associated with a significantly lower incidence of CMV events.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yağmur Demircan Yalçın ◽  
Taylan Berkin Töral ◽  
Sertan Sukas ◽  
Ender Yıldırım ◽  
Özge Zorlu ◽  
...  

AbstractWe report the development of a lab-on-a-chip system, that facilitates coupled dielectrophoretic detection (DEP-D) and impedimetric counting (IM-C), for investigating drug resistance in K562 and CCRF-CEM leukemia cells without (immuno) labeling. Two IM-C units were placed upstream and downstream of the DEP-D unit for enumeration, respectively, before and after the cells were treated in DEP-D unit, where the difference in cell count gave the total number of trapped cells based on their DEP characteristics. Conductivity of the running buffer was matched the conductivity of cytoplasm of wild type K562 and CCRF-CEM cells. Results showed that DEP responses of drug resistant and wild type K562 cells were statistically discriminative (at p = 0.05 level) at 200 mS/m buffer conductivity and at 8.6 MHz working frequency of DEP-D unit. For CCRF-CEM cells, conductivity and frequency values were 160 mS/m and 6.2 MHz, respectively. Our approach enabled discrimination of resistant cells in a group by setting up a threshold provided by the conductivity of running buffer. Subsequent selection of drug resistant cells can be applied to investigate variations in gene expressions and occurrence of mutations related to drug resistance.


BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Cui Zhang ◽  
Cihan Oguz ◽  
Sue Huse ◽  
Lu Xia ◽  
Jian Wu ◽  
...  

Abstract Background Rodent malaria parasites are important models for studying host-malaria parasite interactions such as host immune response, mechanisms of parasite evasion of host killing, and vaccine development. One of the rodent malaria parasites is Plasmodium yoelii, and multiple P. yoelii strains or subspecies that cause different disease phenotypes have been widely employed in various studies. The genomes and transcriptomes of several P. yoelii strains have been analyzed and annotated, including the lethal strains of P. y. yoelii YM (or 17XL) and non-lethal strains of P. y. yoelii 17XNL/17X. Genomic DNA sequences and cDNA reads from another subspecies P. y. nigeriensis N67 have been reported for studies of genetic polymorphisms and parasite response to drugs, but its genome has not been assembled and annotated. Results We performed genome sequencing of the N67 parasite using the PacBio long-read sequencing technology, de novo assembled its genome and transcriptome, and predicted 5383 genes with high overall annotation quality. Comparison of the annotated genome of the N67 parasite with those of YM and 17X parasites revealed a set of genes with N67-specific orthology, expansion of gene families, particularly the homologs of the Plasmodium chabaudi erythrocyte membrane antigen, large numbers of SNPs and indels, and proteins predicted to interact with host immune responses based on their functional domains. Conclusions The genomes of N67 and 17X parasites are highly diverse, having approximately one polymorphic site per 50 base pairs of DNA. The annotated N67 genome and transcriptome provide searchable databases for fast retrieval of genes and proteins, which will greatly facilitate our efforts in studying the parasite biology and gene function and in developing effective control measures against malaria.


2021 ◽  
Vol 23 (5) ◽  
pp. 739-743
Author(s):  
Silvia Schiavoni ◽  
Carlotta Spagnoli ◽  
Susanna Rizzi ◽  
Grazia Gabriella Salerno ◽  
Daniele Frattini ◽  
...  

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Osama Salah Mohamed El Sharkawy ◽  
Zeinab Anwar El kabbany ◽  
Neveen Tawakol Younis ◽  
Khaled Aboulfotouh Ahmad ◽  
Ahmed Darwish Mahmoud ◽  
...  

Abstract Objective To select patients with drug resistant epilepsy following up in Pediatrics Neurology Outpatient Clinic of Children's Hospital, Ain Shams University who are candidates for epilepsy surgery and to detect outcome of epilepsy surgery in such children as regards seizures control. Methods This prospective study was conducted over a period of 36 months and comprises of 3 stages. Stage 1 includes selection of candidates for epilepsy surgery and preoperative evaluation. Evaluation included clinical assessment, video EEG, MRI epilepsy protocol. Stage 2 include surgery phase where decision of surgery was made by a multidisciplinary team. Stage 3 includes post-operative evaluation as regards Seizures frequency, Seizures Severity using Chalfont score, Engel Epilepsy Surgery Outcome Scale and the International League Against Epilepsy (ILAE) outcome classification. Data was tabulated and analyzed with SSPS package for windows. Results 17 patients underwent epilepsy surgery. Results revealed significant decrease in seizures frequency and severity at 6 and 12 months after surgery. As regards Engel Epilepsy Surgery Outcome Scale 11 (64.7%) patients were class I at 12 months. As regards the ILAE outcome classification 10 (58.8%) patients are class 1 at 12 months. Conclusions epilepsy surgery can be a hope for patients with drug resistant epilepsy who are well selected and evaluated preoperatively. New studies on larger number and for longer duration are recommended.


2007 ◽  
Vol 13 (11) ◽  
pp. 1759-1762 ◽  
Author(s):  
Didier Ménard ◽  
Armand Eugène Randrianarivo-Solofoniaina ◽  
Bedja Said Ahmed ◽  
Martial Jahevitra ◽  
Landy Valérie Andriantsoanirina ◽  
...  

Author(s):  
Vinod Kumar Gurjar

Abstract: The extremely drug resistant may be a worldwide public ill health in recent years. Molecules with newer targets and an alternate mechanism of action is an urgent requirement of improvement of latest drugs. The utilization of heterocyclic compounds has been increased dramatically over the last 70 years due to their wide selection of technical applications and their favorable environmental and toxicological properties The 1,8-naphthyridine and quinoline 3-carboxylic acid derivatives that we'll manufacture during this method will change the potency and specificity of fluoroquinolones. Taking under consideration the findings, the goal is to style and manufacture 1, 8-naphthyridine and quinoline 3-carboxylic acid derivatives. The synthesized compounds are going to be characterized using multiple analytical techniques, virtual screening, and in-silico ADME/T prediction. Keywords: 1, 8-Naphthyridine, Quinoline, ADMET, Heterocyclic Compound


2021 ◽  
Vol 20 (2) ◽  
pp. 282-287
Author(s):  
Yuling Wang ◽  
Kai Wang ◽  
Shilei Ding ◽  
Shuguang Wang ◽  
Rubin Gu

Gastric carcinoma is one of the most prevalent malignancies with high morbidity and mortality. While chemotherapy is the major means for the management gastric carcinoma, tumors gradually exhibit drug resistance. Therefore, there is a need for agents capable of enhancing the sensitivity of tumor cells to chemotherapy. Herein, we have examined the effect of Celastrus orbiculatus extracts on chemosensitivity of drug resistant gastric carcinoma cells. Human gastric carcinoma cells (MGC-803 and SGC-7901) were cultured in the presence of cisplatin for the selection of drug resistant gastric cells. Next, the effect of C. orbiculatus extracts on multiplication capacity of drug resistant MGC-803 and SGC-7901 cells was examined by a variety of measures. Following C. orbiculatus extract treatment, the multiplication and invasiveness of drug resistant MGC-803 and SGC-7901 cells declined remarkably, with increased apoptosis and decreased levels of β-catenin, c-Myc, and cyclin D1 proteins, protein markers critical to cell proliferation, differentiation, and apoptosis. In summary, C. orbiculatus extract can effectively improve the sensitivity of cisplatin resistant gastric carcinoma cells to cisplatin and promote the apoptosis of tumor cells through the inhibition of the expression of proteins associated with the Wnt/β-catenin axis.


Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 337
Author(s):  
Juliann Nzembi Makau ◽  
Ken Watanabe ◽  
Hiroki Otaki ◽  
Satoshi Mizuta ◽  
Takeshi Ishikawa ◽  
...  

The emergence of resistance to currently available anti-influenza drugs has heightened the need for antivirals with novel mechanisms of action. The influenza A virus (IAV) nucleoprotein (NP) is highly conserved and essential for the formation of viral ribonucleoprotein (vRNP), which serves as the template for replication and transcription. Recently, using in silico screening, we identified an antiviral compound designated NUD-1 (a 4-hydroxyquinolinone derivative) as a potential inhibitor of NP. In this study, we further analyzed the interaction between NUD-1 and NP and found that the compound interferes with the oligomerization of NP, which is required for vRNP formation, leading to the suppression of viral transcription, protein synthesis, and nuclear export of NP. We further assessed the selection of resistant variants by serially passaging a clinical isolate of the 2009 H1N1 pandemic influenza virus in the presence of NUD-1 or oseltamivir. NUD-1 did not select for resistant variants after nine passages, whereas oseltamivir selected for resistant variants after five passages. Our data demonstrate that NUD-1 interferes with the oligomerization of NP and less likely induces drug-resistant variants than oseltamivir; hence, it is a potential lead compound for the development of novel anti-influenza drugs.


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