Drug Resistance
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Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5126
Enrique Rozengurt ◽  
Guido Eibl

Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.

2021 ◽  
pp. 45-51

Лекарственная устойчивость к антибиотикам вызвала необходимость поиска новых лекарственных средств и лекарственных форм. Известно, что семиорганические аддукты иода обладают широким спектром антимикробного действия. Эти же соединения, содержащие в своем составе молекулу галогена - иода, могут выступать в качестве галогенирующего агента в отношении антибиотиков. Изучено взаимодействие антибиотиков тетрациклина, гентамицина, хлорамфеникола, относящихся к классам поликетидов, аминогликозидов и амфениколов, соответственно, с аддуктом иода методами рефрактометрии, УФ-спектроскопии и ИК-спектроскопии. Показано, что антибиотик хлорамфеникол не взаимодействует с семиорганическим аддуктом иода ди2-аминопропионовой кислоты дитрииодоводород моногидратом (субстанция D1). Antibiotic drug resistance has necessitated the search for new drugs and dosage forms. It is known that semiorganic iodine adducts have a wide spectrum of antimicrobial effects. The same compounds containing a halogen-iodine molecule may act as a antibiotics halogenating agent. The interaction of antibiotics tetracycline, gentamicin, chloramphenicol belonging to the classes of polyketides, aminoglycosides and amphenicols, respectively, with iodine adduct by refractometry, UV spectroscopy and IR spectroscopy was studied. It has been shown that the antibiotic chloramphenicol does not interact with the semiorganic adduct of di-2-aminopropionic acid ditriiodinehydride monohydrate (D1 substance).

2021 ◽  
Vol 20 (1) ◽  
Christian Nsanzabana

AbstractArtemisinin resistance has emerged and spread in the Greater Mekong Sub-region (GMS), followed by artemisinin-based combination therapy failure, due to both artemisinin and partner drug resistance. More worrying, artemisinin resistance has been recently reported and confirmed in Rwanda. Therefore, there is an urgent need to strengthen surveillance systems beyond the GMS to track the emergence or spread of artemisinin and partner drug resistance in other endemic settings. Currently, anti-malarial drug efficacy is monitored primarily through therapeutic efficacy studies (TES). Even though essential for anti-malarial drug policy change, these studies are difficult to conduct, expensive, and may not detect the early emergence of resistance. Additionally, results from TES may take years to be available to the stakeholders, jeopardizing their usefulness. Molecular markers are additional and useful tools to monitor anti-malarial drug resistance, as samples collected on dried blood spots are sufficient to monitor known and validated molecular markers of resistance, and could help detecting and monitoring the early emergence of resistance. However, molecular markers are not monitored systematically by national malaria control programmes, and are often assessed in research studies, but not in routine surveillance. The implementation of molecular markers as a routine tool for anti-malarial drug resistance surveillance could greatly improve surveillance of anti-malarial drug efficacy, making it possible to detect resistance before it translates to treatment failures. When possible, ex vivo assays should be included as their data could be useful complementary, especially when no molecular markers are validated.

2021 ◽  
Vol 2 (4) ◽  
pp. 795-816
Md Salman Shakil ◽  
Kazi Mustafa Mahmud ◽  
Mohammad Sayem ◽  
Mahruba Sultana Niloy ◽  
Sajal Kumar Halder ◽  

Cancer is one of the major causes of death worldwide. Chemotherapeutic drugs have become a popular choice as anticancer agents. Despite the therapeutic benefits of chemotherapeutic drugs, patients often experience side effects and drug resistance. Biopolymers could be used to overcome some of the limitations of chemotherapeutic drugs, as well as be used either as anticancer agents or drug delivery vehicles. Chitosan is a biocompatible polymer derived from chitin. Chitosan, chitosan derivatives, or chitosan nanoparticles have shown their promise as an anticancer agent. Additionally, functionally modified chitosan can be used to deliver nucleic acids, chemotherapeutic drugs, and anticancer agents. More importantly, chitosan-based drug delivery systems improved the efficacy, potency, cytotoxicity, or biocompatibility of these anticancer agents. In this review, we will investigate the properties of chitosan and chemically tuned chitosan derivatives, and their application in cancer therapy.

2021 ◽  
Bilin Tao ◽  
Jizhou Wu ◽  
Beibei Qiu ◽  
Zhongqi Li ◽  
Mengyao Zhan ◽  

Abstract BackgroundMycobacterium tuberculosis complex (MTBC) is the causative agent of tuberculosis (TB). This study aims to map the global distribution of MTBC lineage and to explore the correlation between Global Health Security Index (GHSI) and drug resistance.MethodsWe mapped the global geographic distribution of MTBC lineages using the whole-genome sequencing (WGS) and verified data from the TBProfiler. The hierarchical structure was visualized in different continents and sublineages. We also performed two-dimensional twisted surface and interaction plots to explore the interactions. ResultsLineage 4 was widely distributed globally, while lineage 2 had the highest risk of developing DR-TB. We observed an interaction between GHSI and GDP on the prevalence of multidrug-resistant TB. In countries with ln(GDP per capita) ≥2.35, there was a negative association between GHSI and drug resistance. ConclusionsThere was a significantly different geographic distribution pattern of MTBC lineages in the world. The GHSI was related to the drug resistance of TB and was affected by the social-economic level.

2021 ◽  
Vol 21 (1) ◽  
Nobuyoshi Mori ◽  
Tatsuya Tada ◽  
Satoshi Oshiro ◽  
Kyoko Kuwahara-Arai ◽  
Teruo Kirikae ◽  

Abstract Background The worldwide spread of carbapenemase-producing Enterobacteriaceae (CPE) has reduced the clinical utility of carbapenems. Plasmids often play an important role in the spread of genes encoding drug-resistance factors, especially in the horizontal transfer of these genes among species of Enterobacteriaceae. This study describes a patient infected with three species of CPE carrying an identical transferrable IncL/M plasmid. Methods Clinical isolates of CPE were collected at St. Luke’s International Hospital, Tokyo, Japan, from 2015 to 2019. Three species of CPE isolates, Enterobacter cloacae, Klebsiella aerogenes and Serratia marcescens, were isolated from a patient who developed severe gallstone pancreatitis associated with bloodstream infection, with all three isolates producing IMP-1 metallo-β-lactamase. The complete sequences of the plasmids of the three isolates were determined by both MiSeq and MinION. The medical chart of this patient was retrospectively reviewed conducted to obtain relevant clinical information. Results The three CPE species carried an IncL/M plasmid, pSL264, which was 81,133 bp in size and harbored blaIMP-1. The genetic environment surrounding blaIMP-1 consisted of int1-blaIMP-1-aac(6’)-IIc-qacL-qacEdelta1-sul1-istB-IS21. Conjugation experiments showed that S. marcescens could transmit the plasmid to E. cloacae and K. aerogenes. In contrast, pSL264 could not transfer from E. cloacae or K. aerogenes to S. marcescens. Conclusion The IncL/M plasmid pSL264 harboring blaIMP-1 was able to transfer among different species of Enterobacteriaceae in a patient receiving long-term antimicrobial treatment. The worldwide emergence and spread of IncL/M plasmids harboring carbapenemase-encoding genes among species of Enterobacteriaceae is becoming a serious public health hazard.

2021 ◽  
Vol 5 (1) ◽  
T. L. Peters ◽  
T. Patil ◽  
A. T. Le ◽  
K. D. Davies ◽  
P. M. Brzeskiewicz ◽  

AbstractEGFR mutant non-small cell lung cancer patients' disease demonstrates remarkable responses to EGFR-targeted therapy, but inevitably they succumb to acquired resistance, which can be complex and difficult to treat. Analyzing acquired resistance through broad molecular testing is crucial to understanding the resistance mechanisms and developing new treatment options. We performed diverse clinical testing on a patient with successive stages of acquired resistance, first to an EGFR inhibitor with MET gene amplification and then subsequently to a combination EGFR and MET targeted therapies. A patient-derived cell line obtained at the time of disease progression was used to identify NRAS gene amplification as an additional driver of drug resistance to combination EGFR/MET therapies. Analysis of downstream signaling revealed extracellular signal-related kinase activation that could only be eliminated by trametinib treatment, while Akt activation could be modulated by various combinations of MET, EGFR, and PI3K inhibitors. The combination of an EGFR inhibitor with a MEK inhibitor was identified as a possible treatment option to overcome drug resistance related to NRAS gene amplification.

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258363
Ola D. A. Shammout ◽  
Naglaa S. Ashmawy ◽  
Sarra B. Shakartalla ◽  
Alaa M. Altaie ◽  
Mohammad H. Semreen ◽  

Drug resistance is responsible for the failure of many available anticancer drugs. Several studies have demonstrated the association between the alteration in sphingolipids (SPLs) and the development of drug resistance. To investigate the association between SPLs metabolism and doxorubicin (dox)-resistance in MCF-7 cells, a comparative sphingolipidomics analysis between dox-sensitive (parental) and -resistant MCF-7 cell lines along with validation by gene expression analysis were conducted. A total of 31 SPLs representing 5 subcategories were identified. The data obtained revealed that SPLs were clustered into two groups differentiating parental from dox-resistant cells. Eight SPLs were significantly altered in response to dox-resistance including SM (d18:1/16), SM (d18:1/24:2), SM (d18:1/24:0), SM (d18:1/20:0), SM (d18:1/23:1), HexCer (d18:1/24:0), SM (d18:1/15:0), DHSM (d18:0/20:0). The current study is the first to conclusively ascertain the potential involvement of dysregulated SPLs in dox-resistance in MCF-7 cells. SPLs metabolism in dox-resistant MCF-7 cells is oriented toward the downregulation of ceramides (Cer) and the concomitant increase in sphingomyelin (SM). Gene expression analysis has revealed that dox-resistant cells tend to escape from the Cer-related apoptosis by the activation of SM-Cer and GluCer-LacCer-ganglioside pathways. The enzymes that were correlated to the alteration in SPLs metabolism of dox-resistant MCF-7 cells and significantly altered in gene expression can represent potential targets that can represent a winning strategy for the future development of promising anticancer drugs.

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5117
Chandra K. Maharjan ◽  
Po Hien Ear ◽  
Catherine G. Tran ◽  
James R. Howe ◽  
Chandrikha Chandrasekharan ◽  

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

Lingkai Yang ◽  
Xin Huang ◽  
Haoyu Guo ◽  
Lutong Wang ◽  
Wenbo Yang ◽  

Osteosarcoma is the most common bone tumor affecting both adolescents and children. Although localized osteosarcoma has an overall survival of >70% in the clinic, metastatic, refractory, and recurrent osteosarcoma have poorer survival rates. Exosomes are extracellular vesicles released by cells and originally thought to be a way for cells to discard unwanted products. Currently, exosomes have been reported to be involved in intercellular cross-talk and induce changes in cellular behavior by transferring cargoes (proteins, DNA, RNA, and lipids) between cells. Exosomes regulate osteosarcoma progression, and processes such as tumorigenesis, proliferation, metastasis, angiogenesis, immune evasion, and drug resistance. Increasing evidences shows that exosomes have significant potential in promoting osteosarcoma progression and development. In this review, we describe the current research status of exosomes in osteosarcoma, focusing on the biological functions of osteosarcoma exosomes as well as their application in osteosarcoma as diagnostic biomarkers and therapeutic targets.

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