scholarly journals miR-579-3p controls melanoma progression and resistance to target therapy

2016 ◽  
Vol 113 (34) ◽  
pp. E5005-E5013 ◽  
Author(s):  
Luigi Fattore ◽  
Rita Mancini ◽  
Mario Acunzo ◽  
Giulia Romano ◽  
Alessandro Laganà ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Target Therapy ◽  
Ectopic Expression ◽  
Mek Inhibitors ◽  
Ubiquitin Protein Ligase ◽  
Activating Mutations ◽  
Development Of Resistance ◽  
Negative Prognostic Factor ◽  
Adaptive Mechanisms ◽  
Before And After

Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3′UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies.

RNA N-6-methyladenosine enzymes and resistance of cancer cells to chemotherapy and radiotherapy

Epigenomics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 801-809 ◽  
Author(s):  
Meiyi Xiang ◽  
Wensu Liu ◽  
Wei Tian ◽  
Abin You ◽  
Dajun Deng
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Environmental Changes ◽  
Experimental Studies ◽  
Rna Modification ◽  
Rna Modifications ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Promising Target ◽  
Adaptive Mechanisms

Aim: As one of the early adaptive mechanisms by which cells respond to environmental changes, RNA modification appears to be a very promising target for cancer treatment. Results: RNA modifications are currently a hot topic in epigenetic research. Emerging experimental studies show that expression alterations of multiple m6A enzymes, including demethylase FTO, methyltransferase METTL3 and WTAP, mediate the development of resistance of cancer cells to various treatments. A set of small molecular chemical drugs targeted to these m6A enzymes are under development. Intervention of RNA m6A methylation is a possible therapeutic strategy to overcome drug resistance. Conclusions: RNA m6A methylation may play a crucial role in drug resistance development and intervention in cancer cells.

scholarly journals Fixation eye movement abnormalities and stereopsis recovery following strabismus repair

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Talora L. Martin ◽  
Jordan Murray ◽  
Kiran Garg ◽  
Charles Gallagher ◽  
Aasef G. Shaikh ◽  
...  
Keyword(s):  
Eye Movements ◽  
Eye Movement ◽  
Functional Improvement ◽  
Slow Phase ◽  
Fixational Eye Movements ◽  
Movement Characteristics ◽  
Adaptive Mechanisms ◽  
Before And After ◽  
Gaze Holding ◽  
Fixational Saccades

AbstractWe evaluated the effects of strabismus repair on fixational eye movements (FEMs) and stereopsis recovery in patients with fusion maldevelopment nystagmus (FMN) and patients without nystagmus. Twenty-one patients with strabismus, twelve with FMN and nine without nystagmus, were tested before and after strabismus repair. Eye-movements were recorded during a gaze-holding task under monocular viewing conditions. Fast (fixational saccades and quick phases of nystagmus) and slow (inter-saccadic drifts and slow phases of nystagmus) FEMs and bivariate contour ellipse area (BCEA) were analyzed in the viewing and non-viewing eye. Strabismus repair improved the angle of strabismus in subjects with and without FMN, however patients without nystagmus were more likely to have improvement in stereoacuity. The fixational saccade amplitudes and intersaccadic drift velocities in both eyes decreased after strabismus repair in subjects without nystagmus. The slow phase velocities were higher in patients with FMN compared to inter-saccadic drifts in patients without nystagmus. There was no change in the BCEA after surgery in either group. In patients without nystagmus, the improvement of the binocular function (stereopsis), as well as decreased fixational saccade amplitude and intersaccadic drift velocity, could be due, at least partially, to central adaptive mechanisms rendered possible by surgical realignment of the eyes. The absence of improvement in patients with FMN post strabismus repair likely suggests the lack of such adaptive mechanisms in patients with early onset infantile strabismus. Assessment of fixation eye movement characteristics can be a useful tool to predict functional improvement post strabismus repair.

scholarly journals A microfluidic device enabling drug resistance analysis of leukemia cells via coupled dielectrophoretic detection and impedimetric counting

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yağmur Demircan Yalçın ◽  
Taylan Berkin Töral ◽  
Sertan Sukas ◽  
Ender Yıldırım ◽  
Özge Zorlu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
K562 Cells ◽  
Leukemia Cells ◽  
Drug Resistant ◽  
Wild Type ◽  
Gene Expressions ◽  
Before And After ◽  
The Difference ◽  
Selection Of ◽  
Resistant Cells

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.

Coumarin-1,2,3-triazole Hybrid Molecules: An Emerging Scaffold for Combating Drug Resistance

2021 ◽  
Vol 21 ◽  
Author(s):  
Harish C. Upadhyay
Keyword(s):  
Drug Resistance ◽  
Antimicrobial Agents ◽  
Plant Secondary Metabolites ◽  
Cost Effective ◽  
Resistance Mechanisms ◽  
Biologically Active ◽  
Multidrug Therapy ◽  
Diverse Range ◽  
Development Of Resistance ◽  
Hybrid Molecules

: No doubt antibiotics have saved billions of lives, but lack of novel antibiotics, development of resistance mechanisms in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria hamper the successful treatment of infections. Due to widespread emergence of resistance, even the new families of antimicrobial agents have a short life expectancy. Drugs acting on single target often lead to drug resistance and are associated with various side effects. To overcome this problem either multidrug therapy or single drug acting on multiple targets may be used. The later are called ‘hybrid molecules’ which are formed by clubbing two biologically active pharmacophores together with or without an appropriate linker. In this rapidly evolving era, the development of natural product-based hybrid molecules may be a super-alternative to multidrug therapy to combat drug resistance caused by various bacterial and fungal strains. Coumarins (benzopyran-2-one) are one of the earliest reported plant secondary metabolites having clinically proven diverse range of pharmacological properties. On the other hand, 1,2,3-triazole is a common pharmacophore in many drugs responsible for polar interactions improving the solubility and binding affinity to biomolecular targets. In this review we discuss recent advances in Coumarin-1,2,3-triazole hybrids as potential antibacterial agents aiming to provide a useful platform for the exploration of new leads with broader spectrum, more effectiveness, less toxicity with multiple modes of action for the development of cost-effective and safer drugs in the future.

Antimalarial drug resistance markers in human immunodeficiency virus (HIV)-positive and HIV-negative adults with asymptomatic malaria infections in Port Harcourt, Nigeria

2021 ◽  
Author(s):  
Ifeyinwa Chijioke-Nwauche ◽  
Mary C Oguike ◽  
Chijioke A Nwauche ◽  
Khalid B Beshir ◽  
Colin J Sutherland
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Drug Susceptibility ◽  
Blood Film ◽  
University Hospital ◽  
Hiv Positive ◽  
Asymptomatic Malaria ◽  
Immunodeficiency Virus ◽  
Before And After ◽  
Hiv Negative

Abstract Background In Nigeria, indiscriminate use of antimalarial drugs may contribute to the threat of drug resistance, but this has not been evaluated among people living with human immunodeficiency virus (HIV). Methods HIV-positive adults attending a university hospital HIV clinic and HIV-negative adult volunteers from the university hospital community with a positive blood film were treated with artemether–lumefantrine. Parasite DNA from before and after treatment was polymerase chain reaction amplified to identify molecular markers of drug susceptibility. Results The pfcrt76T genotype was prevalent among both HIV-positive and HIV-negative participants (78.6% and 68.2%, respectively). Three new mutations in the pfmdr1 gene—F73S, S97L and G165R—and the uncommon pfdhps S436F variant were detected, whereas pfdhps K540E and pfdhfr I164L were absent. The A437G allele of pfdhps predominated (62/66 [94%]). The I431 V mutation was found in 19 of 66 pretreatment pfdhps sequences (28.8%). The pfmdr1 86N allele was significantly more common at day 3 post-treatment than at baseline (odds ratio 8.77 [95% confidence interval 1.21 to 380]). Conclusions We found evidence of continued chloroquine use among HIV-positive individuals. Selection for the pfmdr1 86N after artemether–lumefantrine treatment was observed, indicating a possible threat to antimalarial efficacy in the study area. The complexity of pfdhps haplotypes emphasises the need for careful monitoring of anti-folate susceptibility in Nigeria.

scholarly journals Machine-learning reveals that Mycobacterium tuberculosis genotypes and anatomic disease site impacts drug resistance and disease transmission among patients with proven extra-pulmonary tuberculosis

2020 ◽  
Author(s):  
Doctor Busizwe Sibandze ◽  
Beki Themba Magazi ◽  
Lesibana Anthony Malinga ◽  
Nontuthuko Excellent Maningi ◽  
Bong Akee Shey ◽  
...  
Keyword(s):  
Machine Learning ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Disease Transmission ◽  
East Asian ◽  
Extrapulmonary Tuberculosis ◽  
Machine Learning Algorithms ◽  
East African ◽  
Development Of Resistance ◽  
Asian Lineage

Abstract Background: There is a general dearth of information on extrapulmonary tuberculosis (EPTB). Here, we investigated Mycobacterium tuberculosis (Mtb) drug resistance and transmission patterns in EPTB patients treated in the Tshwane metropolitan area, in South Africa.Methods: Consecutive Mtb culture-positive non-pulmonary samples from unique EPTB patients underwent mycobacterial genotyping and were assigned to phylogenetic lineages and transmission clusters based on spoligotypes. MTBDRplus assay was used to search mutations for isoniazid and rifampin resistance. Machine learning algorithms were used to identify clinically meaningful patterns in data. We computed odds ratio (OR), attributable risk (AR) and corresponding 95% confidence intervals (CI). Results: Of the 70 isolates examined, the largest cluster comprised 25 (36%) Mtb strains that belonged to the East Asian lineage. East Asian lineage was significantly more likely to occur within chains of transmission when compared to the Euro-American and East-African Indian lineages: OR= 10.11 (95% CI: 1.56-116). Lymphadenitis, meningitis and cutaneous TB, were significantly more likely to be associated with drug resistance: OR=12.69 (95% CI: 1.82-141.60) and AR = 0.25 (95% CI: 0.06-0.43) when compared with other EPTB sites, which suggests that poor rifampin penetration might be a contributing factor.Conclusions: The majority of Mtb strains circulating in the Tshwane metropolis belongs to East Asian, Euro-American and East-African Indian lineages. Each of these are likely to be clustered, suggesting on-going EPTB transmission. Since 25% of the drug resistance was attributable to sanctuary EPTB sites notorious for poor rifampin penetration, we hypothesize that poor anti-tuberculosis drug dosing might have a role in the development of resistance.

scholarly journals Melanoma Brain Metastases in the Era of Target Therapies: An Overview

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1640 ◽  
Author(s):  
Paolo Becco ◽  
Susanna Gallo ◽  
Stefano Poletto ◽  
Mirko Pio Manlio Frascione ◽  
Luca Crotto ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastases ◽  
Target Therapy ◽  
Mapk Signaling ◽  
Janus Kinase ◽  
Clinical Activity ◽  
Tumor Resistance ◽  
Sequential Approach ◽  
Mek Inhibitors ◽  
Dismal Prognosis

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed.

scholarly journals Current Advances in the Treatment of BRAF-Mutant Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 482 ◽  
Author(s):  
Hima Patel ◽  
Nour Yacoub ◽  
Rosalin Mishra ◽  
Aaron White ◽  
Long Yuan ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Individual Response ◽  
Term Survival ◽  
Mek Inhibitors ◽  
Development Of Resistance ◽  
Patient Responses ◽  
Braf Mutant

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

scholarly journals Targeting CDC7 sensitizes resistance melanoma cells to BRAFV600E-specific inhibitor by blocking the CDC7/MCM2-7 pathway

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shaimaa A. Gad ◽  
Hamdy E. A. Ali ◽  
Rofaida Gaballa ◽  
Rania M. Abdelsalam ◽  
Mourad Zerfaoui ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Metastatic Melanoma ◽  
Clinical Effect ◽  
Specific Inhibitor ◽  
Melanoma Cells ◽  
Development Of Resistance ◽  
Dual Targeting ◽  
Low Concentrations ◽  
Resistant Cells

Abstract Although the utilization of selective BRAFV600E inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has  emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAFV600E and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAFV600E- bearing melanoma cells. Dual targeting of CDC7 and BRAFV600E reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma.

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