Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Actively dividing cells show progressive loss of telomeric DNA during successive rounds of replication due to end-replication problem. Telomere shortening has been proposed as a regulatory mechanism that controls the replicative capacity of primary cells before undergoing cellular senescence. In immortal cells including cancer, cellular senescence can be overcome by reactivation of telomerase or by a telomerase-independent mechanism for lengthening telomeres. In this work, we present a novel example of telomere elongation mechanism in a human stomach adenocarcinoma cell line which was selected for resistance to adriamycin. The resistant cell line (MKN/ADR) had long terminal restriction fragments (TRFs) of up to approximately 50 kb, while its parent cell line (MKN-45) had the TRFs, consisting of a smear extending from approximately 4 to approximately 25 kb. The very large TRFs in MKN/ADR cell line were proven to be telomeric by digestion with the exonuclease Bal31. When telomerase activity was examined using the PCR-based telomeric repeat amplification protocol (TRAP) assay, MKN/ADR cell line showed reduced activity to about 10% of that in MKN-45 cell line. The correlation between reduced telomerase activity and mRNA expression of telomerase subunits in MKN/ADR cell line was assessed by the reverse transcriptase-PCR analysis. The level of human telomerase reverse transcriptase (hTERT) mRNA was lower in MKN/ADR cell line than in MKN-45 cell line. This observation correlates with the finding that telomerase activity is reduced about 10-fold in MKN/ADR cell line. Reverse transcriptase-PCR analysis also revealed a close correlation between telomerase-associated protein (TP1) mRNA expression and telomerase activity in MKN/ADR cell line. In contrast, expression levels of human telomerase RNA (hTR) were identical in both MKN/ADR and MKN-45 cell lines. Taken together, these data suggest that telomeres in MKN/ADR cell line may be regulated through a novel mechanism other than telomerase. Although the basis for telomere elongation mechanism in MKN/ADR cell line is not yet understood, the occurrence of alternative mechanism for telomere elongation in drug-resistant cancer cells may have an important implication for use of telomerase inhibitors in human cancer treatment.
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PMID:A novel telomere elongation in an adriamycin-resistant stomach cancer cell line with decreased telomerase activity. 1201 44

The scale-up of antiretroviral therapy (ART) in South Africa substantially reduced AIDS-related deaths and new HIV infections. However, its success is threatened by the emergence of resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI). The MARISA (Modelling Antiretroviral drug Resistance In South Africa) model presented here aims at investigating the time trends and factors driving NNRTI resistance in South Africa. MARISA is a compartmental model that includes the key aspects of the local HIV epidemic: continuum of care, disease progression, and gender. The dynamics of NNRTI resistance emergence and transmission are then added to this framework. Model parameters are informed using data from HIV cohorts participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) and literature estimates, or fitted to UNAIDS estimates. Using this novel approach of triangulating clinical and resistance data from various sources, MARISA reproduces the time trends of HIV in South Africa in 2005-2016, with a decrease in new infections, undiagnosed individuals, and AIDS-related deaths. MARISA captures the dynamics of the spread of NNRTI resistance: high levels of acquired drug resistance (ADR, in 83% of first-line treatment failures in 2016), and increasing transmitted drug resistance (TDR, in 8.1% of ART initiators in 2016). Simulation of counter-factual scenarios reflecting alternative public health policies shows that increasing treatment coverage would have resulted in fewer new infections and deaths, at the cost of higher TDR (11.6% in 2016 for doubling the treatment rate). Conversely, improving switching to second-line treatment would have led to lower TDR (6.5% in 2016 for doubling the switching rate) and fewer new infections and deaths. Implementing drug resistance testing would have had little impact. The rapid ART scale-up and inadequate switching to second-line treatment were the key drivers of the spread of NNRTI resistance in South Africa. However, even though some interventions could have substantially reduced the level of NNRTI resistance, no policy including NNRTI-based first line regimens could have prevented this spread. Thus, by combining epidemiological data on HIV in South Africa with biological data on resistance evolution, our modelling approach identified key factors driving NNRTI resistance, highlighting the need of alternative first-line regimens.
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PMID:Bridging the gap between HIV epidemiology and antiretroviral resistance evolution: Modelling the spread of resistance in South Africa. 3123 94