O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

We evaluated the pharmacodynamic effects of the O6-methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O6-methylguanine (O6-meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O6-meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O6-meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O6-meG in PBMC DNA during treatment

Monte Carlo Simulations indicate that Chromati: Nanostructure is accessible by Light Microscopy

A long controversy exists about the structure of chromatin. Theoretically, this structure could be resolved by scattering experiments if one determines the scattering function - or equivalently the pair distribution function - of the nucleosomes. Unfortunately, scattering experiments with live cells are very difficult and limited to only a couple of nucleosomes

Chromatin compaction in terminally differentiated avian blood cells: the role of linker histone H5 and non-histone protein MENT

Chromatin has a tendency to shift from a relatively decondensed (active) to condensed (inactive) state during cell differentiation due to interactions of specific architectural and/or regulatory proteins with DNA. A promotion of chromatin folding in terminally differentiated avian blood cells requires the presence of either histone H5 in erythrocytes or non-histone protein, myeloid and erythroid nuclear termination stage-specific protein (MENT), in white blood cells (lymphocytes and granulocytes). These highly abundant proteins assist in folding of nucleosome arrays and self-association of chromatin fibers into compacted chromatin structures. Here, we briefly review structural aspects and molecular mode of action by which these unrelated proteins can spread condensed chromatin to form inactivated regions in the genome

Prevalence and progression of diabetic nephropathy in South Asian, white European and African Caribbean people with type 2 diabetes: A systematic review and meta-analysis

AIMS: To conduct a systematic review and meta-analysis of published observational evidence to assess the difference in the prevalence and progression of diabetic nephropathy, and the development of end-stage renal disease (ESRD) in people from three different ethnic groups with type 2 diabetes (T2DM). MATERIALS AND METHODS: Relevant studies were identified in a literature search of MEDLINE, EMBASE and reference lists of relevant studies published up to May 2018. We decided a priori that there were no differences in the prevalence and progression of diabetic nephropathy, and the development of ESRD in the three ethnicities with T2DM. Pooled relative risks of microalbuminuria by ethnicity were estimated by fitting three random effects meta-analyses models. A narrative synthesis of the nephropathy progression in the studies was carried out. The review was registered in PROSPERO (CRD42018107350). RESULTS: Thirty-two studies with data on 153 827 unique participants were eligible for inclusion in the review. The pooled prevalence ratio of microalbuminuria in South Asian compared with white European participants was 1.14 (95% confidence interval [CI] 0.99, 1.32; P = 0.065), while for African Caribbean vs South Asian participants the pooled prevalence ratio was 1.08 (95% CI 0.93, 1.24; P = 0.327). Results for renal decline were inconsistent, with preponderance towards a high rate of disease progression in South Asian compared with white participants. The estimated pooled incidence rate ratio (IRR) for ESRD was significantly higher in African Caribbean vs white European participants: 2.75 (95% CI 2.01, 3.48; P < 0.001). CONCLUSION: The results of this review did not show a significant link between ethnicity (South Asian, white European and African Caribbean) and the prevalence of microalbuminuria; however, the IRR for ESRD in African Caribbean compared with white European participants was significantly higher. Further research is needed to explore the potential non-albuminuric pathways of progression to ESRD

Distribution and Genetic Profiles of Campylobacter in Commercial Broiler Production from Breeder to Slaughter in Thailand

Poultry and poultry products are commonly considered as the major vehicle of Campylobacter infection in humans worldwide. To reduce the number of human cases, the epidemiology of Campylobacter in poultry must be better understood. Therefore, the objective of the present study was to determine the distribution and genetic relatedness of Campylobacter in the Thai chicken production industry. During June to October 2012, entire broiler production processes (i.e., breeder flock, hatchery, broiler farm and slaughterhouse) of five broiler production chains were investigated chronologically. Representative isolates of C. jejuni from each production stage were characterized by flaA SVR sequencing and multilocus sequence typing (MLST). Amongst 311 selected isolates, 29 flaA SVR alleles and 17 sequence types (STs) were identified. The common clonal complexes (CCs) found in this study were CC-45, CC-353, CC-354 and CC-574. C. jejuni isolated from breeders were distantly related to those isolated from broilers and chicken carcasses, while C. jejuni isolates from the slaughterhouse environment and meat products were similar to those isolated from broiler flocks. Genotypic identification of C. jejuni in slaughterhouses indicated that broilers were the main source of Campylobacter contamination of chicken meat during processing. To effectively reduce Campylobacter in poultry meat products, control and prevention strategies should be aimed at both farm and slaughterhouse levels