Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30% response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. Methods: We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump. Results: We found that the resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Conclusions: Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan

Common variants in P2RY11 are associated with narcolepsy.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov'tresearch support, u.s. gov't, p.h.s.2011 Jan2010 12 19importedErratum in : Nat Genet. 2011 Oct;43(10):1040

Prevalence of type 2 diabetes in psychiatric disorders: an umbrella review with meta-analysis of 245 observational studies from 32 systematic reviews

Aims/hypothesis: Estimates of the global prevalence of type 2 diabetes vary between 6% and 9%. The prevalence of type 2 diabetes has been investigated in psychiatric populations but a critical appraisal of the existing evidence is lacking, and an overview is needed. This umbrella review summarises existing systematic reviews of observational studies investigating the prevalence of type 2 diabetes in people with a psychiatric disorder. Methods: We searched PubMed, EMBASE, PsycINFO and the Cochrane Database of Systematic Reviews from inception to 17 January 2021 and screened reference lists of included systematic reviews. On the basis of prespecified criteria, we included systematic reviews investigating the prevalence of type 2 diabetes in adults (aged ≥18 years) with a psychiatric disorder. Titles and abstracts of 5155 identified records and full texts of 431 selected studies were screened by two independent reviewers, based on predefined eligibility criteria and an a priori developed extraction form, following the PRISMA and MOOSE guidelines. Risk of bias was assessed with the ROBIS instrument. Data extracted from primary studies were synthesised using random-effects meta-analyses. Results: A total of 32 systematic reviews with 245 unique primary studies were identified and met inclusion criteria. Twelve had low risk of bias. They reported type 2 diabetes prevalence estimates ranging from 5% to 22% depending on the specific psychiatric disorder. We meta-analysed data for ten categories of psychiatric disorders and found the following prevalence estimates of type 2 diabetes: in people with a sleep disorder: 40%; binge eating disorder: 21%; substance use disorder: 16%; anxiety disorder: 14%; bipolar disorder: 11%; psychosis: 11%; schizophrenia: 10%; a mixed group of psychiatric disorders: 10%; depression: 9%; and in people with an intellectual disability 8%. All meta-analyses revealed high levels of heterogeneity. Conclusions/interpretation: Type 2 diabetes is a common comorbidity in people with a psychiatric disorder. Future research should investigate whether routine screening for type 2 diabetes and subsequent prevention initiatives for these people are warranted. PROSPERO registration no. CRD42020159870

Deposit Probe Measurements in Large Biomass-Fired Grate Boilers and Pulverized-Fuel Boilers

A number of full-scale deposit probe measuring campaigns conducted in grate-fired and suspension-fired boilers, fired with biomass, have been reviewed and compared. The influence of operational parameters on the chemistry of ash and deposits, on deposit build-up rates, and on shedding behavior has been examined. The firing technology and the fuel utilized influence the fly ash and deposit chemical composition. In grate-firing, K, Cl, and S are enriched in the fly ash compared to the fuel ash, while the fly ash in suspension-firing is relatively similar to the fuel ash. The chemical composition of the deposits formed is determined by the fly ash composition and the flue gas temperature; increases in the local flue gas temperature lead to higher contents of Si and Ca and lower contents of Cl in the deposits. The net deposit build-up rates in grate-fired and suspension-fired boilers are at similar levels, 0–100 g/m²·h, while the ash deposit propensity is an order of magnitude larger in grate fired boilers than in suspension-fired boilers. Deposit build-up rates were found to increase at flue gas temperatures close to the melting temperatures of the fly ash. Furthermore, the rate of deposit build-up increased with the K-content of the fuel ash and fly ash for grate-fired boilers. For suspension-fired boilers, deposition rates are comparatively low for wood-firing and increase with increasing fuel straw shares. Shedding of deposits occurs by melting during straw-firing on a grate at high flue gas temperatures (>900 °C). At lower flue gas temperatures, the deposits can be removed by soot blowing. The required soot blower impact pressure is strongly influenced by the surface temperature, such that a high surface temperature makes the deposit more difficult to remove. During straw/wood-firing in suspension-fired boilers, shedding occurred by debonding with incomplete removal at flue gas temperatures of 600–1000 °C and by debonding with complete removal during wood-firing in suspension-fired boilers at high flue gas temperatures (1300 °C). Shedding events were not observed during wood suspension-firing at low flue gas temperatures (<900 °C). Here, a steady-state mass of deposits on the probe was observed. Increased exposure times and probe temperatures lead to deposits that are difficult to remove. This was observed for grate-firing of straw and for straw/wood firing in suspension-fired boilers