Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC

A conceptual model for pricing health & safety on construction projects

Abstract: The competitive nature of the construction industry (CI) has marginalised health and safety (H&S) on construction projects. Most clients in the CI, if not all, award projects based on price and in most cases to the “cheapest bidder” and not the “safer bidder”. Consequently, such practices have compelled contractors to lower their bid price to increase their chances of being awarded projects, whereas in contrast, H&S is marginalised. The study, which was a case study of nine projects of which six were civil engineering projects and three building construction projects, was purposed to conceptualise a model for pricing H&S on construction projects. The findings showed that contractors do price for H&S using an itemised breakdown even though such items are not included as a trade in the Bill of Quantities (BOQs). With regards to expenditure, the actual costs of H&S ranged between 2.9% and 3.98% for projects with a value below R500 million and between 4.08% and 4.90% for projects with a value above R500 million. Health and safety costs were found to be directly proportional to the projects value and indirectly influenced by the client. Previous studies recommended that H&S should be priced as an itemised trade in the BOQs, but such recommendations are yet to be implemented. The lack of a conceptual model for pricing H&S on construction makes accurate and adequate monitoring of H&S costs unlikely. Thus, a standardised pricing model will assist contractors to price adequately for H&S, and clients, to ensure that provision for H&S measures on construction projects is adequate as required by the Construction Regulations (CR) 2014

High-Level Microbial Production of Propionate in Engineered Escherichia coli

Biological platforms for propionate production have been limited to anaerobic native microbial producers, such as Propionibacterium and Clostridium. In this work, we demonstrated high-level heterologous production of propionate under microaerobic conditions in engineered Escherichia coli (E. coli). Activation of the native Sleeping beauty mutase (Sbm) operon not only transformed E. coli to be propionogenic (i.e. propionate-producing) but also introduced an intracellular “flux competition” between the traditional C2-fermentative pathway (forming acetate and ethanol) and the novel C3-fermentative pathway (forming propionate and 1-propanol). The propionogenic E. coli was further engineered by inactivation or overexpression of various genes involved in the glycerol dissimilation pathways and their individual genetic effects on propionate production were investigated. Generally, knocking out genes involved in glycerol dissimilation (except glpA) can minimize levels of solventogenesis and shift more dissimilated carbon flux toward the C3-fermentative pathway. For effective propionate production, glycerol dissimilation should be channeled through the respiratory pathway and, upon suppressed solventogenesis with minimal production of highly reduced alcohols, the alternative NADH-consuming route associated with propionate synthesis can be critical for more flexible redox balancing. With the implementation of various biochemical and genetic strategies, high propionate titres of more than 11 g/L with high yields up to 0.4 g-propionate/g-glycerol (accounting for ~50% of dissimilated glycerol) were achieved, implying the potential for industrial application. To our knowledge, this represents the most effective non-native engineered microbial system for propionate production.1 yea

Identifying the cost drivers for pricing health & safety (H&S) on construction projects

Abstract: For many years, the construction industry (CI) has been considered as one of the most dangerous industry due its H&S statistics expressed in terms of accidents and injuries which remain high. Notwithstanding the fact that many research studies have been conducted at both academic and industry level to find solutions, it can be rightly argued that the H&S performance in the CI is still questionable. One of the factors that have impacted negatively on the H&S performance in the CI is the competitive nature of the CI where most clients award their contracts based on price. Consequently, this practice has compelled contractors to lower their bid amounts leading to H&S being marginalised..

Rubric-Referenced Self-Assessment and Self-Efficacy for Writing

The authors investigated the relation between long- and short-term rubric use (including self-assessment), gender, and self-efficacy for writing by elementary and middle school students (N = 268). They measured long-term rubric use with a questionnaire. They manipulated short-term rubric use by a treatment that involved reviewing a model and using a rubric to self-assess drafts. The authors collected self efficacy ratings 3 times. Results revealed that girls’ self-efficacy was higher than boys’ self-efficacy before they began writing. The authors found interactions between gender and rubric use: Average self-efficacy ratings increased as students wrote, regardless of condition, but the increase in the self-efficacy of girls in the treatment group was larger than that for girls in the comparison group, and long-term rubric use associated only with the self-efficacy of girls

Costing of health and safety elements in 2 construction projects in Gauteng, South Africa

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Metabolic perturbations in cardiomyopathies: implications for early diagnosis and targeted interventions

Cardiomyopathy (CM) is a heterogeneous group of diseases characterized by structural and functional changes in the heart, with the exact cause often remaining unknown. CM can arise from both inherited and acquired metabolic disturbances. Alterations in energy production and substrate utilization impair the heart's contractile function and limit its ability to respond to stress. Given the complexity and dynamic nature of CM, as well as the multiple etiologies involved, we reviewed metabolomic studies employing high-throughput platforms to understand how metabolic pathways shift across CM subtypes and how these perturbations may inform clinical translation. Several recurring disruptions emerge across CM with alterations in amino acid metabolism (valine, leucine, methionine, tryptophan, tyrosine); mitochondrial redox imbalance (NAD/NADH shifts, niacinamide, acylcarnitines); and oxidative stress as central hallmarks. Each subtype, however, displays a different emphasis. For instance, hypertrophic CM is characterized by nucleotide remodeling, particularly in cases involving MYBPC3 mutations; dilated CM shows accumulation of Krebs cycle intermediates and trimethylamine-N-oxide; restrictive CM is associated with amino acid stress related to amyloidosis; tachycardia-induced CM involves fatty acid remodeling and elevated uric acid, while Takotsubo CM is linked to ketone utilization and glutamate excitotoxicity. Overall, a single metabolomic profile cannot capture CM. What emerges from this review is that subtype-specific shifts, and the way they interact, provide meaningful insight into disease mechanisms and highlight pathways with diagnostic, prognostic, and therapeutic relevance. This broader perspective shifts the focus beyond narrow comparisons, making the translational relevance of metabolomics in CM more apparent

Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia

Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome‐wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studie

Etoricoxib as a treatment of choice for patients with SLCO2A1 mutation exhibiting autosomal recessive primary hypertrophic osteoarthropathy: A case report

We reported a 22-year-old Emirati male with autosomal recessive primary hypertrophic osteoarthropathy caused by a possibly pathogenic homozygous non-synonymous variant in the SLCO2A1 gene (NM_005630.3: c.289C>T, p. Arg97Cys) presenting with joint swelling, forehead furrowing, and significant clubbing in all fingers and toes. Currently, no standard treatments are approved for this disease; medical care is palliative and includes non-steroidal anti-inflammatory drugs, corticosteroids, tamoxifen, retinoids, and risedronate. Colchicine may be helpful for the pain due to subperiosteal new bone formation. Our patient was treated with etoricoxib 60 mg once daily and showed a significant clinical improvement at the 6-month mark that was reversed upon the withdrawal of this medication. This case report highlights the importance of placing etoricoxib among first-line therapy recommendations for cases with confirmed primary hypertrophic osteoarthropathy diagnosis. To the best of our knowledge, this is the only case of primary hypertrophic osteoarthropathy from the Middle Eastern population of Arab ethnicity that has responded to non-steroidal anti-inflammatory drug therapy

Impact of sodium-glucose cotransporter-2 inhibitors on aging biomarkers and plasma ceramide levels in type 2 diabetes: beyond glycemic control

BackgroundAging is a complex biological process marked by the decline of physiological functions and heightened susceptibility to chronic illnesses, notably cardiometabolic disorders. Ceramides (Cer) are lipid derivatives linked to aging and metabolic diseases. Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i), widely used in managing type 2 diabetes, have an unclear impact on aging biomarkers and Cer profiles.ObjectiveThis study explored the association between SGLT2i use, plasma Cer levels (CerC16:0, CerC18:0, CerC22:0, CerC24:0, and CerC24:1), and aging biomarkers-Human Insulin-Like Growth Factor 1 (IGF-1), mammalian target of rapamycin (mTOR), 5-Methylcytosine (5MC), and Human H2AFX (Histone H2AX) in patients with type 2 diabetes mellitus (T2DM).MethodsIn this retrospective study, 95 participants were divided into three groups: patients on SGLT2i (n = 34), patients on non-SGLT2i anti-diabetic treatments (n = 36), and healthy controls (n = 25). Plasma Cer and aging biomarkers were quantified using Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) and ELISA, respectively. Principal component analysis (PCA) assessed group-based clustering, while ANCOVA evaluated group differences with confounder adjustment.ResultsSGLT2i-treated patients showed significantly lower CerC16:0, CerC22:0, and CerC24:1 levels (p p p ConclusionBeyond glucose control, SGLT2i may improve plasma Cer and aging markers in diabetic patients, supporting their broader therapeutic potential in aging and age-related diseases. Further large-scale studies are warranted to confirm these effects and underlying mechanisms