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Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy.
Monocyte/macrophages have been shown to be altered in monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) microenvironment.
We investigated the distribution of different subsets of monocytes (Mo) in blood and BM of newly-diagnosed untreated MGUS (
= 23), SMM (
= 14) and MM (
= 99) patients vs. healthy donors (HD;
= 107), in parallel to a large panel of cytokines and bone-associated serum biomarkers.
Our results showed normal production of monocyte precursors and classical Mo (cMo) in MGUS, while decreased in SMM and MM (
≤ 0.02), in association with lower blood counts of recently-produced CD62L
cMo in SMM (
= 0.004) and of all subsets of (CD62L
, CD62L
and FcεRI
) cMo in MM (
≤ 0.02). In contrast, intermediate and end-stage non-classical Mo were increased in BM of MGUS (
≤ 0.03), SMM (
≤ 0.03) and MM (
≤ 0.002), while normal (MGUS and SMMts provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+ cMo in normal bone homeostasis.Cape Town was the first city in South Africa to experience the full impact of the coronavirus disease 2019 (COVID-19) pandemic. We acquired samples from all suspected cases and their contacts during the first month of the pandemic from Tygerberg Hospital. Nanopore sequencing generated SARS-CoV-2 whole genomes. Phylogenetic inference with maximum likelihood and Bayesian methods were used to determine lineages that seeded the local epidemic. Three patients were known to have travelled internationally and an outbreak was detected in a nearby supermarket. Sequencing of 50 samples produced 46 high-quality genomes. The sequences were classified as lineages B, B.1, B.1.1.1, B.1.1.161, B.1.1.29, B.1.8, B.39, and B.40. All the sequences from persons under investigation (PUIs) in the supermarket outbreak (lineage B.1.8) fall within a clade from the Netherlands with good support (p > 0.9). In addition, a new mutation, 5209A>G, emerged within the Cape Town cluster. The molecular clock analysis suggests that this occurred around 13 March 2020 (95% confidence interval 9-17 March). The phylogenetic reconstruction suggests at least nine early introductions of SARS-CoV-2 into Cape Town and an early localized transmission in a shopping environment. Genomic surveillance was successfully used to investigate and track the spread of early introductions of SARS-CoV-2 in Cape Town.The reindeer (Rangifer tarandus L.) is a unique animal inhabitant of arctic regions. Low ambient temperatures and scant diets (primarily, lichens) have resulted in different evolutional adaptations, including the composition of the ruminal microbiota. In the study presented here, the effects of seasonal and regional aspects of the composition of the ruminal microbiota in reindeer (Nenets breed, 38 animals) were studied (wooded tundra from the Yamalo-Nenetski Autonomous District (YNAD) vs. from the Nenetski Autonomous District (NAD)). The ruminal content of calves (n = 12) and adult animals (n = 26, 15 males and 11 females) was sampled in the summer (n = 16) and winter seasons (n = 22). The composition of the ruminal microbial population was determined by the V3-V4 16S rRNA gene region sequencing. It was found that the population was dominated by Bacteroidetes and Firmicutes phyla, followed by Spirochaetes and Verrucomicrobia. An analysis of the community using non-metric multidimensional scaling and Bray-Curt Veillionelaceae, and Oscilospira spp. The significant differences in the ruminal microbial population were primarily related to the ingredients of diets, affected by region and season. The summer-related increases in the communities of certain pathogens (Mycoplasmataceae, Fusobacterium spp., Porphyromonas endodentalis) were found. Regional differences were primarily related to the ratio of the species involved in ruminal cellulose degradation and ruminal fatty acids metabolism; these differences reflect the regional dissimilarities in botanical diet ingredients.A concept of concrete-plastic columns was presented in the paper. As a proof of concept, a research program was conducted. Seven different cross-sections of columns formwork were 3D printed using plastic. The cross-sections represented three types of columns' shapes most common, rare, and impossible to be realized using traditional formworks (based on fractals). Prepared plastic formworks were filled with cement mortar playing the role of ordinary concrete. After 28 days of curing, the load-strain characteristics of all the concrete columns were tested. Achieved results were discussed. It was proven that concrete-plastic columns were characterized by quasi-plastic behavior while being ultimately destroyed. Columns with fractal-based cross-sections sustained the largest strains while maintaining a significant part of the maximum load. The achieved results proved that it is possible to completely omit traditional steel rebar-stirrup reinforcement. The future direction of needed research should cover larger columns and other concrete-plastic elements. Using fiber-reinforced concrete for the creation of concrete-plastic elements should be also tested.
We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin.
We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS).
A total of 49 patients were included 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression
= 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multivariable model (adjusted hazard ratio low-grade vs. high-grade 0.45, 95% confidence interval 0.22-0.94; adjusted
= 0.035).
In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS.
In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS.The ductus arteriosus (DA) is a physiologic vessel crucial for fetal circulation. As a major regulating factor, the prostaglandin pathway has long been the target for DA patency maintenance or closure. However, the adverse effect of prostaglandins and their inhibitors has been a major unsolved clinical problem. Furthermore, a significant portion of patients with patent DA fail to respond to cyclooxygenase inhibitors that target the prostaglandin pathway. These unresponsive medical patients ultimately require surgical intervention and highlight the importance of exploring pathways independent from this well-recognized prostaglandin pathway. The clinical limitations of prostaglandin-targeting therapeutics prompted us to investigate molecules beyond the prostaglandin pathway. Thus, this article introduces molecules independent from the prostaglandin pathway based on their correlating mechanisms contributing to vascular remodeling. These molecules may serve as potential targets for future DA patency clinical management.Methadone-related deaths are characterized by a wide range of post-mortem blood concentrations, due to the high pharmacokinetic/dynamic inter-individual variability, the potential subjective tolerance state and to other risk factors or comorbidities, which might enhance methadone acute toxicity. In the present study, the association among pre-existing and external conditions and diseases and the resultant methadone death capacity have been investigated. Beside a systematic literature review, a retrospective case-control study was done, dividing cases in which methadone was the only cause of death (controls), and those with associated clinical-circumstantial (naive/non-tolerant state), pathological (pulmonary or cardiovascular diseases) or toxicological (other drugs detected) conditions. Methadone concentrations were compared between the two groups and the association with conditions/diseases was assessed by multiple linear and binomial logistic regressions. Literature cases were 139, in house 35, consisting of 22 controls and 152 cases with associated conditions/diseases. Mean methadone concentrations were 2122 ng/mL and 715 ng/mL in controls and cases respectively, with a statistically significant difference (p less then 0.05). Lower methadone concentrations (by 24, 19 and 33% respectively) were detected in association with naive/non-tolerant state, pulmonary diseases and presence of other drugs, and low levels of methadone ( less then 600 ng/mL) might lead to death in the presence of the above conditions/diseases.Wheat is one of the global strategic crops and ranks third in terms of cereals production. Wheat crops are exposed to many fungal infections during their cultivation stages, some of which have the ability to secrete a number of toxic secondary metabolites that threaten the quality of the grains, consumer health, producer economics, and global trade exchange. Fifty-four random samples were collected from wheat which originated from different countries. The samples included 14 types of soft wheat to study the extent of their contamination with deoxynivalenol (DON) and T-2 toxin by auto-ELISA technology and r-biopharm microtiter plate. All samples were contaminated with DON toxin except one sample, and the values ranged between 40.7 and 1018.8 µg/kg-1. The highest contamination rates were in Lithuanian wheat and the lowest was in Indian wheat. check details Meanwhile, the highest average level of T-2 toxin contamination was in Lithuanian wheat grains with 377.4 µg/kg-1, and the lowest average was 115.3 µg/kg-1 in Polish wheat.
My Website: https://www.selleckchem.com/products/ym201636.html
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