Search

Probiotics have become increasingly popular among cancer patients. However, there is limited data from a real-world setting. This study aims to conduct a retrospective analysis to understand the trend of probiotic prescriptions in Chinese colorectal cancer patients. The Mann-Kendall and Cochran-Armitage trend test was applied to estimate the trend significance. Gephi software identified the combination of probiotic strains. The binary logistic regression investigated influence factors, and Spearman's rank correlation coefficient calculated correlations between probiotics and antitumor drug usage. The probiotic prescription percentage increased from 3.3% in 2015 to 4.2% in 2021 (Z = 12.77, p < 0.001). Although 48.3% of probiotic prescriptions had no indication-related diagnosis, diarrhea (OR 10.91, 95% CI 10.57–11.26) and dyspepsia (3.97, 3.82–4.12) included prescriptions most likely to contain probiotics. Prescriptions from the tertiary hospital (1.43,1.36–1.50), clinics (1.30, 1.28–1.33), and senior patients (1.018 per year, 1.017–1.019) were more likely to contain probiotics. Most probiotic prescriptions (95.0%) contained one probiotic product but multiple strains (69.3%). Enterococcus faecalis (49.7%), Lactobacillus acidophilus (39.4%), and Clostridium butyricum (27.9%) were the most prescribed strains. The probiotics co-prescribed with antitumor agents increased rapidly from 6.6% to 13.8% in seven years (Z = 15.31, p < 0.001). Oral fluorouracil agents (2.35, 2.14–2.59), regorafenib (1.70,1.27–2.26), and irinotecan (1.27,1.15–1.41) had a higher probability to co-prescribed with probiotics. There was no correlation between probiotic strain selection and specific antitumor drug use. The increasing prescription of probiotics in colorectal cancer patients in China may be related to treating the gastrointestinal toxicity of anti-cancer drugs. With unapproved indications and a lack of strain selectivity, evidence-based guidelines are urgently needed to improve probiotic use in this population. [ABSTRACT FROM AUTHOR]

For de novo mutational signature analysis, the critical first step is to decide how many signatures should be expected in a cancer genomics study. An incorrect number could mislead downstream analyses. Here we present SUITOR (Selecting the nUmber of mutatIonal signaTures thrOugh cRoss-validation), an unsupervised cross-validation method that requires little assumptions and no numerical approximations to select the optimal number of signatures without overfitting the data. In vitro studies and in silico simulations demonstrated that SUITOR can correctly identify signatures, some of which were missed by other widely used methods. Applied to 2,540 whole-genome sequenced tumors across 22 cancer types, SUITOR selected signatures with the smallest prediction errors and almost all signatures of breast cancer selected by SUITOR were validated in an independent breast cancer study. SUITOR is a powerful tool to select the optimal number of mutational signatures, facilitating downstream analyses with etiological or therapeutic importance. Author summary: Mutational signatures are the footprints of exogenous exposures and endogenous mutational processes on the cancer genomes. To estimate de novo mutational signatures, the first step is to decide how many signatures should be extracted in a cancer genomics study, which determines downstream analytical steps and has been insufficiently studied. We developed SUITOR, an unsupervised cross-validation method to select the optimal number of signatures without overfitting the data. We demonstrated SUITOR's superior performance using in vitro experimental studies, in silico simulations and in vivo pan-cancer applications of 2,540 whole-genome sequenced tumors across 22 cancer types, and validated signatures of breast cancer in additional 440 breast tumors. SUITOR advances the methodological frontier of identifying de novo mutational signatures and would help discover the causes of cancer and the means of cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

The etiopathogenesis of sporadic Parkinson’s disease (PD) remains elusive although mitochondrial dysfunction has long been implicated. Recent evidence revealed reduced expression of peroxisome proliferator-activated receptor gamma coactivator−1 α (PGC−1α) and downstream regulated nuclear encoded respiratory complex genes in affected brain tissue from PD patients. We sought to determine whether epigenetic modification of the PGC−1α gene could account for diminished expression. In substantia nigra from PD patients but not control subjects, we show significant promoter-proximal non-canonical cytosine methylation of the PGC−1α gene but not an adjacent gene. As neuroinflammation is a prominent feature of PD and a mediator of epigenetic change, we evaluated whether the pro-inflammatory fatty acid, palmitate, would stimulate PGC−1α promoter methylation in different cell types from the CNS. Indeed, in mouse primary cortical neurons, microglia and astrocytes, palmitate causes PGC−1α gene promoter non-canonical cytosine methylation, reduced expression of the gene and reduced mitochondrial content. Moreover, intracerebroventricular (ICV) injection of palmitate to transgenic human α−synuclein mutant mice resulted in increased PGC−1α promoter methylation, decreased PGC−1α expression and reduced mitochondrial content in substantia nigra. Finally we provide evidence that dysregulation of ER stress and inflammatory signaling is associated with PGC−1α promoter methylation. Together, these data strengthen the connection between saturated fatty acids, neuroflammation, ER stress, epigenetic alteration and bioenergetic compromise in PD. [ABSTRACT FROM AUTHOR]

Adaptive immunity in homeotherms depends greatly on CD4+ Th cells which release cytokines in response to specific antigen stimulation. Whilst bony fish and poikilothermic tetrapods possess cells that express TcR and CD4-related genes (that exist in two forms in teleost fish; termed CD4-1 and CD4-2), to date there is no unequivocal demonstration that cells equivalent to Th exist. Thus, in this study we determined whether CD4-1+ lymphocytes can express cytokines typical of Th cells following antigen specific stimulation, using the zebrafish (Danio rerio). Initially, we analyzed the CD4 locus in zebrafish and found three CD4 homologues, a CD4-1 molecule and two CD4-2 molecules. The zfCD4-1 and zfCD4-2 transcripts were detected in immune organs and were most highly expressed in lymphocytes. A polyclonal antibody to zfCD4-1 was developed and used with an antibody to ZAP70 and revealed double positive cells by immunohistochemistry, and in the Mycobacterium marinum disease model CD4-1+ cells were apparent surrounding the granulomas typical of the infection. Next a prime-boost experiment, using human gamma globulin as antigen, was performed and revealed for the first time in fish that zfCD4-1+ lymphocytes increase the expression of cytokines and master transcription factors relevant to Th1/Th2-type responses as a consequence of boosting with specific antigen. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy appears to be a specialized form of cellular growth that involves the proliferation control and cell cycle regulation. NIMA (never in mitosis, gene A)-related kinase-6 (Nek6) is a cell cycle regulatory gene that could induce centriole duplication, and control cell proliferation and survival. However, the exact effect of Nek6 on cardiac hypertrophy has not yet been reported. In the present study, the loss- and gain-of-function experiments were performed in Nek6 gene-deficient (Nek6−/−) mice and Nek6 overexpressing H9c2 cells to clarify whether Nek6 which promotes the cell cycle also mediates cardiac hypertrophy. Cardiac hypertrophy was induced by transthoracic aorta constriction (TAC) and then evaluated by echocardiography, pathological and molecular analyses in vivo. We got novel findings that the absence of Nek6 promoted cardiac hypertrophy, fibrosis and cardiac dysfunction, which were accompanied by a significant activation of the protein kinase B (Akt) signaling in an experimental model of TAC. Consistent with this, the overexpression of Nek6 prevented hypertrophy in H9c2 cells induced by angiotonin II and inhibited Akt signaling in vitro. In conclusion, our results demonstrate that the cell cycle regulatory gene Nek6 is also a critical signaling molecule that helps prevent cardiac hypertrophy and inhibits the Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The effect of regulator of G protein signaling 5 (RGS5) on cardiac hypertrophy, atherosclerosis and angiogenesis has been well demonstrated, but the role in the development of obesity and insulin resistance remains completely unknown. We determined the effect of RGS5 deficiency on obesity, hepatic steatosis, inflammation and insulin resistance in mice fed either a normal-chow diet (NC) or a high-fat diet (HF). Methodology/Principal Findings: Male, 8-week-old RGS5 knockout (KO) and littermate control mice were fed an NC or an HF for 24 weeks and were phenotyped accordingly. RGS5 KO mice exhibited increased obesity, fat mass and ectopic lipid deposition in the liver compared with littermate control mice, regardless of diet. When fed an HF, RGS5 KO mice had a markedly exacerbated metabolic dysfunction and inflammatory state in the blood serum. Meanwhile, macrophage recruitment and inflammation were increased and these increases were associated with the significant activation of JNK, IkBa and NF-kBp65 in the adipose tissue, liver and skeletal muscle of RGS5 KO mice fed an HF relative to control mice. These exacerbated metabolic dysfunction and inflammation are accompanied with decreased systemic insulin sensitivity in the adipose tissue, liver and skeletal muscle of RGS5 KO mice, reflected by weakened Akt/GSK3b phosphorylation. Conclusions/Significance: Our data suggest that loss of RGS5 exacerbates HF-induced obesity, hepatic steatosis, inflammation and insulin resistance. [ABSTRACT FROM AUTHOR]

Background: Diamagnetic levitation is a technique that uses a strong, spatially varying magnetic field to simulate an altered gravity environment, as in space. In this study, using Streptomyces avermitilis as the test organism, we investigate whether changes in magnetic field and altered gravity induce changes in morphology and secondary metabolism. We find that a strong magnetic field (12T) inhibit the morphological development of S. avermitilis in solid culture, and increase the production of secondary metabolites. Methodology/Principal Findings: S. avermitilis on solid medium was levitated at 0 g*, 1 g* and 2 g* in an altered gravity environment simulated by diamagnetic levitation and under a strong magnetic field, denoted by the asterix. The morphology was obtained by electromicroscopy. The production of the secondary metabolite, avermectin, was determined by OD245 nm. The results showed that diamagnetic levitation could induce a physiological response in S. avermitilis. The difference between 1 g* and the control group grown without the strong magnetic field (1 g), showed that the magnetic field was a more dominant factor influencing changes in morphology and secondary metabolite production, than altered gravity. Conclusion/Significance: We have discovered that magnetic field, rather than altered gravity, is the dominant factor in altered gravity simulated by diamagnetic levitation, therefore care should to be taken in the interpretation of results when using diamagnetic levitation as a technique to simulate altered gravity. Hence, these results are significant, and timely to researchers considering the use of diamagnetic levitation to explore effects of weightlessness on living organisms and on physical phenomena. [ABSTRACT FROM AUTHOR]