Kromannmcmanus1264
These therapeutic strategies may robustly reduce the cellular activity of oncogenic STAT3 and overcome the historical limitations of less selective small molecules.Epigenetic activation of Wnt/β-catenin signaling plays a critical role in Wnt-induced tumorigenesis, notably in colorectal cancers. KDM3 and KDM4 histone demethylases have been reported to promote oncogenic Wnt signaling through demethylation of H3K9 on Wnt target gene promoters and are suggested to be potential therapeutic targets. However, potent inhibitors for these regulators are still not available. In addition, which family is most responsible for activation of Wnt target genes and Wnt-induced oncogenesis is not well documented, specifically in colorectal cancer. In this study, we characterized the functional redundancy and differences between KDM3 and KDM4 in regard to regulating Wnt signaling. Our data suggest that KDM3 may play a more essential role than KDM4 in regulating oncogenic Wnt signaling in human colorectal cancer. We also identified that IOX1, a known histone demethylase inhibitor, significantly suppresses Wnt target gene transcription and colorectal cancer tumorigenesis. Mechanistically, IOX1 inhibits the enzymatic activity of KDM3 by binding to the Jumonji C domain and thereby preventing the demethylation of H3K9 on Wnt target gene promoters. Taken together, our data not only identified the critical mechanisms by which IOX1 suppressed Wnt/β-catenin signaling and colorectal cancer tumorigenesis through inhibition of KDM3, but also suggested that IOX1 may represent an attractive small molecule lead for future drug design and discovery.
Type 2 diabetes (T2D) is a multifactorial disease affecting mostly adults older than 40 years. The aim of the study was to examine
gene polymorphism influence on the risk of T2D, especially in young adults.
200 diabetic patients and 221 healthy controls participated in this study. Three
gene polymorphism have been analyzed
(single-nucleotide polymorphism Ile
Val), homozygous deletion of
(null/null) and
(null/null), using TaqMan real-time quantitative PCR.
The distribution of examined polymorphisms was similar in patient group and control group. Statistically significant differences were demonstrated for the combination of
and
/
genotypes between patients diagnosed before 40 years of age and healthy people (12.5% vs 0.9%, p=0.016). Moreover, all three examined gene polymorphism together (
,
and
genotype) was observed in 12.5% of patients diagnosed before 40 years of age and in 0.5% of healthy individuals (p=0.013).
In conclusion, the results suggest that
polymorphism may be one of the risk factors for developing T2D at a younger age than the T2D population average.
In conclusion, the results suggest that GST polymorphism may be one of the risk factors for developing T2D at a younger age than the T2D population average.
Epidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).
We investigated longitudinal data from participants of the 'Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration' Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer's Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1-3 2.2-4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%-6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetle elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.
Both environmental and genetic factors contribute to type 2 diabetes (T2D) risk. Dozens of T2D susceptibility loci have been identified by genome-wide association study. However, these loci account for only a small fraction of the familial T2D risk. We hypothesized that the gene-obesity interaction may contribute to the missing heritability.
Forty-eight T2D-associated variants were genotyped using the TaqMan OpenArray Genotyping System and iPLEX Sequenom MassARRAY platform in two separate studies. Obesity was defined according to multiple indexes (body mass index (BMI), waist circumference and waist-hip ratio). Multiplicative interactions were tested using general logistic regression to assess the gene-obesity interaction effect on T2D risk among a total of 6206 Chinese Hans.
After adjusting for the main effects of genes and obesity, as well as covariates (age, sex, smoking and alcohol consumption status), robust multiplicative interaction effects were observed between rs10811661 in
and multiple obesnteraction effect identified in our study may help to explain some of the missing heritability in the context of T2D susceptibility. In addition, the interaction effect may play a role in the precise prevention of T2D in Chinese individuals.
A 20% reduction in the FEV
is routinely used as an end point for methacholine challenge testing (MCT). Measurement of FEV
is effort dependent, and some patients are not able to perform acceptable and repeatable forced expiration maneuvers. The goal of the present study was to investigate the diagnostic value of airway resistance measurement by forced oscillation technique (FOT), body plethysmography, and interrupter technique compared with the traditionally accepted standard FEV
measurement in evaluating the responsiveness to methacholine during MCT.
We included in the study adult subjects referred for MCT because of asthma-like symptoms and with normal baseline spirometry. We modified routine MCT protocol by adding the assessment of airway resistance to the measurement of FEV
at each step of MCT.
We observed, in the subjects with airway hyper-responsiveness versus those with normal airway responsiveness, a significantly greater percentage change in median (interquartile range) FOT resistance at419.).
Measurements of airway resistance could possibly be used as an alternative method to spirometry in airway challenge. Significant changes in airway mechanics during MCT are detectable by airway resistance measurement in FEV1 non-responders with methacholine-induced asthma-like symptoms. (ClinicalTrials.gov registration NCT02343419.).Targeted therapeutics for cancer generally exploit "oncogene addiction," a phenomenon in which the growth and survival of tumor cells depend on the activity of a particular protein. However, the efficacy of oncogene-targeted therapies varies substantially. For instance, targeting epidermal growth factor receptor (EGFR) signaling is effective in some non-small cell lung cancer (NSCLC) but not in triple-negative breast cancer (TNBC), although these cancers show a similar degree of increase in EGFR activity. Using a genome-wide CRISPR-Cas9 genetic knockout screen, we found that the Elongator (ELP) complex mediates insensitivity to the EGFR inhibitor erlotinib in TNBC cells by promoting the synthesis of the antiapoptotic protein Mcl-1. Depleting ELP proteins promoted apoptotic cell death in an EGFR inhibition-dependent manner. Pharmacological inhibition of Mcl-1 synergized with EGFR inhibition in a panel of genetically diverse TNBC cells. The findings indicate that TNBC "addiction" to EGFR signaling is masked by the ELP complex and that resistance to EGFR inhibitors in TNBC might be overcome by cotargeting Mcl-1.Although inflammation is necessary during the early phases of tissue repair, persistent inflammation contributes to fibrosis. Acute tendon injuries often heal through a fibrotic mechanism, which impedes regeneration and functional recovery. Because inflammation mediated by nuclear factor κB (NF-κB) signaling is implicated in this process, we examined the spatial, temporal, and cell type-specific activation profile of canonical NF-κB signaling during tendon healing. NF-κB signaling was maintained through all phases of tendon healing in mice, including the remodeling phase, and tenocytes and myofibroblasts from the Scleraxis (Scx) lineage were the predominant populations that retained NF-κB activation into the late stages of repair. We confirmed persistent NF-κB activation in myofibroblasts in human tendon scar tissue. Deleting the canonical NF-κB kinase, IKKβ, in Scx-lineage cells in mice increased apoptosis and the deposition of the matrix protein periostin during the late stages of tendon repair, suggesting that persistent NF-κB signaling may facilitate myofibroblast survival and fibrotic progression. Consistent with this, myofibroblasts in human tendon scar samples displayed enhanced prosurvival signaling compared to control tissue. Together, these data suggest that NF-κB may contribute to fibrotic tendon healing through both inflammation-dependent and inflammation-independent functions, such as NF-κB-mediated cell survival.Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathion and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase-interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.The term athlete's heart describes structural, functional and electrical adaptations of the cardiovascular system due to repetitive intense exercise. Physiological cardiac adaptations in athletes, however, may mimic features of cardiac diseases and therefore make it difficult to distinguish physiological adaptions from disease. Furthermore, regular exercise may also lead to pathological adaptions that can promote or worsen cardiac disease (eg, atrial dilation/atrial fibrillation, aortic dilation/aortic dissection and rhythm disorders). Sudden cardiac death (SCD) is a major concern in sports cardiology, and preparticipation screening (PPS) has demonstrated to be effective in identifying athletes at risk for SCD. In Europe, PPS is advocated to include personal and family history, physical examination and ECG, with further workup including echocardiography only if the initial screening investigations show abnormal findings. We review the current available evidence for echocardiography as a screening tool for conditions associated with SCD in recreational and professional athletes and advocate to include screening echocardiography to be performed at least twice in an athlete's career.
