FOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic ...fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated β-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7Tax(R) cells. KIF20A depletion also renders MCF-7 and MCF-7Tax(R) cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance.
Dry granular materials, such as sand, gravel, pills, or agricultural grains, can become rigid when compressed or sheared. Under isotropic compression, the material reaches a certain jamming density ...and then resists further compression. Shear jamming occurs when resistance to shear emerges in a system at a density lower than the jamming density. Although shear jamming is prevalent in frictional granular materials, their stability properties are not well described by standard elasticity theory and thus call for experimental characterization. We report on experimental observations of changes in the mechanical properties of a shear-jammed granular material subjected to small-amplitude, quasistatic cyclic shear. We study a layer of plastic disks confined to a shear cell, using photoelasticimetry to measure all interparticle vector forces. For sufficiently small cyclic shear amplitudes and large enough initial shear, the material evolves to an unexpected “ultrastable” state in which all the particle positions and interparticle contact forces remain unchanged after each complete shear cycle for thousands of cycles. The stress response of these states to small imposed shear is nearly elastic, in contrast to the original shear-jammed state.
Effects of a model oil dispersant (Corexit EC9500A) on sorption/desorption of phenanthrene were investigated with two marine sediments. Kinetic data revealed that the presence of the dispersant at ...18 mg/L enhanced phenanthrene uptake by up to 7%, whereas the same dispersant during desorption reduced phenanthrene desorption by up to 5%. Sorption isotherms confirmed that at dispersant concentrations of 18 and 180 mg/L, phenanthrene uptake progressively increased for both sediments. Furthermore, the presence of the dispersant during desorption induced remarkable sorption hysteresis. The effects were attributed to added phenanthrene affinity and capacity due to sorption of the dispersant on the sediments. Dual-mode models adequately simulated sorption isotherms and kinetic data in the presence of the dispersant. Water accommodated oil (WAO) and dispersant-enhanced WAO increased phenanthrene sorption by up to 22%. This information is important for understanding roles of oil dispersants on the distribution and transport of petroleum PAHs in seawater-sediments.
B7-H3 (CD276), part of the B7 superfamily of immune checkpoint molecules, has been shown to have an immunomodulatory role. Its regulation, receptor and mechanism of action remain unclear. B7-H3 ...protein expression correlates with prostate cancer outcomes, and humanized monoclonal antibodies (that is, enoblituzumab) are currently being investigated for therapeutic use. Here we used genomic expression data to examine the relationship between B7-H3 mRNA expression and prostate cancer.
Prostatectomy tissue from 2781 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Pairwise comparisons were used to identify significant associations between B7-H3 expression and clinicopathologic variables, and survival analyses were used to evaluate the prognostic significance of B7-H3. Pearson's correlation analyses were performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy at the B7-H3 locus was determined using chromatin immunoprecipitation (ChIP), and androgen-dependent expression changes in B7-H3 was evaluated by quantitative reverse transcription PCR in LNCaP cell lines. Oncomine was queried to evaluate B7-H3 expression in metastatic disease.
B7-H3 mRNA expression was positively associated with higher Gleason score (P<0.001), tumor stage (P<0.001), and castrate resistant metastatic disease (P<0.0001). High B7-H3 expression correlated with the development of metastasis and prostate cancer specific mortality, but this was not significant on multi-variable analysis. B7-H3 expression correlated with ERG-positive disease (r=0.99) and AR expression (r=0.36). ChIP revealed an AR-binding site upstream of B7-H3, and the presence of androgens decreased B7-H3 expression in LNCaP suggesting potential direct AR regulation. Gene set enrichment analysis demonstrated an association of B7-H3 with androgen signaling as well as immune regulatory pathways.
Higher B7-H3 expression correlates with Gleason grade, prostate cancer stage and poor oncologic outcomes in prostatectomy cohorts. B7-H3 expression appears to be related to androgen signaling as well as the immune reactome.
Background and Objective: The United States has experienced a large increase in the prevalence of obesity since the 1970s. Our objective was to describe recent trends in obesity and abdominal obesity ...among adults in the United States. Design: Trend study of cross-sectional studies. Subjects: We used data from up to 22 872 men and non-pregnant women aged 20 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2008. Main Outcome Measures: Main outcome measures are mean body mass index and waist circumference, percentages of obesity and abdominal obesity. Obesity was defined as a body mass index 30 kg m-2, and abdominal obesity was defined as a waist circumference 102 cm in men and 88 cm in women. Results: In men, the age-adjusted mean body mass index, mean waist circumference, and prevalence of obesity and abdominal obesity were 27.8 kg m-2, 99.1 cm, and 26.9 and 37.8%, respectively, during 1999-2000 and 28.5 kg m-2 (P trend=0.001), 100.8 cm (P trend=0.002), and 32.0 (P trend=0.001) and 43.7% (P trend=0.002), respectively, during 2007-2008. In women, the age-adjusted mean body mass index, mean waist circumference, and prevalence of obesity and abdominal obesity were 28.2 kg m-2, 92.2 cm, and 33.2 and 55.8%, respectively, during 1999-2000 and 28.6 kg m-2 (P trend=0.181), 94.9 cm (P trend=0.006), and 35.2 (P trend=0.180) and 61.8% (P trend=0.036), respectively, during 2007-2008. Significant linear trends for increasing prevalence of obesity were noted among men with the least and most education. Conclusion: Between 1999 and 2008, both obesity and abdominal obesity increased in men, and abdominal obesity increased in women.
Background: Obesity is associated with an increased risk of developing a variety of chronic diseases, most of which are associated with psychiatric disorders. We examined the associations of ...depression and anxiety with body mass index (BMI) after taking into consideration the obesity-related comorbidities (ORCs) and other psychosocial or lifestyle factors. Methods: We analyzed the data collected from 177 047 participants (aged >or= 18 years) in the 2006 Behavioral Risk Factor Surveillance System. Current depression was assessed by the Patient Health Questionnaire-8 diagnostic algorithm. Lifetime diagnoses of depression, anxiety and ORCs were self-reported. The prevalence of the three psychiatric disorders was age standardized to the 2000 US population. Multivariate-adjusted prevalence ratios were computed to test associations of depression and anxiety with BMI using SUDAAN software. Results: The age-adjusted prevalence of current depression, lifetime diagnosed depression and anxiety varied significantly by gender. Within each gender, the prevalence of the three psychiatric disorders was significantly higher in both men and women who were underweight (BMI<18.5 kg/m2), in women who were overweight (BMI: 25-<30 kg/m2) or obese (BMI >or= 30 kg/m2), and in men who had class III obesity (BMI >or= 40 kg/m2) than in those with a normal BMI (18.5-<25 kg/m2). After adjusting for demographics, ORCs, lifestyle or psychosocial factors, compared with men with a normal BMI, men with a BMI >or= 40 kg/m2 were significantly more likely to have current depression or lifetime diagnosed depression and anxiety; men with a BMI<18.5 kg/m2 were also significantly more likely to have lifetime diagnosed depression. Women who were either overweight or obese were significantly more likely than women with a normal BMI to have all the three psychiatric disorders. Conclusions: Our results demonstrate that disparities in the prevalence of depression and anxiety exist among people with different BMI levels independent of their disease status or other psychosocial or lifestyle factors.
Severe refractory asthma is associated with enhanced nitrative stress. To determine the mechanisms for high nitrative stress in human severe asthma (SA), 3-nitrotyrosine (3NT) was compared with Th1 ...and Th2 cytokine expression. In SA, high 3NT levels were associated with high interferon (IFN)-γ and low interleukin (IL)-13 expression, both of which have been reported to increase inducible nitric oxide synthase (iNOS) in human airway epithelial cells (HAECs). We found that IL-13 and IFN-γ synergistically enhanced iNOS, nitrite, and 3NT, corresponding with increased H(2)O(2). Catalase inhibited whereas superoxide dismutase enhanced 3NT formation, supporting a critical role for H(2)O(2), but not peroxynitrite, in 3NT generation. Dual oxidase-2 (DUOX2), central to H(2)O(2) formation, was also synergistically induced by IL-13 and IFN-γ. The catalysis of nitrite and H(2)O(2) to nitrogen dioxide radical (NO(2)(•)) requires an endogenous peroxidase in this epithelial cell system. Thyroid peroxidase (TPO) was identified by microarray analysis ex vivo as a gene distinguishing HAEC of SA from controls. IFN-γ induced TPO in HAEC and small interfering RNA knockdown decreased nitrated tyrosine residues. Ex vivo, DUOX2, TPO, and iNOS were higher in SA and correlated with 3NT. Thus, a novel iNOS-DUOX2-TPO-NO(2)(•) metabolome drives nitrative stress in HAEC and likely in SA.
Genome architecture and organization play critical roles in cell life. However, it remains largely unknown how genomic loci are dynamically coordinated to regulate gene expression and determine cell ...fate at the single cell level. We have developed an inducible system which allows Simultaneous Imaging and Manipulation of genomic loci by Biomolecular Assemblies (SIMBA) in living cells. In SIMBA, the human heterochromatin protein 1α (HP1α) is fused to mCherry and FRB, which can be induced to form biomolecular assemblies (BAs) with FKBP-scFv, guided to specific genomic loci by a nuclease-defective Cas9 (dCas9) or a transcriptional factor (TF) carrying tandem repeats of SunTag. The induced BAs can not only enhance the imaging signals at target genomic loci using a single sgRNA, either at repetitive or non-repetitive sequences, but also recruit epigenetic modulators such as histone methyltransferase SUV39H1 to locally repress transcription. As such, SIMBA can be applied to simultaneously visualize and manipulate, in principle, any genomic locus with controllable timing in living cells.
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