This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1H-indol-1-yl)methyl)benzamide (6) has potent inhibitory ...selectivity against histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood–brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer’s disease in the future.
Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. ...Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E
, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE
biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens.
.
This study aims to explore the association between life events and coping styles, and how resilience and self-esteem mediate the association.
A cross-sectional study was conducted among 981 ...left-behind adolescents (LBAs) in five junior high schools in Hunan Province, China, from April 13 to April 20, 2020. We utilized self-designed sociodemographic questionnaire, Adolescent Self-Rating Life Events Checklist, Resilience Scale Chinese Adolescent, Rosenberg Self-Esteem Scale, and Simplified Coping Style Questionnaire to assess the mental health of LBAs. Statistic description, Pearson correlation analysis, and structural equation model were adopted to analyze the data.
Results revealed that life events could negatively predict resilience (β = -0.29,
< 0.001) and self-esteem (β = -0.39,
< 0.001) and positively predict LBAs' positive coping style (β = 0.28,
< 0.001) and negative coping style (β = 0.21,
< 0.001). Self-esteem could also positively predict the resilience of LBAs (β = 0.62,
< 0.001); resilience could negatively predict the negative coping style (β = -0.21,
< 0.001) and positively predict the positive coping style (β = 0.79,
< 0.001). Life events not only have direct effects on negative coping style (β = 0.21) and positive coping style (β = 0.28) but also have indirect effects on coping styles by affecting resilience (β = -0.29) and self-esteem (β = -0.39). The total effect of life events on coping styles was 0.32, where 34.37% was mediated by resilience and self-esteem.
We proved that resilience and self-esteem mediated most of the effects of life events on coping styles. The findings had important implications for interventions to promote mental health of LBAs, particularly the enhancement of resilience and self-esteem.
Targetable drivers governing 5-fluorouracil and cisplatin (5FU + CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Here, we establish 5FU + ...CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 confers chemoresistance and self-renewal in an RNA editing-dependent manner. WES coupled with RNA-seq identify enrichment of hyper-edited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3'UTR of stearoyl-CoA desaturase (SCD1) increases binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogates chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveil a potential target to circumvent chemoresistance.
A series of dual selective HDAC6/HSP90 inhibitors, rationally designed via a hybrid scaffold construction approach, effectively killed cancer cells, down-regulated immune checkpoints and systemic ...immune suppressors, and enhanced T cell anti-tumor activity. The HDAC6/HSP90 dual inhibitors work as both anti-cancer agents and immunosensitizers which can overcome the immunosuppressive tumor microenvironment, bringing a new perspective of chemoimmunotherapy into solid tumor treatment.
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•Compound 17 (C.17) is a potent HDAC6/HSP90 dual inhibitor.•C.17 identified as an anti-cancer agent reversing harsh tumor microenvironment.•C.17 reduces inhibitory proteins (PD-L1, IDO) in the tumor region.•Systemic regulatory T cells downregulated by C.17 via suppressing serum TGF-β.•C.17 exhibits low toxicity to immune cells and normal cells.•Combining C.17 with anit-PD1 antibody achieves synergistic tumor destruction.
The tumor microenvironment is mainly flooded with immunosuppressive cells and inhibitory cytokines, resulting in the inability of effective immune cells to infiltrate and recognize tumors and even the loss of anti-cancer ability.
We propose a novel HDAC6/HSP90 dual inhibitory strategy as well as a chemoimmunotherapeutic agent that does not only kill tumor cells but also destroys the tumor microenvironment and enhances anti-cancer immunity.
A hybrid scaffold construction approach was leveraged to furnish a series of rationally designed resorcinol-based hydroxamates as dual selective HDAC6/HSP90 inhibitors. The drug design campaign commenced with a fragment recruitment process to pinpoint validated structural units to inhibit HDAC6 and HSP90, followed by their installation in flexible HDAC inhibitory templates via an efficient and facile multistep synthetic route. Subsequent evaluations identified a strikingly potent selective HDAC6/HSP90 dual inhibitor (compound 17) via molecular and biological analysis in vitro and in vivo.
Compound 17 exhibited not only direct cytotoxicity to cancer cells but also downregulated immune checkpoints (PD-L1 and IDO) expression in tumors via the inhibition of STAT1 pathway and degradation of oncogene proteins (Src, AKT, Rb, and FAK), leading to in vivo tumor growth inhibition. These multiple effects enabled the effector T cells to largely infiltrate into the tumor region and release granzyme B to kill cancer cells. In addition, compound 17 also decreased TGF-β secretion from normal cells, resulting in the systemic reduction of immunosuppressive regulatory T cells. Delightfully, a cocktail treatment of compound 17 and anti-PD-1 antibodies demonstrated synergistic efficacy to eliminate solid tumors with 83.9% of tumor growth inhibition.
In summary, the impressive activity profile of compound 17, as an effective anticancer agent and a potential immunosensitizer, forecasts the application of HDAC6/HSP90 dual inhibitory strategy to overcome the immunosuppressive tumor microenvironment.
Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly ...understood.
We applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments.
Our analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function.
We portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.
Long non-coding RNAs (lncRNAs) can be used as prognostic biomarkers in many types of cancer.
We sought to establish an lncRNA signature to improve postoperative risk stratification for patients with ...localized clear cell renal cell carcinoma (ccRCC).
Based on the RNA-seq data of 444 stage I–III ccRCC tumours from The Cancer Genome Atlas project, we built a four-lncRNA-based classifier using the least absolute shrinkage and selection operation (LASSO) Cox regression model in 222 randomly selected samples (training set) and validated the classifier in the remaining 222 samples (internal validation set). We confirmed this classifier in an external validation set of 88 patients with stage I–III ccRCC from a Japan cohort and using quantitative reverse transcription polymerase chain reaction (RT-PCR) in another three independent sets that included 1869 patients from China with stage I–III ccRCC.
Univariable and multivariable Cox regression, Harrell's concordance index (c-index), and time-dependent receiver operating characteristic curves were used to evaluate the association of the classifier with overall survival, disease-specific survival, and disease-free survival.
Using the LASSO Cox regression model, we built a classifier named RCClnc4 based on four lncRNAs: ENSG00000255774, ENSG00000248323, ENSG00000260911, and ENSG00000231666. In the RNA-seq and RT-PCR data sets, the RCClnc4 signature significantly stratified patients into high-risk versus low-risk groups in terms of clinical outcome across and within subpopulations and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.34 95% confidence interval {CI}: 1.03–1.75; p=0.028 to 1.89 95% CI, 1.55–2.31; p<0.001) after adjusting for clinical and pathologic factors. The RCClnc4 signature achieved a higher accuracy (mean c-index, 0.72) than clinical staging systems such as TNM (mean c-index, 0.62) and the stage, size, grade, and necrosis (SSIGN) score (mean c-index, 0.64), currently reported prognostic signatures and biomarkers for the estimation of survival. When integrated with clinical characteristics, the composite clinical and lncRNA signature showed improved prognostic accuracy in all data sets (TNM + RCClnc4 mean c-index, 0.75; SSIGN + RCClnc4 score mean c-index, 0.75). The RCClnc4 classifier was able to identify a clinically significant number of both high-risk stage I and low-risk stage II–III patients.
The RCClnc4 classifier is a promising and potential prognostic tool in predicting the survival of patients with stage I–III ccRCC. Combining the lncRNA classifier with clinical and pathological parameters allows for accurate risk assessment in guiding clinical management.
The RCClnc4 classifier could facilitate patient management and treatment decisions.
Our RCClnc4 classifier could add prognostic value to existing clinicopathological risk factors for stage I–III clear cell renal cell carcinoma and provide a more accurate and individualized risk assessment beyond reported signature. The RCClnc4 classifier may facilitate patient management and treatment decisions.
Developing flexible electrodes with high active materials loading and excellent mechanical stability is of importance to flexible electronics, yet remains challenging. Herein, robust flexible ...electrodes with an encapsulated core‐multishell structure are developed via a spraying‐hydrothermal process. The multilayer electrode possesses an architecture of substrate/reduced graphene oxide (rGO)/bimetallic complex/rGO/bimetallic complex/rGO from the inside to the outside, where the cellulosic fibers serve as the substrate, namely, the core; and the multiple layers of rGO and bimetallic complex, are used as active materials, namely, the shells. The inner two rGO interlayers function as the cement that chemically bind to two adjacent layers, while the two outer rGO layers encapsulate the inside structure effectively protecting the electrode from materials detachment or electrolyte corrosion. The electrodes with a unique core‐multishell structure exhibit excellent cycle stability and exceptional temperature tolerance (−25 to 40 °C) for lithium and sodium storage. A combination of experimental and theoretical investigations are carried out to gain insights into the synergetic effects of cobalt‐molybdenum‐sulfide (CMS) materials (the bimetallic complex), which will provide guidance for future exploration of bimetallic sulfides. This strategy is further demonstrated in other substrates, showing general applicability and great potential in the development of flexible energy storage devices.
The encapsulated core–multishell structure with an architecture of substrate/reduced graphene oxide (rGO)/bimetallic complex/rGO/bimetallic complex/rGO is used to fabricate robust and high energy density electrodes for lithium/sodium storage, with a high proportion of active material (20 wt%) and mechanical strength. The underlying synergistic effect of bimetal ions is revealed via experimental investigations and theoretical calculations.
Genomewide Association Study of Leprosy Zhang, Fu-Ren; Zhang, Chi; Zhang, Lin ...
The New England journal of medicine,
12/2009, Letnik:
361, Številka:
27
Journal Article
Recenzirano
Odprti dostop
Little is known about genetic susceptibility to infectious disease. This study implicates variation in genes encoding molecules in the NOD2 (nucleotide-binding oligomerization domain containing 2) ...signaling pathway (which regulates innate immunity) in susceptibility to infection with
Mycobacterium leprae
and leprosy.
This study implicates variation in genes encoding molecules in the NOD2 signaling pathway (which regulates innate immunity) in susceptibility to infection with
Mycobacterium leprae
and leprosy.
Leprosy is a chronic infectious disease caused by
Mycobacterium leprae
. It affects the skin and peripheral nerves and can cause irreversible impairment of nerve function and consequent chronic disabilities.
1
Despite a dramatic decrease in its prevalence over the past two decades (largely due to the worldwide introduction of multidrug therapy in 1982),
2
leprosy remains a major public health problem and one of the most important preventable disabilities in many developing countries.
3
It is therefore particularly unfortunate that research into the mechanisms underlying infection and clinical sequelae has been limited by the fact that
M. leprae
infects only humans and . . .
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