Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF‐E2‐related factor 2 (Nrf2) is of great significance. ...Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch‐like ECH‐associated protein 1 (Keap1) reduced the expression of glucose‐6‐phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia‐inducing factor 1α (HIF‐1α) in MCF‐7 and MDA‐MB‐231 cells. Overexpression of Nrf2 up‐regulated the expression of Notch1 via G6PD/HIF‐1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES‐1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2‐driven breast cancer metastasis.
Although great achievements have been made in the synthesis of giant lanthanide clusters, novel structural models are still scarce. Herein, we report a giant lanthanide cluster Dy76, constructed from ...Dy3(μ3‐OH)4 and Dy5(μ4‐O)(μ3‐OH)8 building blocks. As the largest known Dy cluster, the structure of Dy76 can be seen as arising from the fusion of two Dy48 clusters; these clusters can be isolated under various synthetic conditions and were characterized by single‐crystal X‐ray diffraction. This new, fused structural model of the pillar motif has not been found in Ln clusters. Furthermore, the successful conversion of Dy76 back into Dy48 in a retrosynthetic manner supports the proposed fusion formation mechanism of Dy76. Electrospray ionization mass spectrometry (ESI‐MS) analysis suggests that the metal cluster skeleton of Dy76 shows good stability in various solvents. This work not only reveals a new structural type of Ln clusters but also provides insight into the novel fusion assembly process.
We go together: Two dysprosium clusters with 48 and 76 metal atoms, respectively, were generated under solvothermal conditions by using 3‐furancarboxylic acid. The bi‐nanopillar Dy76 was formed by the fusion of two Dy48 nanopillars.
Tumor associated macrophages (TAMs) are considered with the capacity to have both negative and positive effects on tumor growth. The prognostic value of TAM for survival in patients with solid tumor ...remains controversial.
We conducted a meta-analysis of 55 studies (n = 8,692 patients) that evaluated the correlation between TAM (detected by immunohistochemistry) and clinical staging, overall survival (OS) and disease free survival (DFS). The impact of M1 and M2 type TAM (n = 5) on survival was also examined.
High density of TAM was significantly associated with late clinical staging in patients with breast cancer risk ratio (RR) = 1.20 (95% confidence interval (CI), 1.14-1.28) and bladder cancer RR = 3.30 (95%CI, 1.56-6.96) and with early clinical staging in patients with ovarian cancer RR = 0.52 (95%CI, 0.35-0.77). Negative effects of TAM on OS was shown in patients with gastric cancer RR = 1.64 (95%CI, 1.24-2.16), breast cancer RR = 8.62 (95%CI, 3.10-23.95), bladder cancer RR = 5.00 (95%CI, 1.98-12.63), ovarian cancer RR = 2.55 (95%CI, 1.60-4.06), oral cancer RR = 2.03 (95%CI, 1.47-2.80) and thyroid cancer RR = 2.72 (95%CI, 1.26-5.86),and positive effects was displayed in patients with colorectal cancer RR = 0.64 (95%CI, 0.43-0.96). No significant effect was showed between TAM and DFS. There was also no significant effect of two phenotypes of TAM on survival.
Although some modest bias cannot be excluded, high density of TAM seems to be associated with worse OS in patients with gastric cancer, urogenital cancer and head and neck cancer, with better OS in patients with colorectal cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epithelial cell adhesion molecule (EpCAM) is known to be highly expressed in a variety of epithelial carcinomas, and it is involved in cell adhesion and proliferation. However, its expression profile ...and biological function in nasopharyngeal carcinoma (NPC) remains unclear. In this study, higher expression of EpCAM was found in NPC samples compared with non-cancer nasopharyngeal mucosa by qRT-PCR. Additionally, immunohistochemistry (IHC) analysis of NPC specimens from 64 cases showed that high EpCAM expression was associated with metastasis and shorter survival. Multivariate survival analysis identified high EpCAM expression as an independent prognostic factor. Ectopic EpCAM expression in NPC cells promoted epithelial-mesenchymal transition (EMT), induced a cancer stem cell (CSC)-like phenotype, and enhanced metastasis in vitro and in vivo without an effect on cell proliferation. Notably, EpCAM overexpression reduced PTEN expression and increased the level of AKT, mTOR, p70S6K and 4EBP1 phosphorylation. Correspondingly, an AKT inhibitor and rapamycin blocked the effect of EpCAM on NPC cell invasion and stem-like phenotypes, and siRNA targeting PTEN rescued the oncogenic activities in EpCAM knockdown NPC cells. Our data demonstrate that EpCAM regulates EMT, stemness and metastasis of NPC cells via the PTEN/AKT/mTOR pathway.
Hepatocellular carcinoma (HCC) is a male‐dominant cancer, and androgen receptor (AR) has been linked to the pathogenesis of HCC. However, AR expression and its precise role in HCC remain ...controversial. Moreover, previous antiandrogen and anti‐AR clinical trials in HCC failed to demonstrate clinical benefits. In this study, we found that AR is overexpressed in the nucleus of approximately 37% of HCC tumors, which is significantly associated with advanced disease stage and poor survival. AR overexpression in HCC cells markedly alters AR‐dependent transcriptome, stimulates oncogenic growth, and determines therapeutic response to enzalutamide, a second generation of AR antagonist. However, AR inhibition evokes feedback activation of AKT‐mTOR (mechanistic target of rapamycin) signaling, a central regulator for cell growth and survival. On the other hand, mTOR promotes nuclear AR protein expression by restraining ubiquitin‐dependent AR degradation and enhancing AR nuclear localization, providing a mechanistic explanation for nuclear AR overexpression in HCC. Finally, cotargeting AR and mTOR shows significant synergistic anti‐HCC activity and decreases tumor burden by inducing apoptosis in vivo. Conclusion: Nuclear AR overexpression is associated with the progression and prognosis of HCC. However, enzalutamide alone has limited therapeutic utility attributed to feedback activation of the AKT‐mTOR pathway. Moreover, mTOR drives nuclear AR overexpression. Cotargeting AR and mTOR is a promising therapeutic strategy for HCC. (Hepatology 2018;67:2271‐2286).
Purpose
Obstructive sleep apnea (OSA) is associated with increased levels of systemic inflammatory markers, increased arterial stiffness, and endothelial dysfunction, which may lead to increased ...cardiovascular risk. We aimed to quantify the effects of continuous positive airway pressure (CPAP) on cardiovascular biomarkers and to establish predictors of response to CPAP.
Methods
We searched PubMed and the Cochrane Library from inception to May 31, 2017. Randomized controlled trials (RCTs) assessing the efficacy of CPAP on high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), tumor necrosis factor- alpha (TNF-α), augmentation index (AIx), pulse wave velocity (PWV), and flow-mediated dilatation (FMD) in patients with OSA were selected by consensus.
Results
We included 15 RCTs comprising 1090 patients in the meta-analysis. The pooled standard mean difference (SMD) of effect of CPAP on hs-CRP was − 0.64 (95% confidence interval (CI) − 1.19 to − 0.09;
P
= 0.02). CPAP was associated with a reduction in AIx of 1.53% (95% CI, 0.80 to 2.26%;
P
< 0.001) and a significant increase in FMD of 3.96% (95% CI 1.34 to 6.59%;
P
= 0.003). Subgroup analyses found CPAP was likely to be more effective in improving FMD levels in severe OSA patients or patients with effective CPAP use ≥ 4 h/night.
Conclusions
Among patients with OSA, CPAP improves inflammatory marker hs-CRP, arterial stiffness marker AIx, and endothelial function marker FMD. These biomarkers may provide information related to response to treatment. Future studies will need to clarify the efficacy of these biomarkers in assessing cardiovascular risk reduction among OSA treated with CPAP.
Atroposelective electrophilic sulfenylation of N‐aryl aminoquinone derivatives has been achieved for the first time. This transformation is enabled by a new chiral 6,6′‐disubstituted SPINOL‐derived ...sulfide catalyst, which was first synthesized and then successfully explored for catalyzing enantioselective reactions. Various axially chiral sulfur‐containing diarylamine derivatives were readily obtained in moderate to excellent yields with moderate to excellent enantioselectivities. A class of relatively flexible stereogenic C−N axes was easily constructed. The experimental results and a computational study suggested that an intramolecular N−H⋅⋅⋅S hydrogen bond is important for the stability of the C−N axis, which is consistent with our hypothesis. Density functional theory calculations revealed the origin of atroposelectivity and underscored the importance of catalyst rigidity in this sulfenylation reaction.
Atroposelective electrophilic sulfenylation of N‐aryl aminoquinone derivatives catalyzed by a new chiral SPINOL‐derived sulfide has been achieved. Axially chiral sulfur‐containing diarylamine derivatives were obtained in moderate to excellent yields with moderate to excellent enantioselectivities. The intramolecular N−H⋅⋅⋅S hydrogen bond is a key parameter for the stability of the C−N axis. DFT calculations revealed the origin of atroposelectivity.
Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on ...microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic-lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic-lysosomal pathway, leading to microglial polarization towards anti-inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia in vitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic-lysosomal activation in hypoperfusion-induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.
A novel and simple electrochemical immunoassay for C-reactive protein was developed using metal–organic frameworks (Au-MOFs) as signal unit. In this study, we found MOFs could be used as signal ...probe. And this new class of signal probe differs from traditional probe. The signal of the copper ions (Cu2+) from MOFs could be directly detected without acid dissolution and preconcentration, which would greatly simplify the detection steps and reduce the detection time. Moreover, MOFs contain large amounts of Cu2+ ions, providing high electrochemical signals. Our report represents the first example of using MOFs themselves as electrochemical signal probe for biosensors. Platinum nanoparticle modified covalent organic frameworks (Pt-COFs) with high electronic conductivity was employed as the substrate, which is the first time demonstrating the use of Pt-COFs for electrochemical immunoassay. Under the optimized experimental conditions, the proposed sensing strategy provides a linear dynamic ranging from 1 to 400 ng/mL. A detection limit of 0.2 ng/mL was obtained, indicating an improved analytical performance. With these merits, this stable, simple, low-cost, sensitive and selective electrochemical immunoassay shows promise for applications in the point-of-care diagnostics of dieses and environmental monitoring.
PoDPBT, an O‐benzoyltransferase belonging to the BAHD family, can catalyze the benzoylation of 8‐debenzoylpaeoniflorin to paeoniflorin. PoDPBT is the first enzyme demonstrated to be involved in the ...modification stage of paeoniflorin biosynthesis. DFGGG, a new DFGWG‐like motif, was revealed in the BAHD family. The transcriptome database provides a resource for further investigation of other enzyme genes involved in paeoniflorin biosynthesis.
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