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Previous studies have suggested that increased antioxidant intakes might reduce risk of cognitive disorders including Alzheimer's disease (AD). Which avenue of antioxidant intake (vitamin E/C) is more effective for decreasing risk, however, is largely unknown.To quantitatively investigate the relationships between the pattern of antioxidant intakes and risks of dementia and cognitive decline.We searched all related prospective cohort studies reporting antioxidant intakes (diet and/or supplement) from patients with cognitive disorders. We conducted dose-response meta-analyses to assess potential linear and non-linear dose-response relationships. Summary RRs and 95% CIs were calculated using a random- or fixed-effects model.73 eligible cohort studies totaling 28,257 participants were included in the meta-analysis; the pooled relative risks of AD were 0.75 (95% CI 0.57-0.99; IThe risk of incident AD is significantly reduced by higher consumption of vitamin C by the intake avenue of diet plus supplement.

Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe2+ efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.

Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells (MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.

The European physical journal / D 75(7), 205 (2021). doi:10.1140/epjd/s10053-021-00218-0, Ionization of laser-dressed atomic helium is investigated with focus on photoelectron angular distributions stemming from two-color multi-photon excited states. The experiment combines extreme ultraviolet (XUV) with infrared (IR) radiation, while the relative polarization and the temporal delay between the pulses can be varied. By means of an XUV photon energy scan over several electronvolts, we get access to excited states in the dressed atom exhibiting various binding energies, angular momenta, and magnetic quantum numbers. Furthermore, varying the relative polarization is employed as a handle to switch on and off the population of certain states that are only accessible by two-photon excitation. In this way, photoemission can be suppressed for specific XUV photon energies. Additionally, we investigate the dependence of the photoelectron angular distributions on the IR laser intensity. At our higher IR intensities, we start leaving the simple multi-photon ionization regime. The interpretation of the experimental results is supported by numerically solving the time-dependent Schr��dinger equation in a single-active-electron approximation., Published by Springer, Heidelberg

To study the effect of weaning age on the gut microbiota diversity in the lambs of Chongming white goats, fresh feces from the lambs weaned at 30, 45, and 60 days of age were collected 3 days after weaning at 33, 48, and 63 days of age, for microbial composition analysis by 16S rRNA sequencing. The serum concentrations of lipid metabolites were also investigated at the fecal collection dates. Serum and feces from the ewe-reared groups at 33, 48, and 63 days of age were used as controls. The alpha diversity increased significantly after weaning and with the aging of the lambs. Levels of Ruminococcaceae, Lachnospiraceae, and Ruminococcus varied significantly according to the weaning treatment in lambs (P < 0.05). Butyrate-producing gut bacteria such as Ruminococcaceae_UCG-010, Ruminococcaceae_UCG-013, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-005, Ruminococcaceae_UCG-002, Lachnospiraceae_AC2044_group, and Lachnospiraceae_NK4B4 were identified as significantly increased genera (P < 0.05) in the feces of weaned Chongming white lambs. Additionally, the abundance of fiber degradation-associated bacteria including Ruminococcaceae_UCG-005, Ruminococcus_1, and Ruminococcus_2 significantly increased with lamb weaning age (P < 0.05). Correlation analysis showed that Lachnospiraceae_AC2044_group, norank_f__Bacteroidales_S24-7_group, and Ruminococcaceae_UCG_005 were negatively correlated, and Lachnoclostridium was positively correlated with levels of cholesterol, while Blautia showed positive correlation with low-density lipoprotein cholesterol in serum samples from weaned lambs. This study helped to understand the maturing development of gut microbiota in Chongming white goats under weaning stress. KEY POINTS: • Effects of weaning age on the gut microbiota diversity in Chongming white goat lambs were studied. • Some butyrate-producing gut bacteria were significantly increased after weaned. • Correlations of gut microbiota and lipid metabolites were analyzed.

Long non-coding RNAs (lncRNAs) are reported to play vital roles in the progress of multiple cancers. However, the functions of lncRNAs in breast cancer remain to be discovered. We performed microarrays to identify the differentially expressed mRNAs and lncRNAs in breast tissues with or without miR-34a knockout. To explore the functions of the differentially expressed mRNA and lncRNA in breast cancer, we conducted a series of experiments. We found that Adam12 and lnc015192 were significantly upregulated in miR-34a knockout breast tissues. Knockdown of Adam12 and lnc015192 inhibited breast cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT). Further experiments revealed that lnc015192 regulated Adam12 expression by functioning as a competing endogenous RNA (ceRNA) for miR-34a. In summary, our study demonstrate that Adam12 and lnc015192 promote breast cancer metastasis partly by sponging miR-34a through the ceRNA mechanism.

The management of advanced nasopharyngeal carcinoma (NPC) remains a challenge. The ubiquitous nature of Epstein–Barr virus (EBV) infection in nonkeratinizing NPC has forced us to investigate novel drugs for NPC in the presence of EBV. In this study, we performed a small-scale screening of a library of compounds that target epigenetic regulators in paired EBV-positive and EBV-negative NPC cell lines. We found that bromodomain and extra-terminal (BET) inhibitor JQ1 preferentially inhibits the growth of EBV-positive NPC cells. JQ1 induces apoptosis, decreases cell proliferation and enhances the radiosensitivity in NPC cells, especially EBV-positive cells. Significantly, JQ1-induced cell death is c-Myc-dependent. Notably, RNA-seq analysis demonstrated that JQ1 represses TP63, TP53 and their targets. JQ1 also lessens the expression of PD-L1 in NPC. Moreover, the high potency of JQ1 in NPC cells was further confirmed in vivo in CNE2-EBV+ tumor-bearing mice. These findings indicate that JQ1 is a promising therapeutic candidate for advanced NPC.

Curcumin, a biphenyl compound derived from rhizome, is a powerful anti-cancer agent. Emodin is an active component isolated from the root and rhizome of Rheum palmatum that has been widely used in traditional Chinese medicine for the treatment of various diseases. Currently, there are no studies examining the effect of curcumin in combination with emodin on tumor cell growth. In this study, we report for the first time that combined curcumin and emodin administration synergistically inhibits proliferation (MTT assay), survival (flow cytometry), and invasion (transwell migration assay) of breast cancer cells. Synergism is determined by the Chou-Talalay method. Moreover, we demonstrate that miR-34a is upregulated by curcumin and emodin. This microRNA helps mediate the anti-tumor effects of curcumin and emodin by downregulating Bcl-2 and Bmi-1. Our results not only provide insight into the mechanism of synergy between curcumin and emodin in breast cancer cells, but also suggest a new and potentially useful approach for breast cancer therapy.

Several researches reported that overexpression of SIRT1 was associated with poor survival in several human cancers. However, some researches reported that SIRT1 had an antitumor potential. The definite role of SIRT1 is not clear now, and few studies have documented the value of SIRT1 in triple-negative breast cancer (TNBC). Therefore, the aim of this study is to evaluate the role of SIRT1 in TNBC and non-TNBC for prognosis. A total of 51 TNBC patients and 83 non-TNBC patients who were diagnosed from October 2001 to September 2006 were involved in this study. Immunohistochemical staining for SIRT1 and p53 on tissue microarrays were used. Expression of SIRT1 was seen in 55 % of TNBC patients and 53 % of non-TNBC patients. Expression of SIRT1 was associated with lymph nodes status, stage, distant metastatic relapse, and p53 status in TNBC patients. Expression of SIRT1 in non-TNBC patients was significantly correlated with lymph nodes status, age, stage, distant metastatic relapse, PR status, and p53 status. SIRT1+ group was associated with shorter DFS and OS compared with SIRT1- group in TNBC, non-TNBC, and overall breast cancer patients, according to univariate Cox regression analysis. Our study provides evidence that expression of SIRT is associated with worse prognosis in TNBC and non-TNBC and SIRT1 could be a potential therapeutic target in breast cancer.