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Uterine corpus endometrial carcinoma (UCEC) is a significant cause of cancer-related mortality among women worldwide. Prior research has demonstrated an association between cyclin-dependent kinase inhibitor 2 A (CDKN2A) and various tumors. As a member of the INK4 family, CDKN2A is involved in cell cycle regulation by controlling CDKs. In the present study, bioinformatics was used to analyze public datasets. The expression levels, signaling pathways, and copy number variations of CDKN2A in UCEC were explored, along with its immune cell subset associations. CDKN2A expression was found to be elevated in UCEC, particularly in the signaling pathways involved in cell proliferation and inflammation. Analysis of somatic copy number alterations in the TCGA (The Cancer Genome Atlas)-UCEC dataset revealed a connection between CDKN2A and drug metabolism in UCEC. Assessment of the relationship between CDKN2A and genes involved in immunotherapy for UCEC patients showed a negative correlation between CDKN2A and CD8 + T cell activity, as well as IL-2 and TP53. Collectively, these insights suggest that CDKN2A may be a potential biomarker for prognosis and treatment strategies in UCEC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: This study investigates the therapeutic mechanisms of Cai's Herbal Tea in Type 1 Diabetes Mellitus (T1DM) mice, focusing on its effects on mitochondrial change and autophagy via the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway., Methods: The composition of Cai's Herbal Tea was analyzed by Ultra-High Performance Liquid Chromatography-Quadrupole Time of Flight Mass Spectrometry (UHPLC-Q/TOF-MS). C57BL/6 mice and Min6 pancreatic beta cells were divided into control, diabetic mellitus (DM)/high glucose (HG), and treatment groups (low, medium, and high doses of Cai's Tea, and Metformin). Key physiological parameters, pancreatic islet health, Min6 cell morphology, viability, and insulin (INS) secretion were assessed. Small Interfering RNA-AMPK (si-AMPK) was utilized to confirm the pathway involvement., Results: Cai's Herbal Tea improved body weight, pancreatic islet pathological injury, and INS secretion whereas reduced total triglycerides, fasting blood sugar, and Interferon gamma (INF-γ) in T1DM mice, particularly at higher doses. In Min6 cells, Cai's Tea mitigated HG-induced damage and proinflammatory response, enhancing cell viability and INS secretion. Notably, it reduced swelling and improved cristae structure in treated groups of mitochondria and promoted autophagy via the AMPK-mTOR pathway, evidenced by increased LC3II/LC3I and P-AMPK/AMPK ratios, and decreased P-mTOR/mTOR and P62 expressions in pancreatic islet β-cells. Furthermore, these effects were converted by si-AMPK interference., Conclusion: Cai's Herbal Tea exhibits significant therapeutic efficacy in T1DM mice by improving mitochondrial health and inducing autophagy through the AMPK-mTOR pathway in pancreatic islet β-cells. These findings highlight its potential as a therapeutic approach for T1DM management., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest. Ethics approval and consent to participate: All animal studies met the guidelines of the China National Council on Experimental Animal Care and Use. Study procedures were approved by the Ethics Committee of Zhejiang Eyong Pharmaceutical Research and Development Center (SYXK (Zhe) 2021–0033). Consent for publication: Not applicable., (© 2024. The Author(s).)

The long non-coding RNA (LncRNA) X-inactive specific transcript (XIST) regulates the biological process of osteoclasts and the process of related diseases. This study was attempted to investigate the mechanism of LncRNA XIST acting in osteoclast formation and orthodontic induced inflammatory root resorption (OIIRR). The compression force (CF) -induced cell model and the orthodontic tooth movement (OTM) rat model were designed and established in this study. The expression of LncRNA XIST, miR-130b-3p, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as well as osteoclast related marker genes and inflammatory factors level were measured in this study. The interaction among LncRNA XIST, microRNA-130b-3p (miR-130b-3p) and PTEN were researched through luciferase activity and western blot assay. Pathological sections were used to analyze root resorption and osteoclast formation. The OTM rat model was successfully constructed, which was characterized by increased tooth spacing and increased root resorption pits. PTEN and LncRNA XIST was overexpressed in OTM group. Mechanism analysis showed that the overexpression of LncRNA XIST enhanced the PTEN level by sponging miR-130b-3p. The overexpression of LncRNA XIST increased the secretion of inflammatory factors and positive osteoclasts number, but inhibited the differentiation of osteoclasts by sponging miR-130b-3p and promoting the level of PTEN. This finding demonstrates that LncRNA XIST regulates osteoclast formation and aggravated OIIRR through miR-130b-3p/PTEN axis, suggesting that LncRNA XIST may be used as potential targets for OIIRR therapy.

Specular highlight removal ensures the acquisition of high-quality images, which finds its important applications in stereo matching, text recognition and image segmentation. In order to prevent the leakage of images containing personal information, such as identification card (ID) photos, clients often train specular highlight removal models using local data resulting in a lack of precision and generalization of the trained model. To address this challenge, this paper introduces a new method to remove highlight in images using federated learning (FL) and attention generative adversarial network (AttGAN). Specifically, the former builds a global model in the central server and updates the global model by aggregating model parameters of clients. This process does not involve the transmission of image data, which enhances the privacy of clients; the later combining attention mechanisms and generative adversarial network aims to improve the quality of highlight removal by focusing on key image regions, resulting in more realistic and visually pleasing results. The proposed FL-AttGAN method is numerically evaluated, using SD1, SD2 amd RD datasets. The results show that the proposed FL-AttGAN outperforms existent methods., (© 2024. The Author(s).)

Background: A cost-effective Escherichia coli expression system has gained popularity for producing virus-like particle (VLP) vaccines. However, the challenge lies in balancing the endotoxin residue and removal costs, as residual endotoxins can cause inflammatory reactions in the body., Results: In this study, porcine parvovirus virus-like particles (PPV-VLPs) were successfully assembled from Decreased Endotoxic BL21 (BL21-DeE), and the effect of structural changes in the lipid A of BL21 on endotoxin activity, immunogenicity, and safety was investigated. The lipopolysaccharide purified from BL21-DeE produced lower IL-6 and TNF-α than that from wild-type BL21 (BL21-W) in both RAW264.7 cells and BALB/c mice. Additionally, mice immunized with PPV-VLP derived form BL21-DeE (BL21-DeE-VLP) showed significantly lower production of inflammatory factors and a smaller increase in body temperature within 3 h than those immunized with VLP from BL21-W (BL21-W-VLP) and endotoxin-removed VLP (ReE-VLP). Moreover, mice in the BL21-DeE-VLP immunized group had similar levels of serum antibodies as those in the BL21-W-VLP group but significantly higher levels than those in the ReE-VLP group. Furthermore, the liver, lungs, and kidneys showed no pathological damage compared with the BL21-W-VLP group., Conclusion: Overall, this study proposes a method for producing VLP with high immunogenicity and minimal endotoxin activity without chemical or physical endotoxin removal methods. This method could address the issue of endotoxin residues in the VLP and provide production benefits., (© 2024. The Author(s).)

Red-spotted grouper nervous necrosis virus (RGNNV) is a major viral pathogen of grouper and is able to antagonize interferon responses through multiple strategies, particularly evading host immune responses by inhibiting interferon responses. Ovarian tumor (OTU) family proteins are an important class of DUBs and the underlying mechanisms used to inhibit interferon pathway activation are unknown. In the present study, primers were designed based on the transcriptome data, and the ovarian tumor (OTU) domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) and OTUB2 genes of Epinephelus coioides (EcOTUB1 and EcOTUB2) were cloned and characterized. The homology alignment showed that both EcOTUB1 and EcOTUB2 were most closely related to E. lanceolatus with 98 % identity. Both EcOTUB1 and EcOTUB2 were distributed to varying degrees in grouper tissues, and the transcript levels were significantly up-regulated following RGNNV stimulation. Both EcOTUB1 and EcOTUB2 promoted replication of RGNNV in vitro, and inhibited the promoter activities of interferon stimulated response element (ISRE), nuclear transcription factors kappaB (NF-κB) and IFN3, and the expression levels of interferon related genes and proinflammatory factors. Co-immunoprecipitation experiments showed that both EcOTUB1 and EcOTUB2 could interact with TRAF3 and TRAF6, indicating that EcOTUB1 and EcOTUB2 may play important roles in interferon signaling pathway. The results will provide a theoretical reference for the development of novel disease prevention and control techniques., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reports in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The pandemic of the porcine reproductive and respiratory syndrome virus (PRRSV) has caused huge economic losses and continues to threaten the swine industry worldwide. Nucleocapsid protein (N protein) is the primary antigen of PRRSV for development of sensitive diagnostic assays. Two high affinity nanobodies against N protein, Nb12 and Nb35, were selected and employed to develop a sandwich ELISA. Further we improved the ELISA method to obtain greater sensitivity, a trivalent nanobody (3 × Nb35) and a bivalent nanobody-HRP fusion protein (2 × Nb12-HRP) were expressed and used. This modified ELISA was found to have high sensitivity for detecting PRRSV, with a detection limit of 10 TCID 50 /ml (median tissue culture infectious dose), which was approximately 200-fold greater than the single-copy nanobody-based sandwich ELISA. The developed assay shows high specificity and can detect almost all circulating lineages of PRRSV-2 in China. This study provides suggestions for reforming nanobodies and for the further development of multivalent nanobody-based ELISAs for other various viruses., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Degradation of unliganded androgen receptor (AR) in prostate cancer cells can be prevented by proteasome inhibition, but this is associated with only modest increases in polyubiquitylated AR. An inhibitor (VLX1570) of the deubiquitylases associated with the proteasome did not increase ubiquitylation of unliganded AR, indicating that AR is not targeted by these deubiquitylases. We then identified a series of AR ubiquitylation sites, including a not previously identified site at K911, as well as methylation sites and previously identified phosphorylation sites. Mutagenesis of K911 increases AR stability, chromatin binding, and transcriptional activity. We further found that K313, a previously reported ubiquitylation site, could also be methylated and acetylated. Mutagenesis of K313, in combination with K318, increases AR transcriptional activity, indicating that distinct posttranslational modifications at K313 differentially regulate AR activity. Together these studies expand the spectrum of AR posttranslational modifications, and indicate that the K911 site may regulate AR turnover on chromatin., (© 2024. The Author(s).)

Dye pollution in the aquatic environment can harm ecosystems and human health. Here, we developed a new green adsorbent by applying an improved drying process. Diatomite was embedded in a network structure formed between chitosan and polyvinyl alcohol without using any crosslinking agent to prepare chitosan-polyvinyl alcohol-diatomite hydrogel beads through alkali solidification. The beads were tested for removing a cationic dye (methylene blue (MB)) from water. The structure of the adsorbent beads was analysed using scanning electron microscopy, energy-dispersive spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier-transform infrared spectroscopy. The adsorption capacity was investigated, and the results indicated excellent MB adsorption properties. The adsorbents had a rough surface and high swelling capacity of 66.9 g/g. The maximum MB adsorption capacity was 414.70 mg/g, and the adsorption followed the Freundlich isothermal and quasi-second-order kinetic models. The adsorption was an endothermic spontaneous process governed by both intra-particle and external diffusion processes. The proposed adsorption mechanisms involved hydrogen bonding and electrostatic interactions. These adsorbent beads have considerable application potentials owing to their high adsorption capacity, green composition, and non-polluting nature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region., Methods: RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites., Results: In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site., Conclusion: Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling., (© 2023 Wiley Periodicals LLC.)

Background: Androgen receptor (AR) activation and repression dual-functionality only became known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene that functionally entangles with AR signaling in PCa. Further exploration of AR regulatory mechanisms on MYC gene transcription bears clinical and translation significance., Methods: Bioinformatics analysis of PCa cell line and clinical RNA-Seq and ChIP-Seq (chromatin immunoprecipitation-sequencing) datasets to anchor interactions of AR and MYC transcriptional networks. ChIP-qPCR and 3C (chromosome conformation capture) analyses to probe MYC distal regulation by AR binding sites (ABSs). CRISPR/Cas9-mediated genome-editing to specify functions of ABS within the 8q24-MYC locus on androgen-mediated MYC transcription. Global FoxA1 and HoxB13 distribution profiling to advance AR transcriptional mechanisms., Results: Here we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At ~ 25 Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites., Conclusion: Together, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Epigenetic reprogramming, mediated by genomic alterations and dysregulation of histone reader and writer proteins, plays a critical role in driving prostate cancer progression and treatment resistance. However, the specific function and regulation of EHMT1 (also known as GLP) and EHMT2 (also known as G9A), well-known histone 3 lysine 9 methyltransferases, in prostate cancer progression remain poorly understood. Through comprehensive investigations, we discovered that both EHMT1 and EHMT2 proteins have the ability to activate oncogenic transcription programs in prostate cancer cells. Silencing EHMT1/2 or targeting their enzymatic activity with small-molecule inhibitors can markedly decrease prostate cancer cell proliferation and metastasis in vitro and in vivo . In-depth analysis of posttranslational modifications of EHMT1 protein revealed the presence of methylation at lysine 450 and 451 residues in multiple prostate cancer models. Notably, we found that lysine 450 can be demethylated by LSD1. Strikingly, concurrent demethylation of both lysine residues resulted in a rapid and profound expansion of EHMT1's chromatin binding capacity, enabling EHMT1 to reprogram the transcription networks in prostate cancer cells and activate oncogenic signaling pathways. Overall, our studies provide valuable molecular insights into the activity and function of EHMT proteins during prostate cancer progression. Moreover, we propose that the dual-lysine demethylation of EHMT1 acts as a critical molecular switch, triggering the induction of oncogenic transcriptional reprogramming in prostate cancer cells. These findings highlight the potential of targeting EHMT1/2 and their demethylation processes as promising therapeutic strategies for combating prostate cancer progression and overcoming treatment resistance., Significance: In this study, we demonstrate that EHMT1 and EHMT2 proteins drive prostate cancer development by transcriptionally activating multiple oncogenic pathways. Mechanistically, the chromatin binding of EHMT1 is significantly expanded through demethylation of both lysine 450 and 451 residues, which can serve as a critical molecular switch to induce oncogenic transcriptional reprogramming in prostate cancer cells., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Centromere localization of the chromosome passenger complex (CPC) is paramount for achieving accurate sister chromosome segregation in mitosis. Although it has been widely recognized that the recruitment of CPC is directly regulated by two histone codes, phosphorylation of histone H3 at threonine 3 (H3T3ph) and phosphorylation of histone H2A at threonine 120 (H2AT120ph), the regulation of CPC localization by other histone codes remains elusive. We show that dysfunction of disruptor of telomeric silencing 1 like (DOT1L) leads to mislocation of the CPC in prometaphase, caused by disturbing the level of H3T3ph and its reader Survivin. This cascade is initiated by over-dephosphorylation of H3T3ph mediated by the phosphatase RepoMan-PP1, whose scaffold RepoMan translocalizes to chromosomes, while the level of H3K79me2/3 is diminished. Together, our findings uncover a biological function of DOT1L and H3K79 methylation in mitosis and give insight into how genomic stability is coordinated by different histone codes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the nutritional status of patients with advanced kidney cancer and analyse the risk factors for malnutrition in such patients., Methods: The study selected the clinical data of 103 patients with advanced kidney cancer who were admitted to Qingdao Jiaozhou Central Hospital from February 2020 to February 2022 for a retrospective analysis. The Subjective Global Assessment of Nutrition scale was used to evaluate the nutritional status of all research subjects. Patients' baseline data, such as gender, age and clinical classifications, and laboratory indicators, such as albumin and C-reactive protein (CRP), were collected, and multivariate logistic regression was used to screen the independent risk factors for malnutrition in patients with advanced kidney cancer., Results: A total of 78 (76.00%) individuals among the 103 patients with advanced kidney cancer had malnutrition. The results of univariate analysis showed marked differences in the age, body mass index (BMI), albumin, haemoglobin, CRP, diabetes, anorexia and family monthly income of patients of the good nutrition and malnutrition groups ( p < 0.05). The results of logistic regression showed that age ≥65 years old (odds ratio (OR) = 29.187), albumin <40 g/L (OR = 0.025), haemoglobin <110 g/L (OR = 0.049), the presence of diabetes (OR = 28.138), the presence of anorexia (OR = 98.739), BMI <18.5 kg/m 2 (OR = 0.024) and CRP <3 mg/L (OR = 24.819) were independent influencing factors of malnutrition in the patients with advanced kidney cancer (all p < 0.05)., Conclusions: The incidence of malnutrition in patients with advanced kidney cancer is relatively high. Therefore, the understanding of malnutrition in such patients in clinical work must be fortified, and attention should be paid to screening the above risk factors and implementing active measures in nutrition therapy to reduce the risk of malnutrition in patients with advanced kidney cancer and prolong their survival time., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s).)

Background: No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant-an orally administered small molecule CGRP antagonist-with placebo in the acute treatment of migraine among adults in these countries., Methods: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran-Mantel Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed., Findings: 1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4-13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6-20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events., Interpretation: Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population., Funding: BioShin Limited., Translations: For the Chinese and Korean translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests B-KK has received personal compensation for serving on a scientific advisory board for Lundbeck Korea, Pfizer Korea, and Novartis; he has received personal compensation for serving as a speaker or moderator for Allergan Korea, Lilly Korea, Teva Korea, GSK Korea, Lundbeck Korea, and SK-Pharma. M-HK has received personal compensation for serving on a scientific advisory board for Lundbeck Korea, Novartis, Allergan Korea, Lilly Korea, and Teva Korea. H-SM was a principal investigator for a multicentre trial sponsored by Lundbeck, Novartis, and Eli Lilly; she received lecture honoraria from GSK Korea, SK Pharma, Teva Korea, Lundbeck Korea, Allergan Korea, and Yuyu Pharma in the past 24 months. DM, MH, DAS, and RC were employed by Biohaven Pharmaceuticals, the developer of rimegepant, during the trial. RC and ZL are currently employed by Pfizer, the development and commercial rights owner of rimegepant. YG and ZL were employed by BioShin Limited, the trial sponsor, during the conduct of the trial. SY, AG, MZ, ZW, JL, GT, and QY declare no competing interests, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Lung cancer in never-smokers is the major cancer cause of death globally. We compared the efficacy of low-dose computed tomography (LDCT) lung cancer screening among never-smokers versus ever-smokers using systematic review and meta-analysis., Methods: LDCT lung cancer screening studies that simultaneously included both ever-smoker and never-smoker participants published by April 30, 2021, were searched through PubMed and Scopus. Primary outcome measure was relative risk (RR) of lung cancer diagnosed among never-smokers versus ever-smokers., Results: A total of 14 studies (13 from Asia) were included (141,396 ever-smokers, 109,251 never-smokers, 1961 lung cancer cases diagnosed). RR of lung cancer diagnosed between ever-smokers versus never-smokers overall was 1.21 (95% confidence interval [CI]: 0.89-1.65), 1.37 (95% CI: 1.08-1.75) among males, and 0.88 (95% CI: 0.59-1.31) among females. RR was 1.78 (95% CI: 1.41-2.24) and 1.22 (95% CI: 0.89-1.68) for Asian female never-smokers versus male never-smokers and versus male ever-smokers, respectively, and 0.99 (95% CI: 0.65-1.50) versus high-risk ever-smokers (≥30 pack-years). Proportional meta-analysis revealed significantly more lung cancers diagnosed at first scan (95.4% [95% CI: 84.9-100.0] versus 70.9% [95% CI: 54.6-84.9], p = 0.010) and at stage 1 (88.5% [95% CI: 79.3-95.4] versus 79.7% [95% CI: 71.1-87.4], p = 0.071) among never-smokers versus ever-smokers, respectively. RR of lung cancer death and 5-year all-cause mortality in never-smokers versus ever-smokers was 0.27 (95% CI: 0.1-0.55, p < 0.001) and 0.13 (95% CI: 0.05-0.33, p < 0.001), respectively., Conclusions: The RR of lung cancer detected by LDCT screening among female never-smokers and male ever-smokers in Asia was statistically similar. Overall and lung cancer specific mortality from the lung cancer diagnosed from LDCT screening was significantly reduced among never-smokers compared to ever-smokers., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Oil/water mixtures from industrial and domestic wastewater adversely affect the environment and human beings. In this context, the development of a facile and improved separation method is crucial. Herein, dopamine was used as a bioadhesive to bind tea polyphenol (TP) onto the surface of a polyvinylidene fluoride (PVDF) membrane to form the first hydrophilic polymer network. Sodium periodate (NaIO 4 ) is considered an oxidising agent for triggering self-polymerisation and can be used to introduce hydrophilic groups via surface manipulation to form the second hydrophilic network. In contrast to the individual polydopamine (PDA) and TP/NaIO 4 composite coatings for a hydrophobic PVDF microfiltration membrane, a combination of PDA, TP, and NaIO 4 has achieved the most facile treatment process for transforming the hydrophobic membrane into the hydrophilic state. The hierarchical superhydrophilic network structure with a simultaneous underwater superoleophobic membrane exhibited excellent performance in separating various oil-in-water emulsions, with a high water flux (1530 L.m -2 h -1 .bar) and improved rejection (98%). The water contact angle of the modified membrane was 0° in 1 s. Moreover, the steady polyphenol coating was applied onto the surface, which endowed the membrane with an adequate antifouling and recovery capability and a robust durability against immersion in an acid, alkali, or salt solution. This facile scale-up method depends on in situ plant-inspired chemistry and has remarkable potential for practical applications.

Porcine circovirus type 2 (PCV2) is a highly prevalent virus in pig farms worldwide that causes significant economic losses in the swine industry. The PCV2 virus-like particles (VLPs) are potent subunit vaccines that are widely used. Currently, the adopted quality control of VLPs vaccines is mainly based in animal testing, the titration of neutralizing antibodies, or other biochemical/biophysical assays. In this study, we generated a monoclonal antibody that can distinguish assembled PCV2 VLPs from the capsid proteins. Subsequently, a convenient Sandwich ELISA was developed based on the monoclonal antibody (mAb) that recognizes the PCV2 VLPs specifically. This assay can be used for the quantity and quality control of PCV2 VLPs vaccines for both the intermediate or final products with high accuracy.

Porcine parvovirus (PPV) is widely prevalent in pig farms. PPV is closely related to porcine respiratory disease complex (PRDC) and porcine circovirus disease (PCVD), which seriously threatens the healthy development of the pig industry. Although commercial antibody detection kits are available, they are expensive and unsuitable for large-scale clinical practice. Here, a soluble VP2 protein of PPV is efficiently expressed in the E. coli expression system. The VP2 protein can be self-assembled into virus-like particles (VLPs) in vitro. After multiple steps of chromatography purification, PPV-VLPs with a purity of about 95% were obtained. An indirect, enzyme-linked immunosorbent assay (I-ELISA), comparable to a commercial PPV kit, was developed based on the purified PPV-VLPs and was used to detect 487 clinical pig serum samples. The results showed that the I-ELISA is a simple, cost-effective, and efficient method for the diagnosis of clinical pig serum and plasma samples. In summary, high-purity, tag-free PPV-VLPs were prepared, and the established VLP-based I-ELISA is of great significance for the sero-monitoring of antibodies against PPV.

Aim: Data for avelumab (anti-PD-L1 antibody) in Chinese patients are limited. Patients & methods: Phase I/Ib, open-label, dose-escalation study of Chinese patients with advanced solid tumors. Primary study objectives were to evaluate the maximum tolerated dose (MTD) and pharmacokinetics (PK) of avelumab. Results: 24 patients received avelumab 3 mg/kg every 2 weeks (Q2W; n = 3), 10 mg/kg Q2W (n = 7), 20 mg/kg Q2W (n = 6) or 10 mg/kg weekly for 12 weeks and then Q2W thereafter (n = 8). MTD was not reached. Avelumab exposure was increased in higher dose groups. Partial responses occurred in two patients (confirmed in one patient); best overall response was stable disease in nine patients. Conclusion: Data for avelumab in Chinese patients with advanced solid tumors were consistent with previous global studies.

Indoor air quality (IAQ) has assumed new significance given the extensive amount of time spent indoor due to the coronavirus pandemic and particulate matter (PM) pollution. Accordingly, the development of window air filters to effectively intercept PM from outdoor air under natural ventilation conditions is an important research topic. However, most existing filters inevitably suffer from the compromise among filtration capability, transparency, and air permeability. In this study, we fabricate a high-performance transparent air filter to improve IAQ via natural ventilation. polyvinylidene fluoride (PVDF) superfine nanofibers of size 20-35 nm are prepared using extremely dilute solution electrospinning; a multi-scale nanofiber structure is then designed. By adjusting the ratio of PVDF superfine nanofibers (SNs) to PVDF coarse fibers (CNs), we balance the structure-performance relationship. Benefiting from the multiscale structural features that include a small pore size (0.72 μm) and high porosity (92.22%), the resulting filters exhibit excellent performance including high interception efficiency (99.92%) for PM 0.3 , low air resistance (69 Pa), high transparency (∼80%) and stable filtration after 100 h of UV irradiation. This work describes a new strategy for the fabrication of nanofibers with true-nanoscale diameters and the design of high-performance air filters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The usage of single-use face masks (SFMs) has increased since the outbreak of the coronavirus pandemic. However, non-degradability and mismanagement of SFMs have raised serious environmental concerns. Moreover, both melt-blown and nanofiber-based mask filters inevitably suffer from poor filtration performance, like a continuous decrease in the removal efficiency for particulate matter (PM) and weak breathability. Herein, we report a new method to create biodegradable and reusable fibrous mask filters. The filter consists of a true nanoscale bio-based poly(lactic acid) (PLA) fiber (an average size of 37 ± 4 nm) that is fabricated via electrospinning of an extremely dilute solution. Furthermore, we designed a multiscale structure with integrated features, such as low basis weight (0.91 g m -2 ), small pore size (0.73 μm), and high porosity (91.72%), formed by electrospinning deposition of true nanoscale fibers on large pore of 3D scaffold nanofiber membranes. The resultant mask filter exhibited a high filtration efficiency (PM 0.3 -99.996%) and low pressure drop (104 Pa) superior to the commercial N95 filter. Importantly, this filter has a durable filtering efficiency for PM and natural biodegradability based on PLA. Therefore, this study offers an innovative strategy for the preparation of PLA nanofibers and provides a new design for high-performance nanofiber filters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Androgen receptor (AR) is the principal molecule in prostate cancer (PCa) etiology and therapy. AR re-activation still remains a major challenge during treatment of castration-resistant prostate cancer (CRPC) tumors that relapse after castration therapies. Recent reports have indicated the enrichment of Ser81-phosphorylated AR (pS81) in the nucleus of CRPC cells, and CDK1 and CDK9 as the kinases phosphorylating AR at S81. In the current study we showed that pS81 is preferentially localized in the nucleus in both rapid biopsy metastatic CRPC samples and PCa xenografts, and nuclear pS81 localization is correlated with AR transactivation in tumor xenografts. Chromatin immunoprecipitation (ChIP) analysis demonstrated an alignment of S81 phosphorylation and AR-mediated transactivation with the chromatin locus openness. Moreover, pS81-specific ChIP-Seq showed a disproportional occupancy of pS81 on AR-activated promoters, while 3C-ChIP assays further indicated an enrichment of pS81 at the PSA enhancer-promoter loop, a known AR activating hub. In the latter, CDK9 was shown to modulate the transactivation of the AR and RNA Pol II. Indeed, ChIP and re-ChIP assays also confirmed that AR-dependent activation of the PSA enhancer and promoter mediated by pS81 was coupled with activation of Pol II and the pTEFb complex. Mechanistically, we determined that CDK1 and CDK9 sustained the pS81 AR modification in the soluble and chromatin-bound fractions of PCa cells, respectively. Finally, we demonstrated that CDK1 activity was maintained throughout the cell cycle, and that CDK1 inhibitors restored androgen sensitivity in CRPC tumor cells. Based on these findings, CDK1 and CDK9 could be targeted as pS81 kinases in patients with CRPC, either alone or in conjunction with direct AR antagonists., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: Increased thromboembolism (TE) has been reported in ALK+ and ROS1+ non-small cell lung cancer (NSCLC)., Materials and Methods: Odds ratios (OR) and hazard ratios (HR) of TE were calculated from meta-analysis and time-to-event analysis respectively for either ALK+ or ROS1+ NSCLC patients., Results: We identified eight studies (766 ALK+, 143 ROS1+, 2314 non-ALK+ and non-ROS1+ NSCLC patients) for the meta-analysis. For ALK+ NSCLC, the pooled OR was 2.00 (95% CI: 1.60-2.50) for total TE (TTE) by random-effects model, 2.10 (95% CI: 1.70-2.60) for venous thromboembolism (VTE), and 1.24 (95% CI: 0.80-1.91) for arterial thromboembolism (ATE). For ROS1+ NSCLC, the pooled OR was 3.08 (95% CI: 1.95-4.86) for TTE, and 3.15 (95% CI: 1.83-5.43) for VTE. Six studies (739 ALK+, 137 ROS1+, 561 EGFR+, 714 "wildtype" NSCLC patients) were included in the time-to-event analysis. The TTE incidence rate was 17.4 (95% CI: 15.3-19.5) per 100 pateint-years for ALK+ NSCLC, and 32.1 (95% CI: 24.6-39.6) per 100 patient-years for ROS1+ NSCLC with a 50 % cumulative incidence rate at year 3 of diagnosis. HR for TTE was 2.35 (95% CI: 1.90-2.92, p < 0.001) and 3.23 (95% CI: 2.40-4.34, p < 0.001) for ALK+ and ROS1+ NSCLC, respectively. Comparing ROS1+ NSCLC to ALK+ NSCLC, HR for TTE was 1.37 (95% CI: 1.05-1.79, p = 0.020)., Conclusions: ALK+ and ROS1+ NSCLC patients had an increased risk of TE. ROS1+ NSCLC had further increased risk of TE over ALK+ NSCLC., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Graphene oxide (GO), a novel carbon-based nanomaterial, has promising applications in biomedicine. However, it induces potential cytotoxic effects on the gastrointestinal (GI) tract cells, and these effects have been largely uncharacterized. The present study aimed to explore the toxic effects of GO on the intestinal tract especially under pre-existing inflammatory conditions, such as inflammatory bowel disease (IBD), and elucidate underlying mechanisms., Results: Our findings indicated that oral gavage of GO worsened acute colitis induced by 2.5% dextran sodium sulfate (DSS) in mice. In vitro, GO exacerbated DSS-induced inflammation and apoptosis in the FHC cell line, an ideal model of intestinal epithelial cells (IECs). Further, the potential mechanism underlying GO aggravated mice colitis and cell inflammation was explored. Our results revealed that GO treatment triggered apoptosis in FHC cells through the activation of reactive oxygen species (ROS)/AMP-activated protein kinase (AMPK)/p53 pathway, as evidenced by the upregulation of cytochrome c (Cytc), Bax, and cleaved caspase-3 (c-cas3) and the downregulation of Bcl-2. Interestingly, pretreatment with an antioxidant, N-acetyl-L-cysteine, and a specific inhibitor of AMPK activation, Compound C (Com.C), effectively inhibited GO-induced apoptosis in FHC cells., Conclusions: Our data demonstrate that GO-induced IECs apoptosis via ROS/AMPK/p53 pathway activation accounts for the exacerbation of colitis in vivo and aggravation of inflammation in vitro. These findings provide a new insight into the pathogenesis of IBD induced by environmental factors. Furthermore, our findings enhance our understanding of GO as a potential environmental toxin, which helps delineate the risk of exposure to patients with disturbed intestinal epithelial barrier/inflammatory disorders such as IBD.

An editorial decision has been made to retract this manuscript due to breach of publishing guidelines, following the identification of non-original and manipulated figures. Reference: Jingbao Zhang, Yanfei Gao, Changbo Ma, Yi Wang: Murrayanine Induces Cell Cycle Arrest, Oxidative Stress, and Inhibition of Phosphorylated p38 Expression in A549 Lung Adenocarcinoma Cells. Med Sci Monit 2019; 25:2002-2008. 10.12659/MSM.913873.

Graphene oxide (GO) is one of the most promising nanomaterials used in biomedicine. However, studies about its adverse effects on the intestine in state of inflammation remain limited. This study aimed to explore the underlying effects of GO on intestinal epithelial cells (IECs) in vitro and colitis in vivo. We found that GO could exert toxic effects on NCM460 cells in a dose- and time-dependent manner and promote inflammation. Furthermore, GO caused lysosomal dysfunction and then blockaded autophagy flux. Moreover, pharmacological autophagy inhibitor 3-Methyladenine could reverse GO-induced LC3B and p62 expression levels, reduce expression levels of IL-6, IL-8, TLR4, and CXCL2, and increase the level of IL-10. In vivo, C57BL/6 mice were treated with 2.5% dextran sulfate sodium (DSS) in drinking water for five consecutive days to induce colitis. Then, GO at 60 mg/kg dose was administered through the oral route every two days from day 2 to day 8. These results showed that GO aggravated DSS-induced colitis, characterized by shortening of the colon and severe pathological changes, and induced autophagy. In conclusion, GO caused the abnormal autophagy in IECs and exacerbated DSS-induced colitis in mice. Our research indicated that GO may contribute to the development of intestinal inflammation by inducing IECs autophagy dysfunction.

Introduction: Taletrectinib (AB-106/DS-6051b) is an oral, potent selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI). Preclinically, taletrectinib has activity against ROS1 G2032R solvent-front mutation., Methods: Patients with ROS1+ NSCLC enrolled into two phase 1 studies conducted in United States (U101, NCT02279433) and Japan (J102, NCT02675491) were analyzed for objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival, and safety., Results: A total of 22 patients with ROS1+ NSCLC out of the total 61 patients enrolled were analyzed. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. Data cutoff was August 19, 2020. Median follow-up time for all 22 patients was 14.9 months (95% confidence interval [CI]: 4.1-33.8). A total of 18 patients with ROS1+ were assessable for response. The confirmed ORR for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4-87.9) with a disease control rate of 100% (70.1-100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7-70.0) with a disease control rate of 88.3% (95% CI: 443.6-97.0). The median progression-free survival for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6-not reached) and 14.2 months (95% CI: 1.5-not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%)., Conclusions: Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced ROS1+ NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile., (© 2020 The Authors.)

Purpose: Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib., Patients and Methods: Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1 / NTRK rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity., Results: A total of 46 patients were enrolled. Steady-state peak concentration ( C max ) and exposure (AUC 0-8 ) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC 0-24 between low-fat-diet-fed/fasted state was 123% (90% confidence interval, 104%-149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory ROS1 + NSCLC. One patient with TPM3-NTRK1 differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation., Conclusions: Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory ROS1 + NSCLC., (©2020 American Association for Cancer Research.)

High-entropy alloys (HEAs) with good ductility and high strength are usually prepared by a combination of forging and heat-treatment processes. In comparison, the as-cast HEAs typically do not reach strengths similar to those of HEAs produced by the forging and heat-treatment processes. Here we report a novel equiatomic-ratio CoCrCuMnNi HEA prepared by vacuum arc melting. We observe that this HEA has excellent mechanical properties, i.e., a yield strength of 458 MPa, and an ultimate tensile strength of 742 MPa with an elongation of 40%. Many nanometer precipitates (5-50 nm in size) and domains (5-10 nm in size) are found in the inter-dendrite and dendrite zones of the produced HEA, which is the key factor for its excellent mechanical properties. The enthalpy of mixing between Cu and Mn, Cr, Co, or Ni is higher than those of mixing between any two of Cr, Co, Ni and Mn, which leads to the separation of Cu from the CoCrCuMnNi HEA. Furthermore, we reveal the nanoscale-precipitate-phase-forming mechanism in the proposed HEA.

High-entropy alloys are a class of materials that contain five or more elements in near-equiatomic proportions 1,2 . Their unconventional compositions and chemical structures hold promise for achieving unprecedented combinations of mechanical properties 3-8 . Rational design of such alloys hinges on an understanding of the composition-structure-property relationships in a near-infinite compositional space 9,10 . Here we use atomic-resolution chemical mapping to reveal the element distribution of the widely studied face-centred cubic CrMnFeCoNi Cantor alloy 2 and of a new face-centred cubic alloy, CrFeCoNiPd. In the Cantor alloy, the distribution of the five constituent elements is relatively random and uniform. By contrast, in the CrFeCoNiPd alloy, in which the palladium atoms have a markedly different atomic size and electronegativity from the other elements, the homogeneity decreases considerably; all five elements tend to show greater aggregation, with a wavelength of incipient concentration waves 11,12 as small as 1 to 3 nanometres. The resulting nanoscale alternating tensile and compressive strain fields lead to considerable resistance to dislocation glide. In situ transmission electron microscopy during straining experiments reveals massive dislocation cross-slip from the early stage of plastic deformation, resulting in strong dislocation interactions between multiple slip systems. These deformation mechanisms in the CrFeCoNiPd alloy, which differ markedly from those in the Cantor alloy and other face-centred cubic high-entropy alloys, are promoted by pronounced fluctuations in composition and an increase in stacking-fault energy, leading to higher yield strength without compromising strain hardening and tensile ductility. Mapping atomic-scale element distributions opens opportunities for understanding chemical structures and thus providing a basis for tuning composition and atomic configurations to obtain outstanding mechanical properties.

Salt induced micelle-to-vesicle transitions of ionic surfactants depend on the surfactant chain length, headgroup structure, counterion type and concentration, but the interfacial molarities of counterions and water that balance the hydrophobic effect are difficult to determine. In anionic micelles of twin-tailed sodium bis(2-ethylhexyl)sulfosuccinate (AOT), the chemical trapping (CT) method provides estimates of the interfacial molarities of anionic headgroups (RSO3-m) and neutral (H2Om) nucleophiles during salt induced transitions of AOT micelles to vesicles. Product yields were measured by HPLC from the competitive dediazoniation reaction using a specially designed hydrophobic probe, 4-hexadecyl-2,6-dimethylbenzenediazonium cation, 16-ArN2+. The reactions were run at constant concentration of 15 mM AOT mixed with 0 to 50 mM added salts, containing cations of different sizes and valences including tetraalkylammonium cations (MR4+, R = 1-4) and metal cations (M1-3+). Parallel reactions in aqueous salt solutions with a short chain analog, 1-ArN2+, were used as references to calculate interfacial molarities. Aggregates were structurally characterized by TEM and DLS. Typically, interfacial RSO3- molarities increase with added salts from 1 to 2 M and water molarities decrease from about 40 to 20 M with the micelle to vesicle transition. These changes are consistent with the ion-pair/hydration model, in which the added cations form neutral but polar ion-pairs with RSO3- that have a lower demand for hydration and water was released into the surrounding aqueous phase. The extent of ion-pairing increases with cation size, charge and hydrophobicity and decreases with interfacial water molarity, which permits tighter interfacial packing and vesicle formation at lower added salt concentrations.

BACKGROUND Murrayanine is a carbazole alkaloid derived from Murraya koenigii, which has been used in traditional Chinese medicine in the treatment of cancer. This study aimed to investigate the effects of murrayanine on human lung adenocarcinoma cells in vitro and to investigate the mechanisms of its action. MATERIAL AND METHODS A549 human lung adenocarcinoma cells and MRC-5 human lung fibroblasts were grown in culture, and an MTT assay determined cell viability. Cells were treated for 24 h with increasing doses of murrayanine (0, 9, 18, and 36 µM). Fluorescence, using 4', 6-diamidino-2-phenylindole (DAPI), acridine orange, ethidium bromide, and propidium iodide (PI), were used for the detection of apoptosis. The cell cycle was studied with fluorescence-activated cell sorting (FACS), and Western blot evaluated protein expression. RESULTS Murrayanine treatment resulted in significant dose-dependent inhibition of the growth of A549 cells (p<0.05), with an IC₅₀ of 9 µM, and arrested the cells at the G2/M phase of the cell cycle, reduced the expression of cyclin D and E, CDK2, 4, and 6, and increased the expression of p21 and p27. Murrayanine treatment increased apoptosis of the A549 cells and increased cleaved of caspase-3 and caspase-9, and the Bax/Bcl-2 ratio. Murrayanine treatment increased levels of reactive oxygen species (ROS), disrupted the mitochondrial membrane potential, inhibited invasion, and inhibited phosphorylation of p38 mitogen-activated protein kinase (MAPK) of the A549 cells. CONCLUSIONS Murrayanine induced cell cycle arrest, oxidative stress, and inhibited the expression of phosphorylated p38 in A549 adenocarcinoma cells.

To evaluate the clinical efficacy and safety of adenomyomectomy using "H" type incision combined with Mirena (LNG-IUS) in the treatment of adenomyosis.A total of 57 women with adenomyosis who underwent adenomyomectomy using "H" type incision combined with LNG-IUS were selected. Visual analog scale (VAS), menstrual flow, uterine volume, serum CA125 levels and hemoglobin amounts were compared before and after the surgery. Meanwhile, postoperative pregnancy, adverse reactions, and recurrence were observed.VAS score, menstrual flow, uterine volume, and serum CA125 levels in 53 patients were significantly reduced after surgery (P < . 001). Moreover, statistical significances were obtained for VAS score at 13 and 6 months, menstrual flow at 1, 3, 6, 12, and 24 months, uterine volume at 1, 3, 6, 12, 24, and 36 months and CA125 levels at 1 and 3 months (P < .05). Of the 5 patients with fertility requirements, 1 became pregnant after IVF-ET, progressed to preterm, and delivered healthy twins. Among all related adverse reactions, amenorrhea was the most common (n = 20, 37.7%). There were no cases of LNG-IUS removal, ectopia, expulsion, and incarceration, except in 2 patients due to pregnancy, 1 due to uterine bleeding, and 1 due to Mirena perforation from incision of the uterine fundus. All patients showed no relapse.Adenomyomectomy using "H" type incision combined with Mirena constitutes a novel and effective conservative surgical procedure for adenomyosis treatment.

Realizing improved strength-ductility synergy in eutectic alloys acting as in situ composite materials remains a challenge in conventional eutectic systems, which is why eutectic high-entropy alloys (EHEAs), a newly-emerging multi-principal-element eutectic category, may offer wider in situ composite possibilities. Here, we use an AlCoCrFeNi 2.1 EHEA to engineer an ultrafine-grained duplex microstructure that deliberately inherits its composite lamellar nature by tailored thermo-mechanical processing to achieve property combinations which are not accessible to previously-reported reinforcement methodologies. The as-prepared samples exhibit hierarchically-structural heterogeneity due to phase decomposition, and the improved mechanical response during deformation is attributed to both a two-hierarchical constraint effect and a self-generated microcrack-arresting mechanism. This work provides a pathway for strengthening eutectic alloys and widens the design toolbox for high-performance materials based upon EHEAs.

Aim: To confirm non-inferiority and test potential superiority of capecitabine/cisplatin (XP) over 5-fluorouracil (5-FU)/cisplatin (FP) as first-line treatment for advanced gastric cancer (AGC) in Chinese patients., Methods: In open-label phase III ML17032 trial, AGC (stage IIIA-IV) patients with or without metastases were randomized 1:1 to receive cisplatin (80 mg/m 2 /day intravenous [IV] day 1) with either capecitabine (1000 mg/m 2 /day oral [PO] twice daily [BID], days 1-14; XP) or 5-FU (800 mg/m 2 /day continuous IV days 1-5; FP) every 3 weeks. The primary objective was to confirm the non-inferiority of XP over FP for progression-free survival (PFS)., Results: The intent-to-treat (ITT) population included 126 Chinese patients (XP-62, FP-64; 67.5% male, mean age 54.7 years). The primary analysis was performed on the per-protocol (PP) population (105 patients; XP-51, FP-54; 65.7% male). Median PFS in the XP and FP groups was 7.2 and 4.5 months, respectively. The adjusted hazard ratio (HR) for PFS was 0.52 (95% confidence interval [CI]: 0.32-0.83, P = 0.006). Unadjusted HR for PFS in the ITT population was 0.63 (95% CI, 0.42-0.94, P = 0.022). The most frequent drug-related grade 3/4 adverse events (AEs) were neutropenia (XP-20.7%, FP-17.7%) and gastrointestinal disorders (XP-19.0%, FP-19.4%). The overall incidence of grade 3/4 AEs (XP-43.1%, FP-46.8%), serious AEs (XP-1.7%, FP-3.2%), and AEs related to treatment discontinuation (XP-10.3%, FP-16.1%) were comparable., Conclusion: XP had a similar safety profile and may demonstrate superiority for PFS compared to FP as first-line treatment of Chinese patients with AGC (NCT02563054)., (© 2018 John Wiley & Sons Australia, Ltd.)

In bone tissue engineering, the fabrication of a scaffold with a hierarchical architecture, excellent mechanical properties, and good biocompatibility remains a challenge. Here, a solution of polylactic acid (PLA) and Tussah silk fibroin (TSF) was electrospun into nanofiber yarns and woven into multilayer fabrics. Then, composite scaffolds were obtained by mineralization in simulated body fluid (SBF) using the multilayer fabrics as a template. The structure and related properties of the composite scaffolds were characterized using different techniques. PLA/TSF (mass ratio, 9:1) nanofiber yarns with uniform diameters of 72±9μm were obtained by conjugated electrospinning; the presence of 10wt% TSF accelerated the nucleation and growth of hydroxyapatite on the surface of the composite scaffolds in SBF. Furthermore, the compressive mechanical properties of the PLA/TSF multilayer nanofiber fabrics were improved after mineralization; the compressive modulus and stress of the mineralized composite scaffolds were 32.8 and 3.0 times higher than that of the composite scaffolds without mineralization, respectively. Interestingly, these values were higher than those of scaffolds containing random nanofibers. Biological assay results showed that the mineralization and multilayer fabric structure of the composite nanofiber scaffolds significantly increased cell adhesion and proliferation and enhanced the mesenchymal stem cell differentiation toward osteoblasts. Our results indicated that the mineralized nanofiber scaffolds with multilayer fabrics possessed excellent cytocompatibility and good osteogenic activity, making them versatile biocompatible scaffolds for bone tissue engineering., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cadmium (Cd) is a toxic heavy metal and harmful to human health due to its ability to accumulate in organs. Previous studies have shown that Cd can induce DNA damage and autophagy. Autophagy can stabilize genetic material and DNA integrity. The aim of the present study was to determine the exact mechanism and role of autophagy induced by Cd in spermatozoa cells. Mouse spermatocyte-derived cells (GC-2) were treated with 20 μM Cd chloride for 24 h. The level of reactive oxygen species (ROS), DNA damage, autophagy and the expression of the molecular signaling pathway ATM/AMP-activated protein kinase (AMPK)/mTOR were determined. The results showed that Cd induced autophagy and DNA damage in GC-2 cells via ROS generation, and the autophagy signal pathway AMPK/mTOR was activated by ATM which is a DNA damage sensor. Melatonin, a well-known antioxidant, ameliorated DNA damage, and inhibited autophagy via the AMPK/mTOR signal pathway. Furthermore, after inhibition of autophagy by knockdown of AMPKα, increased DNA damage by Cd treatment was observed in GC-2 cells. These findings demonstrated the protective role of autophagy in DNA damage and suggested that the mechanism of autophagy induced by Cd was through the ATM/AMPK/mTOR signal pathway in spermatozoa cells., (Copyright © 2017. Published by Elsevier Ltd.)

P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription. AR S81 is also phosphorylated by CDK1, and blocking basal CDK1-mediated S81 phosphorylation markedly suppresses AR activity and initiation of this positive feedback loop. Finally, androgen-independent AR activity in castration-resistant prostate cancer (CRPC) cells is driven by increased CDK1-mediated S81 phosphorylation. Collectively these findings reveal a mechanism involving PP1α, CDK9 and CDK1 that is used by AR to initiate and sustain P-TEFb activity, which may be exploited to drive AR in CRPC., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Interest in two-dimensional (2D) van der Waals materials has grown rapidly across multiple scientific and engineering disciplines in recent years. However, ferroelectricity, the presence of a spontaneous electric polarization, which is important in many practical applications, has rarely been reported in such materials so far. Here we employ first-principles calculations to discover a branch of the 2D materials family, based on In 2 Se 3 and other III 2 -VI 3 van der Waals materials, that exhibits room-temperature ferroelectricity with reversible spontaneous electric polarization in both out-of-plane and in-plane orientations. The device potential of these 2D ferroelectric materials is further demonstrated using the examples of van der Waals heterostructures of In 2 Se 3 /graphene, exhibiting a tunable Schottky barrier, and In 2 Se 3 /WSe 2 , showing a significant band gap reduction in the combined system. These findings promise to substantially broaden the tunability of van der Waals heterostructures for a wide range of applications.

The ferritic Fe-Cr-Ni-Al-Ti alloys strengthened by hierarchical-Ni 2 TiAl/NiAl or single-Ni 2 TiAl precipitates have been developed and received great attentions due to their superior creep resistance, as compared to conventional ferritic steels. Although the significant improvement of the creep resistance is achieved in the hierarchical-precipitate-strengthened ferritic alloy, the in-depth understanding of its high-temperature deformation mechanisms is essential to further optimize the microstructure and mechanical properties, and advance the development of the creep resistant materials. In the present study, in-situ neutron diffraction has been used to investigate the evolution of elastic strain of constitutive phases and their interactions, such as load-transfer/load-relaxation behavior between the precipitate and matrix, during tensile deformation and stress relaxation at 973 K, which provide the key features in understanding the governing deformation mechanisms. Crystal-plasticity finite-element simulations were employed to qualitatively compare the experimental evolution of the elastic strain during tensile deformation at 973 K. It was found that the coherent elastic strain field in the matrix, created by the lattice misfit between the matrix and precipitate phases for the hierarchical-precipitate-strengthened ferritic alloy, is effective in reducing the diffusional relaxation along the interface between the precipitate and matrix phases, which leads to the strong load-transfer capability from the matrix to precipitate.

Although well characterized as a transcriptional activator that drives prostate cancer (PCa) growth, androgen receptor (AR) can function as a transcriptional repressor, and high-level androgens can suppress PCa proliferation. The molecular basis for this repression activity remains to be determined. Genes required for DNA replication are highly enriched among androgen-repressed genes, and AR is recruited to the majority of these genes, where it rapidly represses their transcription. This activity is enhanced in PCa cells expressing high AR levels and is mediated by recruitment of hypophosphorylated retinoblastoma protein (Rb). Significantly, AR also indirectly increases the expression of DNA replication genes through stimulatory effects on other metabolic genes with subsequent CDK activation and Rb hyperphosphorylation. In castration-resistant PCa cells, which are dependent on high-level AR expression, this anti-proliferative repression function might be exploited through treatment with androgen in combination with agents that suppress AR-driven metabolic functions or cell cycle progression., Competing Interests: of Potential Conflicts of Interest: No potential conflicts of interest were disclosed., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

As a commonly used method to enhance the ductility in bulk metallic glasses (BMGs), the introduction of geometric constraints blocks and confines the propagation of the shear bands, reduces the degree of plastic strain on each shear band so that the catastrophic failure is prevented or delayed, and promotes the formation of multiple shear bands. The clustering of multiple shear bands near notches is often interpreted as the reason for improved ductility. Experimental works on the shear band arrangements in notched metallic glasses have been extensively carried out, but a systematic theoretical study is lacking. Using instability theory that predicts the onset of strain localization and the free-volume-based finite element simulations that predict the evolution of shear bands, this work reveals various categories of shear band arrangements in double edge notched BMGs with respect to the mode mixity of the applied stress fields. A mechanistic explanation is thus provided to a number of related experiments and especially the correlation between various types of shear bands and the stress state.

Exploration of the catalytic activity of low-dimensional transition metal (TM) or noble metal catalysts is a vital subject of modern materials science because of their instrumental role in numerous industrial applications. Recent experimental advances have demonstrated the utilization of single atoms on different substrates as effective catalysts, which exhibit amazing catalytic properties such as more efficient catalytic performance and higher selectivity in chemical reactions as compared to their nanostructured counterparts; however, the underlying microscopic mechanisms operative in these single atom catalysts still remain elusive. Based on first-principles calculations, herein, we present a comparative study of the key kinetic rate processes involved in CO oxidation using a monomer or dimer of two representative TMs (Pd and Ni) on defective TiO2(110) substrates (TMn@TiO2(110), n = 1, 2) to elucidate the underlying mechanism of single-atom catalysis. We reveal that the O2 activation rates of the single atom TM catalysts deposited on TiO2(110) are governed cooperatively by the classic spin-selection rule and the well-known frontier orbital theory (or generalized d-band picture) that emphasizes the energy gap between the frontier orbitals of the TM catalysts and O2 molecule. We further illuminate that the subsequent CO oxidation reactions proceed via the Langmuir-Hinshelwood mechanism with contrasting reaction barriers for the Pd monomer and dimer catalysts. These findings not only provide an explanation for existing observations of distinctly different catalytic activities of Pd@TiO2(110) and Pd2@TiO2(110) [Kaden et al., Science, 2009, 326, 826-829] but also shed new insights into future utilization and optimization of single-atom catalysis.

We report the observation of the generation of dislocations in single-crystal phase-change In2Se3 nanowires under electrical pulses and the impact of these dislocations on electrical properties. Particularly, we correlated the atomic-scale structural characteristics with local electrical resistance variations, by performing transmission electron microscopy and scanning Kelvin probe microscopy on the same nanowires. By coupling the experimental results with first-principles density functional theory calculations, we show that the immobile dislocations are generated via vacancy condensations. Importantly, these dislocations lead to several orders of magnitude increase in the electrical resistance, while maintaining the single crystallinity of the lattice. These results significantly advance the fundamental understanding of the structure-property relation in this phase-change material under transient electrical excitations. From a practical perspective, the significant increase in the electrical resistance, driven by the formation of dislocations, can be exploited as a new electronic state in the single-crystalline phase in this phase-change material.

Foam fractionation and resin adsorption were used to recover soybean saponins from the industrial residue of soybean meal. First, a two-stage foam fractionation technology was studied for concentrating soybean saponins from the leaching liquor. Subsequently, resin adsorption was used to purify soybean saponins from the foamate in foam fractionation. The results showed that the enrichment ratio, the recovery percentage, and the purity of soybean saponins by using the two-stage foam fractionation technology could reach 4.45, 74%, and 67%, respectively. After resin adsorption and desorption, the purity of soybean saponins in the freeze-dried powder from the desorption solution was 88.4%.

Background: Previous reports have documented protein phosphatase 1 (PP1) as an essential androgen receptor (AR) activator. However, more systemic studies are needed to further define PP1 effects on AR, particularly in the settings of prostate cancer cells and under conditions mimicking androgen ablation., Methods: PP1 effects on AR protein expression, degradation, ubiquitination, and stabilization were examined in non-prostate cancer cells, followed by validation on exogenous settings in androgen-sensitive (LNCaP and VCaP) and castration-resistant (C4-2) prostate cancer cells. Effects of PP1 on AR protein expression, on AR-mediated transcription of exogenous reporter and endogenous gene, and on LNCaP and C4-2 cell proliferation were monitored under androgen-containing versus androgen-depleted conditions to assess the effects of PP1 on AR responsiveness to androgen., Results: In this report, we determined that PP1 functions to stabilize AR proteins that exclusively undergo the proteasome-dependent degradation, and the stimulatory effects of PP1 were predominantly mediated by the AR ligand-binding domain (LBD). Consistently, PP1 enhances AR protein stability by disrupting the LBD-mediated and K48-linked ubiquitination cascade. We further validated the above findings in the prostate cancer cells by showing that PP1 inhibition can increase ubiquitin- and proteasome-dependent degradation of endogenous AR under androgen deprivation. Significantly, we found that PP1 could markedly activate AR transcriptional activities under conditions mimicking androgen ablation and that androgen sensitivity was substantially evoked by PP1 inhibition in the prostate cancer cell lines., Conclusions: As summarized in a simplified model, our studies defined an essential PP1-mediated pathway for AR protein stabilization that can compensate the loss of androgen and established a mechanistic link between PP1 and androgen responsiveness. The amplified PP1-dependence for AR activation under the androgen ablated conditions provides a rationale to therapeutically target the PP1-AR module in the castration-resistant prostate cancer (CRPC). Our findings also suggested an alternative AR-targeting compounds screening strategy that aims to circumvent PP1-AR interaction., (© 2016 Wiley Periodicals, Inc.)

An understanding of load sharing among constituent phases aids in designing mechanical properties of multiphase materials. Here we investigate load partitioning between the body-centered-cubic iron matrix and NiAl-type precipitates in a ferritic alloy during uniaxial tensile tests at 364 and 506 °C on multiple length scales by in situ neutron diffraction and crystal plasticity finite element modeling. Our findings show that the macroscopic load-transfer efficiency is not as high as that predicted by the Eshelby model; moreover, it depends on the matrix strain-hardening behavior. We explain the grain-level anisotropic load-partitioning behavior by considering the plastic anisotropy of the matrix and elastic anisotropy of precipitates. We further demonstrate that the partitioned load on NiAl-type precipitates relaxes at 506 °C, most likely through thermally-activated dislocation rearrangement on the microscopic scale. The study contributes to further understanding of load-partitioning characteristics in multiphase materials.

The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1α) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1α increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1α binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1α inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1α may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4-2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1α may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1α or the AR-PP1α interaction may be effective in castration-resistant prostate cancer (CRPC).