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Tumor metastasis is a complex process. A better understanding of the mechanistic underpinnings of the metastatic cascade could uncover approaches to better prevent and target metastases. Here, we integrated transcriptomic profiling in primary esophageal squamous cell carcinoma (ESCC) and matched lymph node metastatic tissues and genome-wide CRISPR/Cas9 functional screening to identify the key drivers of cancer metastasis. Anoctamin 1 (ANO1) expression was found to be elevated in primary tumors and further increased in metastatic tissues. High expression of ANO1 was associated with poor patient survival, and ANO1 overexpression promoted cancer invasion and metastasis. Mechanistically, ANO1 inactivated the LXR pathway and increased intracellular cholesterol accumulation by interacting with JUN to repress the transcription of cholesterol hydroxylase, CYP27A1. In a paracrine manner, IL1β secreted from ANO1-expressing ESCC cancer cells activated NF-κB signaling in fibroblasts to stimulate production of the chemokine CCL1, which in turn enhanced invasion of ESCC cancer cells. Furthermore, molecular docking and in silico screening of 1,500,000 small molecules identified K786–4469 as a lead compound that targeted ANO1 and suppressed cancer metastasis in vitro and in vivo. Overall, these findings uncover a noncanonical function of ANO1 in regulating cholesterol metabolism and fibroblast function, revealing ANO1 as a potential prognostic biomarker and therapeutic target for metastatic ESCC. Significance: Metastatic cancer cells upregulate ANO1 to activate cell-intrinsic and -extrinsic mechanisms that alter cholesterol metabolism and stimulate fibroblasts, which can be targeted with ANO1 inhibitors to inhibit metastatic growth. See related commentary by Singh and Mehla, p. 1759

Hypoxic-ischemic white matter injury (WMI) pathogenesis in preterm infants is not well established, and iron-related proteins in the brain may play an important role in imbalanced iron metabolism. We aimed to investigate the iron-related protein changes in neonatal rats after hypoxia-ischemia (HI), clarify the role of iron-related proteins in hypoxic-ischemic WMI, and potentially provide a new target for the clinical treatment of hypoxic-ischemic WMI in preterm infants. We adopted a WMI animal model of bilateral common carotid artery electrocoagulation combined with hypoxia in neonatal 3-day-old Sprague-Dawley rats. We observed basic myelin protein (MBP) and iron-related protein expression in the brain (ferritin, transferrin receptor [TfR], and membrane iron transporter 1 [FPN1]) via Western blot and double immunofluorescence staining. The expression of MBP in the WMI group was significantly downregulated on postoperative days (PODs) 14, 28, and 56. Ferritin levels were significantly increased on PODs 3, 7, 14, and 28 and were most significant on POD 28, returning to the sham group level on POD 56. FPN1 levels were significantly increased on PODs 7, 28, and 56 and were still higher than those in the sham group on POD 56. TfR expression was significantly upregulated on PODs 1, 7, and 28 and returned to the sham group level on POD 56. Immunofluorescence staining showed that ferritin, TfR, and FPN1 were expressed in neurons, blood vessels, and oligodendrocytes in the cortex and corpus callosum on POD 28. Compared with the sham group, the immune-positive markers of three proteins in the WMI group were significantly increased. The expression of iron-related proteins in the brain (ferritin, FPN1, and TfR) showed spatiotemporal dynamic changes and may play an important role in hypoxic-ischemic WMI.

The wet oxidation method could gently reduce the dislocation and improve impurities getter efficiency in the process of oxidizing PRL to PSG. Although wet oxidation could cause some damage, the final result (PCE) is still improved.

Motoric cognitive risk syndrome (MCR) is a newly proposed pre-dementia syndrome. Several studies on the prevalence of MCR have been published; however, the data vary across studies with different epidemiological characteristics. Thus, this study aimed to quantitatively analyse the overall prevalence and associated epidemiological characteristics of MCR among older adults aged ≥ 60 years.The Cochrane Library, PubMed, Web of Science, CINAHL, Embase, Scopus, PsycInfo, China National Knowledge Infrastructure, Weipu Database, China Biology Medicine disc and Wanfang Database were searched from their inception to January 2022. A modified Newcastle-Ottawa Scale evaluated the risk of bias. Statistical heterogeneity among the included studies was analysed using Cochran's Q and ISixty-two studies comprising 187,558 samples were obtained. The pooled MCR prevalence was 9.0% (95% confidence interval: 8.3-9.8). A higher MCR prevalence was observed in females, older adults with a low educational level, depression and cardiovascular risk factors, South American populations, and studies with small sample sizes and cross-section designs. Furthermore, subjective cognitive complaint using scale score and gait speed using instrument gait showed higher MCR prevalence.MCR is common in older adults, and various epidemiological characteristics influence its prevalence. Thus, preventive measures are required for older adults with higher MCR prevalence.

Knowledge of wellbore multiphase flow characteristics is important for early gas invasion identification and treatment, especially in oil-based drilling fluid. The wellbore multiphase flow law in downhole dual-gradient drilling (DDGD) is more complex than that in conventional single-gradient drilling. There was no relevant literature report at present. In this paper, considering the synergistic feedback relationship of multiphase flow, interphase mass transfer, and wellbore temperature, a fully transient wellbore multiphase flow model was established based on oil-based drilling fluid in deepwater DDGD. The model also coupled the variable temperature–mass flows caused by the dynamic transfer of hollow glass balls and formation gas. The bubble interface mass transfer theory was adopted to describe the interphase mass transfer rate. The model was verified through the experimental measurement data. The calculated results indicated that the dynamic transfer of hollow glass balls varied the wellbore pressure gradient and flow rate in DDGD, resulting in a sudden decrease in gas fraction and gas solubility along the flow direction at the separator. Additionally, the transient interphase mass transfer and wellbore temperature had large impact on the wellbore multiphase flow behaviors. Moreover, the model based on bubble interface mass transfer theory could more accurately characterize the development of the wellbore multiphase flow. This research could provide a certain theoretical basis for the detection and treatment of gas invasion in deepwater DDGD.

The objective of our study was to explore the expression pattern of circular ribonucleic acid (RNA)_0,007,331 (circ_0,007,331) in breast cancer (BC) and its functional association with cellular paclitaxel (PTX) resistance and proliferation, migration, invasion and apoptosis.Real-time quantitative polymerase chain reaction was applied to measure RNA expression. The PTX resistance of BC cells was analyzed by cell counting kit-8 assay. Flow cytometry was applied to assess cell cycle progression and cell apoptosis. Transwell assays were utilized to analyze cell migration and invasion abilities. Protein expression was determined by Western blot assay. The target relationship between microRNA-200b-3p (miR-200b-3p) and circ_0,007,331 or Anillin (ANLN) was verified by dual-luciferase reporter assay and RNA-pull down assay. The in vivo role of circ_0,007,331 was analyzed using xenograft tumor model.Circ_0,007,331 expression was elevated in PTX-resistant BC cell lines relative to parental BC cell lines. Circ_0,007,331 contributed to the PTX resistance, proliferation, migration, invasion and suppressed the apoptosis of BC cells. Circ_0,007,331 interacted with miR-200b-3p in BC cells. Circ_0,007,331 silencing-mediated effects in BC cells were largely overturned by the knockdown of miR-200b-3p. ANLN was a target of miR-200b-3p in BC cells. Circ_0,007,331 silencing reduced ANLN expression partly through upregulating miR-200b-3p in BC cells. miR-200b-3p overexpression-induced effects in BC cells were largely counteracted by the accumulation of ANLN. Circ_0,007,331 silencing aggravated PTX-mediated inhibitory effect on tumor growth in vivo.Circ_0,007,331 contributed to the PTX resistance, proliferation and motility and inhibited the apoptosis of BC cells through mediating miR-200b-3p/ANLN signaling.

To systematically evaluate and integrate the qualitative research on physical activity (PA) experience of patients with chronic obstructive pulmonary disease (COPD).Web of Science, Cochrane Library, Embase, CINAHL and other databases were searched, and the qualitative research on PA experience of patients with COPD was collected. The systematic review was conducted in line with Joanna Briggs Institute (JBI) methodology for systematic reviews of qualitative evidence.12 studies were included and 3 themes were summarized, included: COPD patients experience more barriers while participating in physical activities than facilitators; COPD patients experience more positive effects post-physical activities than negative effects; Guaranteeing safety, goal setting, and establishing a professional support group improve compliance in COPD patients.Health care professionals should help patients overcome the obstacles of PA, pay attention to the PA experience of patients, adopt diversified PA methods, improve PA participation and compliance, and make patients develop good PA habits.

Background A major goal of coronavirus disease 2019 (COVID-19) vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of messenger RNA (mRNA) and ChAdOx1 COVID-19 vaccines against severe outcomes in 4 Canadian provinces between December 2020 and September 2021. Methods We conducted this multiprovincial, retrospective, test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random-effects models. Results We included 2 508 296 tested participants, with 31 776 COVID-19 hospitalizations and 5842 deaths. Vaccine effectiveness was 83% after a first dose and 98% after a second dose against both hospitalization and death (separately). Against severe outcomes, effectiveness was 87% (95% confidence interval [CI], 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95% CI, 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95% CI, 75%–94%) ≥56 days after a first dose, increasing to 97% (95% CI, 91%–99%) ≥56 days after a second dose. Lower 1-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules and against Alpha, Gamma, and Delta variants. Conclusions Two doses of mRNA or ChAdOx1 vaccine provide excellent protection against severe outcomes.

To evaluate the efficacy and safety of Cidan Capsule combined with adjuvant transarterial chemoembolization (TACE) in patients with a high risk of early recurrence after curative resection of hepatocellular carcinoma (HCC).A multicenter, randomized controlled trial was conducted in patients with high-risk recurrence factors after curative resection of HCC from 9 medical centers between July 2014 and July 2018. Totally 249 patients were randomly assigned to TACE with or without Cidan Capsule administration groups by stratified block in a 1:1 ratio. Postoperative adjuvant TACE was given 4-5 weeks after hepatic resection in both groups. Additionally, 125 patients in the TACE plus Cidan group were administrated Cidan Capsule (0.27 g/capsule, 5 capsules every time, 4 times a day) for 6 months with a 24-month follow-up. Primary endpoints included disease-free survival (DFS) and tumor recurrence rate (TRR). Secondary endpoint was overall survival (OS). Any drug-related adverse events (AEs) were observed and recorded.As the data cutoff in July 9th, 2018, the median DFS was not reached in the TACE plus Cidan group and 234.0 days in the TACE group (hazard ratio, 0.420, 95% confidence interval, 0.290-0.608; P0.01). The 1- and 2-year TRR in the TACE plus Cidan and TACE groups were 31.5%, 37.1%, and 60.8%, 63.4%, respectively (P0.01). Median OS was not reached in both groups. The 1- and 2-year OS rates in TACE plus Cidan and TACE groups were 98.4%, 98.4%, and 89.5%, 87.9%, respectively (P0.05). The most common grade 3-4 AEs included fatigue, abdominal pain, lumbar pain, and nausea. One serious AE was reported in 1 patient in the TACE plus Cidan group, the death was due to retroperitoneal mass hemorrhage and hemorrhagic shock, and was not related to study drug.Cidan Capsule in combination with TACE can reduce the incidence of early recurrence in HCC patients at high-risk of recurrence after radical hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment. (Registration No. NCT02253511).

Accurate soil organic carbon (SOC) maps are helpful for guiding forestry production and management. Different ecological landscape areas within a large region may have different soil–landscape relationships, so models specifically for these areas may capture these relationships more accurately than the global model for the entire study area. The aim of this study was to investigate the role of zonal modelling in predicting forest SOC and to produce highly accurate forest SOC distribution maps. The prediction objects were SOC at five soil depths (0–20, 20–40, 40–60, 60–80, and 80–100 cm). First, the forest type map and soil texture class map were used to divide the relative homogeneous regions in Shaoguan City, Guangdong Province, China. Second, seven terrain variables derived from a 12.5-m digital elevation model (DEM) and five vegetation variables generated from 10-m Sentinel-2 remote sensing images were used as predictors to develop regional artificial neural network (ANN) models for each homogeneous region, as well as a global ANN model for the entire study area (1000 sample points). Finally, 10-fold cross-validation was used to assess the ANN prediction model performance, and independent validation was used to evaluate the produced forest SOC prediction maps (194 additional samples). The cross-validation results showed that the accuracies of the regional models were better than that of the global model. Independent validation results also showed that the precision (R2) of 0- to 100-cm forest SOC maps generated by forest type modelling had an improvement of 0.05–0.15, and that by soil texture class modelling had an improvement of 0.07–0.13 compared to the map generated by the global model. In conclusion, delineating relatively homogeneous regions via simple methods can improve prediction accuracy when undertaking soil predictions over large areas, especially with complex forest landscapes. In addition, SOC in the study area is generally more abundant in broadleaf forest and clay areas, with overall levels decreasing with soil depth. Accurate SOC distribution information can provide references for fertilization and planting. Plants with particularly high soil fertility requirements may perhaps be planted in broadleaf forests or clay areas, and plants with particularly developed roots may require furrow application of a small amount of SOC.

Supplementary Table 1 shows primary antibody list

Supplementary Table 3 shows DEGs between ESCC primary tumors and matched lymph node metastatic tumors

Supplementary Table 8 shows Cytokines upregulated in the CM from ANO1 overexpressing EC9706 cells compared with control cells

Tumor metastasis is a complex process. A better understanding of the mechanistic underpinnings of the metastatic cascade could uncover approaches to better prevent and target metastases. Here, we integrated transcriptomic profiling in primary esophageal squamous cell carcinoma (ESCC) and matched lymph node metastatic tissues and genome-wide CRISPR/Cas9 functional screening to identify the key drivers of cancer metastasis. Anoctamin 1 (ANO1) expression was found to be elevated in primary tumors and further increased in metastatic tissues. High expression of ANO1 was associated with poor patient survival, and ANO1 overexpression promoted cancer invasion and metastasis. Mechanistically, ANO1 inactivated the LXR pathway and increased intracellular cholesterol accumulation by interacting with JUN to repress the transcription of cholesterol hydroxylase, CYP27A1. In a paracrine manner, IL1β secreted from ANO1-expressing ESCC cancer cells activated NF-κB signaling in fibroblasts to stimulate production of the chemokine CCL1, which in turn enhanced invasion of ESCC cancer cells. Furthermore, molecular docking and in silico screening of 1,500,000 small molecules identified K786–4469 as a lead compound that targeted ANO1 and suppressed cancer metastasis in vitro and in vivo. Overall, these findings uncover a noncanonical function of ANO1 in regulating cholesterol metabolism and fibroblast function, revealing ANO1 as a potential prognostic biomarker and therapeutic target for metastatic ESCC.Significance:Metastatic cancer cells upregulate ANO1 to activate cell-intrinsic and -extrinsic mechanisms that alter cholesterol metabolism and stimulate fibroblasts, which can be targeted with ANO1 inhibitors to inhibit metastatic growth.See related commentary by Singh and Mehla, p. 1759

Supplementary Table 2 shows qRT-PCR primers

Supplementary Table 6 shows DEGs of EC9706 overexpressing ANO1 and control cells

Background Cattle (Bos taurus) are a major large livestock, however, compared with other species, the transcriptional specificity of bovine oocyte development has not been emphasised. Results To reveal the unique transcriptional signatures of bovine oocyte development, we used integrated multispecies comparative analysis and weighted gene co-expression network analysis (WGCNA) to perform bioinformatic analysis of the germinal follicle (GV) and second meiosis (MII) gene expression profile from cattle, sheep, pigs and mice. We found that the expression levels of most genes were down-regulated from GV to MII in all species. Next, the multispecies comparative analysis showed more genes involved in the regulation of cAMP signalling during bovine oocyte development. Moreover, the green module identified by WGCNA was closely related to bovine oocyte development. Finally, integrated multispecies comparative analysis and WGCNA picked up 61 bovine-specific signature genes that participate in metabolic regulation and steroid hormone biosynthesis. Conclusion In a short, this study provides new insights into the regulation of cattle oocyte development from a cross-species comparison.

Supplementary Table 7 shows Human transcription factor in ANO1 interacting proteins detected by IP-MS

Supplementary Table 9 shows Top 30 cytokines upregulated in the CM from fibroblasts cultured with CM-ANO1 compared with CM-CON

Supplementary figures shows Supplementary figures and figure legends

Supplementary Methods shows supplementary Materials and Methods

Supplementary Table 4 shows DEGs between highly metastasis ESCC sub cell line KYSE150-Luc-LM3 and the parental cell line

Postmenopausal osteoporosis is a metabolic disease caused by an imbalance between osteoclasts and osteoblasts. At present, the drug strategy for treating postmenopausal osteoporosis has some limitations and is unable to satisfy the demands of patients. Phillyrin (Phil) is an herbal extract from Forsythiae Fructus, with an inhibitory effect on osteolysis. In this study, we described the role of Phil in ovariectomy-induced osteoporosis and its effect on osteoclast differentiation in vitro. Eighteen female C57BL/6 mice were randomly divided into three groups: sham group (sham surgery and injection with 0.9% normal saline), ovariectomized group (ovariectomy and injection with 0.9% normal saline), and Phil group (ovariectomy and injecting Phil with 100 mg/kg for 2 days). Mice were sacrificed after 6-week Phil administration and femurs were harvested for microcomputed tomography (micro-CT) and histomorphology analyses. In vitro, we used different concentrations of Phil to study its effect on osteoclastogenesis. The results showed that the BV/TV, Tb.Th, and Tb.N in trabecular bone were increased in the Phil group compared with the OVX group, and the trabecular bone mass was remarkably decreased in the OVX group compared with the sham group. The number of osteoclasts was increased in the OVX group compared to the sham group, and the number and area of osteoclasts were decreased in the Phil group compared to the control group. Compared with the OVX group, the number and area of osteoclasts were reduced in the Phil group. In conclusion, Phil could inhibit the formation of osteoclasts, promote the growth of bone trabecular, and relieve osteoporosis caused by ovariectomy, with a certain clinical adoption value.

Supplementary Figure S1 - PDF file 115K, Gene expression of PNLIP, CLPS, PNLIRP1 and PNLIPRP2 in Panc1, MIApaca2 and non-tumorigenic hTERT-HPNE cell lines

Supplementary Figure S2 - PDF file 119K, Palmitate and Stearate inhibits cell growth of pancreatic cancer cell lines

Supplementary Materials and Methods - PDF file 88K, Additional description of materials and methods

N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into the regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3, whereas SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration–approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immunodeficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m6A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC.Significance:This study finds that METTL3 promotes cancer metastasis by activating EGR1/Snail signaling in an m6A-dependent manner, revealing vulnerability to METTL3 blockade in esophageal squamous cell carcinoma.

Supplementary Table S2 - PDF file 64K, A list of 55 metabolites differentially expressed in two independent cohorts of PDAC cases

Supplementary Figure from Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m6A Methyltransferase METTL3

Supplementary Table S5 - PDF file 71K, Gene expression profiles of PNLIP, CLPS, PNLIPRP1 and PNLIPRP2 in PDAC in the Oncomine database

Supplementary Table S4 - PDF file 71K, 157 gene surrogates of 8 fatty acids are differentially expressed between tumor and nontumor tissues in PDAC cases

Supplementary Table S1 - PDF file 67K, Characteristics of Patients

Supplementary Table from Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m6A Methyltransferase METTL3

Supplementary Data from Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m6A Methyltransferase METTL3