Explore the vast range of titles available.

The tumor microenvironment is a highly complex ecosystem of diverse cell types, which shape cancer biology and impact the responsiveness to therapy. Here, we analyze the microenvironment of esophageal squamous cell carcinoma (ESCC) using single-cell transcriptome sequencing in 62,161 cells from blood, adjacent nonmalignant and matched tumor samples from 11 ESCC patients. We uncover heterogeneity in most cell types of the ESCC stroma, particularly in the fibroblast and immune cell compartments. We identify a tumor-specific subset of CST1 + myofibroblasts with prognostic values and potential biological significance. CST1 + myofibroblasts are also highly tumor-specific in other cancer types. Additionally, a subset of antigen-presenting fibroblasts is revealed and validated. Analyses of myeloid and T lymphoid lineages highlight the immunosuppressive nature of the ESCC microenvironment, and identify cancer-specific expression of immune checkpoint inhibitors. This work establishes a rich resource of stromal cell types of the ESCC microenvironment for further understanding of ESCC biology. The microenvironment of oesophageal squamous cell carcinomas (ESCC) is heterogeneous and can strongly impact response to treatment. Here, the authors characterize the ESCC tumour microenvironment with single-cell RNA-seq, finding CST1 + myofibroblasts with potential biological and prognostic significance as well as immunosuppression signatures.

Squamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by tumor protein p63 (TP63) , a master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify sterol regulatory element binding transcription factor 1 (SREBF1) as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/ Kruppel like factor 5 (KLF5) is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC. The relevance and underlying molecular mechanisms of epigenetic regulation in squamous cell carcinomas (SCC) await further characterization. Here, the authors show a transcriptional regulatory loop involving SREBF1, TP63 and KLF5 driving tumourigenesis in SCC through fatty acid, ERBB and mTOR pathway regulation.

•This study is the first to include preoperative indicators to predict muscle quality.•This study predicts muscle quality through routine clinical data, which are beneficial for diagnosis in community hospitals.•This study establishes a nomogram to visualize the predictive model, which is beneficial to clinical practice.•This study includes a multifaceted prediction of muscle quality, with a high value of nomogram prediction performance and high clinical application. The skeletal muscle mass index and skeletal muscle radiodensity have promise as specific diagnostic indicators for muscle quality. However, the difficulties in measuring low skeletal muscle mass index and low skeletal muscle radiodensity limit their use in routine clinical practice, impeding early screening and diagnosis. The objective of this study is to develop a nomogram that incorporates preoperative factors for predicting low skeletal muscle mass index and low skeletal muscle radiodensity. A total of 1692 colorectal cancer patients between 2015 and 2021 were included. The patients were randomly divided into a training cohort (n = 1353) and a validation cohort (n = 339). Nomogram models were calibrated using the area under the curve, calibration curves, and the Hosmer-Lemeshow test to assess their predictive ability. Finally, a decision curve was applied to assess the clinical usefulness. In a prediction model for low skeletal muscle mass index, age, body mass index, and grip strength were incorporated as variables. For low skeletal muscle radiodensity, age, sex, body mass index, serum hemoglobin level, and grip strength were included as predictors. In the training cohort, the area under the curve value for low skeletal muscle mass index was 0.750 (95% CI, 0.726–0.773), whereas for low skeletal muscle radiodensity, it was 0.763 (95% CI, 0.739–0.785). The Hosmer-Lemeshow test confirmed that both models fit well in both cohorts. Decision curve analysis was applied to assess the clinical usefulness of the model. The incorporation of preoperative factors into the nomogram-based prediction model represents a significant advancement in the muscle quality assessment. Its implementation has the potential to early screen patients at risk of low skeletal muscle mass index and low skeletal muscle radiodensity.

Background Increasing evidence shows that dysregulated long non-coding RNAs (lncRNAs) can serve as potential biomarkers for cancer prognosis. However, lncRNA signatures, as potential prognostic biomarkers for esophageal squamous cell carcinoma (ESCC), have been seldom reported. Methods Based on our previous transcriptome RNA sequencing analysis from 15 paired ESCC tissues and adjacent normal tissues, we selected 10 lncRNAs with high score rank and characterized the expression of those lncRNAs, by qRT-PCR, in 138 ESCC and paired adjacent normal samples. These 138 patients were divided randomly into training ( n  = 77) and test ( n  = 59) groups. A prognostic signature of lncRNAs was identified in the training group and validated in the test group and in an independent cohort ( n  = 119). Multivariable Cox regression analysis evaluated the independence of the signature in overall survival (OS) and disease-free survival (DFS) prediction. GO and KEGG pathway analysis, combined with cell transwell and proliferation assays, are applied to explore the function of the three lncRNAs. Results A novel three-lncRNA signature, comprised of RP11-366H4.1.1 (ENSG00000248370), LINC00460 (ENSG00000233532) and AC093850.2 (ENSG00000230838), was identified. The signature classified patients into high-risk and low-risk groups with different overall survival (OS) and disease-free survival (DFS). For the training group, median OS: 23.1 months vs. 39.1 months, P  < 0.001; median DFS: 15.2 months vs. 33.3 months, P  < 0.001. For the test group, median OS: 23 months vs. 59 months, P  < 0.001; median DFS: 16.4 months vs. 50.8 months, P  < 0.001. For the independent cohort, median OS: 22.4 months vs. 60.4 months, P  < 0.001). The signature indicates that patients in the high-risk group show poor OS and DFS, whereas patients with a low-risk group show significantly better outcome. The independence of the signature was validated by multivariable Cox regression analysis. GO and KEGG pathway analysis for 588 protein-coding genes-associated with the three lncRNAs indicated that the three lncRNAs were involved in tumorigenesis. In vitro assays further demonstrated that the three lncRNAs promoted the migration and proliferation of ESCC cells. Conclusions The three-lncRNA signature is a novel and potential predictor of OS and DFS for patients with ESCC.

Purpose This study aimed to explore effects of maternal folic acid (FA) supplementation during pregnancy on neurodevelopment in 1-month-old infants and to determine whether effects may be related to maternal circulating inflammatory cytokine concentrations. Methods This birth cohort study recruited 1186 mother–infant pairs in Tianjin, China, between July 2015 and July 2017. The women completed interviewer-administered questionnaires on their lifestyles and FA supplementation during pregnancy. Neurodevelopment was assessed in 1-month-old infants using a standard neuropsychological examination table. In 192 women, serum homocysteine (Hcy) and inflammatory cytokine concentrations were measured at 16–18 weeks of gestation. Results The infants whose mothers took FA supplements during pregnancy had a significantly higher development quotient (DQ) compared with those whose mothers were non-users ( P  < 0.05). After adjustment for maternal characteristics, supplementary FA use for 1–3 months, 3–6 months, and > 6 months were associated with the increases of 7.7, 11.0, and 7.4 units in the scale of infant DQ score compared with women reporting no supplement use, respectively ( P  < 0.05). FA supplementation was associated with a decreased serum concentration of Hcy ( β  =  - 0.19), which was correlated with women’s serum inflammatory cytokine concentrations at 16–18 weeks of gestation ( β  = 0.57). Serum inflammatory cytokine concentrations were inversely related to DQ score in the 1-months-old offspring ( β  =  - 0.22). Conclusions Maternal FA supplementation during pregnancy favors neurodevelopment in the offspring at 1-month-old. This association may be mediated by changes in serum Hcy and inflammatory cytokine concentrations throughout pregnancy.

GaN high-electron-mobility transistors (HEMTs) have attracted widespread attention for high-power microwave applications, owing to their superior properties. However, the charge trapping effect has limitations to its performance. To study the trapping effect on the device large-signal behavior, AlGaN/GaN HEMTs and metal-insulator-semiconductor HEMTs (MIS-HEMTs) were characterized through X-parameter measurements under ultraviolet (UV) illumination. For HEMTs without passivation, the magnitude of the large-signal output wave (X21FB) and small-signal forward gain (X2111S) at fundamental frequency increased, whereas the large-signal second harmonic output wave (X22FB) decreased when the device was exposed to UV light, resulting from the photoconductive effect and suppression of buffer-related trapping. For MIS-HEMTs with SiN passivation, much higher X21FB and X2111S have been obtained compared with HEMTs. It suggests that better RF power performance can be achieved by removing the surface state. Moreover, the X-parameters of the MIS-HEMT are less dependent on UV light, since the light-induced performance enhancement is offset by excess traps in the SiN layer excited by UV light. The radio frequency (RF) power parameters and signal waveforms were further obtained based on the X-parameter model. The variation of RF current gain and distortion with light was consistent with the measurement results of X-parameters. Therefore, the trap number in the AlGaN surface, GaN buffer, and SiN layer must be minimized for a good large-signal performance of AlGaN/GaN transistors.

Dementia imposes a heavy burden on society and families, therefore, effective drug treatments, exploring and preventing factors associated with dementia, are paramount. To provide reference points for the best frequency of physical exercise (physical exercise), we investigated the association between frequency of PE and cognition in Chinese old adults. 16,181 Chinese participants aged 65 years or older were included in this study. Associations between PE and cognition were estimated multivariate logistic and linear regression analyses. Associations were further investigated across dementia subtypes (Alzheimer dementia, vascular dementia, and other types of dementia). Subgroup analyses were performed in different age groups, in populations with and without stroke, and those with and without hypertension. PE associated with dementia after adjusting for full covariates (OR: 0.5414, 95% CI: 0.4536-0.6491,  < 0.001). Exercise performed at ≥3 times/week associated with lower risk of dementia (OR: 0.4794-0.6619, all value <0.001). PE was associated with improved cognition ( : 12851,  < 0.001), and any PE frequency contributed to cognitive improvement ( values for exercise performed ≥1 time/week were <0.001). Similar conclusions were identified when we repeated analyses in different dementia subtypes and age groups. Subgroup analyses suggested that the cognition of individuals without hypertension also benefitted from exercising 1-2 times/week (OR: 0.6168, 95% CI: 0.4379-0.8668,  = 0.005). The best exercise frequency is exercising ≥3 times/week for individuals from different dementia subtypes and age groups. While for those without hypertension, PE at 1-2 times /week is also beneficial.

CD8 + T cell spatial distribution in the context of tumor microenvironment (TME) dictates the immunophenotypes of tumors, comprised of immune-infiltrated, immune-excluded and immune-desert, discriminating “hot” from “cold” tumors. The infiltration of cytotoxic CD8 + T cells is associated with favorable therapeutic response. Hitherto, the immunophenotypes of esophageal squamous cell carcinoma (ESCC) have not yet been comprehensively delineated. Herein, we comprehensively characterized the immunophenotypes of ESCC and identified a subset of ESCC, which was defined as cold tumor and characterized with CD8 + T cell-desert TME. However, the mechanism underlying the defect of CD8 + T cells in TME is still pending. Herein, we uncovered that tumor cell-intrinsic EZH2 with high expression was associated with the immunophenotype of immune-desert tumors. Targeted tumor cell-intrinsic EZH2 rewired the transcriptional activation of CXCL9 mediated by NF-κB and concomitantly reinvigorated DC maturation differentiation via inducing the reduction of VEGFC secretion, thereby enhancing the infiltration of cytotoxic CD8 + T cells into TME and inhibiting tumor immune evasion. Our findings identify EZH2 as a potential therapeutic target and point to avenues for targeted therapy applied to patients with ESCC characterized by CD8 + T cell-desert tumors. Tumor-intrinsic EZH2 inhibits the production of CXCL9 and the differentiation of mature dendritic cells, leading to the dearth of CD8 + T cells in esophageal squamous cell carcinoma.

Magnetic cryopreservation has been successfully used for tooth banking with satisfactory implantation outcomes, suggesting that the method preserves human periodontal ligament cells and dental pulp stem cells (DPSCs). Therefore, magnetic cryopreservation may be applied for the preservation of DPSCs; however, this method has not been evaluated yet. A reliable cryopreservation method for live-cell preservation is important for the clinical applications of regenerative medicine. The conventional slow-freezing procedure with 10% dimethylsulfoxide (DMSO) may not be appropriate for stem cell-based therapies because DMSO is cytotoxic. The objective of this study was to investigate whether magnetic cryopreservation can be applied for DPSC cryopreservation. Cells isolated from human dental pulp were subjected to magnetic cryopreservation. Postthawing cell viability, adhesion, proliferation, expression of markers for mesenchymal stem cells (MSCs), differentiation ability of magnetically cryopreserved DPSCs and DNA stability were compared to those of cells subjected to the conventional slow-freezing method. The results indicated that a serum-free cryopreservation medium (SFM) containing 3% DMSO is optimal for magnetic cryopreservation. Post-thaw magnetically cryopreserved DPSCs express MSC markers, and perform osteogenesis and adipogenesis after induction similarly to fresh MSCs. No significant DNA damage was found in magnetically cryopreserved DPSCs. Magnetic cryopreservation is thus a reliable and effective method for storage of DPSCs. The smaller amount of DMSO required in SFM for cryopreservation is beneficial for the clinical applications of post-thaw cells in regenerative medicine.

Alzheimer’s disease (AD) is the most common type of dementia. Amyloid-β protein (Aβ) is identified as the core protein of neuritic plaques. Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. Previous studies indicated that folate deficiency elevated Aβ deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Aβ by regulating α-, β-, and γ-secretase. Herein, we demonstrated that folic acid reduced the deposition of Aβ42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of β-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and γ-secretase complex catalytic component—presenilin 1 (PS1)—in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important α-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of γ-secretase complex. Moreover, folic acid regulated the expression of miR-126-3p and miR-339-5p, which target ADAM9 and BACE1, respectively. Taken together, the effect of folic acid on Aβ deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing β-secretase and increasing α-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression.