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Cutaneous squamous cell carcinoma (cSCC) is a global malignant tumor with a high degree of malignancy. Once metastasis occurs, it will lead to poor prognosis and even death. This study attempts to find out the central genes closely related to cSCC metastasis, so as to clarify the molecular regulatory mechanism of cSCC metastasis and open up new ideas for clinical treatment.Firstly, cSCC data set GSE98767 was used to establish a tumor metastasis model via clustering analysis. The key module and hub genes associated with cSCC metastasis were analyzed by weighted gene co-expression analysis (WGCNA). Next, the prognostic functions of hub genes were identified by functional and pathway enrichment analysis, pan-cancer analysis, and receiver operating characteristic-area under the curve (ROC-AUC) validation. Finally, the key genes were verified by clinical sample detection and biological in vitro test.A total of 19 hub genes related to cSCC metastasis were identified. They were highly expressed in cSCC metastatic tissues and were mainly enriched in cellular material and energy metabolism pathways. Overall survival (OS) and disease-free survival (DFS) results from pan-cancer analysis showed that eight and six highly expressed genes, respectively, with PAPSS2 and SCG5 had highly reliable ROC-AUC validation values and were poor prognostic factors. Clinical and biological tests also confirmed the upregulation of PAPSS2 and SCG5 in cSCC. Deletion of PAPSS2 and SCG5 resulted in decreased viability, migration, and invasion of A-431 cells.PAPSS2 and SCG5 may be important factors for cSCC metastasis, and they are involved in the regulation of cSCC cell viability, migration, and invasion.

To systematically investigate the physiological distribution and benign lesion incidental uptake of Al18F-NOTA-FAPI-04 (18F-FAPI) in cancer patients to establish the normal uptake range in relevant organs and lesions.Twenty patients who underwent 18F-FAPI PET/CT imaging were retrospectively assessed. Organ and benign lesion tracer uptake was quantified based on standardized uptake values (SUVmax and SUVmean). We compared the variation in tracer uptake in certain organs between men and women, analyzed the possible reasons for diffuse uptake in the thyroid, and assessed tracer uptake variations in the uterus in different menstrual cycle phases. Incidental tracer uptake in benign lesions was also assessed.Physiological 18F-FAPI uptake was observed in the urinary tract, biliary tract system, submandibular glands, pancreas, thyroid, uterus, intestine, prostate gland, parotid gland, myocardium, kidney cortex, and muscles, but not the brain, lungs, liver, spleen, colon, and breasts. The SUVmean for each organ was similar for women and men (all P0.05). Diffuse tracer uptake in the thyroid was caused by normal thyroid or thyroiditis; there were no statistically significant differences between them (SUVmax: t = -1.3, P = 0.25; SUVmean: t = -1.1, P = 0.31). There was a significant difference for uterus uptake among different menstrual cycle phases (SUVmax: F = 5.08, P = 0.04; SUVmean: F = 5.19, P = 0.04). Incidental benign lesion tracer uptake was observed in patients with esophagitis, thyroiditis, arthritis, fractures, and uterine fibroids.This study provides a reference range for 18F-FAPI uptake in relevant organs and benign lesions. Benign lesion 18F-FAPI uptake may reduce 18F-FAPI PET/CT specificity.

The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP’s propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.

As an essential regulator of DNA damage, ataxia-telangiectasia mutated (ATM) gene has been widely studied in oncology. However, the independent effects of ATM missense variants and protein-truncating variants (PTVs) on neoplasms have not been heavily studied. Whole-exome sequencing data and the clinical health records of 394,694 UK Biobank European participants were used in this analysis. We mined genetic associations from gene-level and variant-level phenome-wide association studies, and conducted a variant-level conditional association study to test whether the effects of ATM missense variants on neoplasms were independent of ATM PTV carrier status. The gene-level PTV collapsing analysis was consistent with established ATM PTV literature showing that the aggregated impact of 286 ATM PTVs significantly (p 2 × 10

Butyrate, normally produced by probiotics in the gut, not only provides energy for cells, but also changes the phosphorylation, acetylation and methylation levels of many proteins in cells. As a result, it affects the expression of many genes and the transmission of cell signals. Through G protein-coupled receptors, butyrate promotes the secretion of intestinal mucus and the formation of epithelial barriers, and attenuates the impacts of the pathogenic bacteria and their metabolites on human body. The Toll-like receptors (TLRs) are a group of pattern recognition receptors, and their activation causes the translocation of nuclear factor κB (NF-κB) from the cytoplasm to the nucleus and eventually leads to expression and secretion of various pro-inflammatory factors and chemokines. The expression of TLRs is also involved in the pathogenesis of some inflammatory diseases and tumors. The purpose of this review is to summarize the effects of butyrate on TLRs and their downstream signaling pathways. We not only summarized the production of butyrate, the expression of TLRs and the influence of their interaction on the body under the conditions of inflammation and tumor, but also discussed the potential role of butyrate as a bacterial metabolite in the treatments of some human diseases.

Purpose Cone-beam CT (CBCT) has been widely utilized in image-guided radiotherapy. Planning CT (pCT)-aided CBCT scatter correction could further enhance image quality and extend CBCT application to dose calculation and adaptive planning. Nevertheless, existing pCT-based approaches demand accurate registration between pCT and CBCT, leading to limited imaging performance and increased computational cost when large anatomical discrepancies exist. In this work, we proposed a robust and fast CBCT scatter correction method using local filtration technique and rigid registration between pCT and CBCT (LF-RR). Methods First of all, the pCT was rigidly registered with CBCT, then forward projection was performed on registered pCT to create scatter-free projections. The raw scatter signals were obtained via subtracting the scatter-free projections from the measured CBCT projections. Based on frequency and intensity threshold criteria, reliable scatter signals were selected from the raw scatter signals, and further filtered for global scatter estimation via local filtration technique. Finally, corrected CBCT was reconstructed with the projections generated by subtracting the scatter estimation from the raw CBCT projections using FDK algorithm. The LF-RR method was evaluated via comparison with another pCT-based scatter correction method based on Median and Gaussian filters (MG method). Results Proposed method was first validated on an anthropomorphic pelvis phantom, and showed satisfied performance on scatter removal even when anatomical mismatches were intentionally created on pCT. The quantitative analysis was further performed on four clinical CBCT images. Compared with the uncorrected CBCT, CBCT corrected by MG with rigid registration (MG-RR), MG with deformable registration (MG-DR), and LF-RR reduced the CT number error from 79 ± 35 to 25 ± 18 , 17 ± 13 and 7 ± 3 HU for adipose and from 115 ± 61 to 36 ± 22 , 30 ± 24 , 7 ± 3 HU for muscle, respectively. After correction, the spatial non-uniformity (SNU) of CBCT corrected with MG-RR, MG-DR and LF-RR was 51 ± 13 , 60 ± 21 , and 21 ± 9 HU for adipose, and 50 ± 22 , 57 ± 41 , and 25 ± 6 HU for muscle, respectively. Meanwhile, the contrast-to-noise ratio (CNR) between muscle and adipose was increased by a factor of 2.70, 2.89 and 2.56, respectively. Using the LF-RR method, the scatter correction of 656 projections can be finished within 10 s and the corrected volumetric images (200 slices) can be obtained within 2 min. Conclusion We developed a fast and robust pCT-based CBCT scatter correction method which exploits the local-filtration technique to promote the accuracy of scatter estimation and is resistant to pCT-to-CBCT registration uncertainties. Both phantom and patient studies showed the superiority of the proposed correction in imaging accuracy and computational efficiency, indicating promisingfuture clinical application.

Background Hepatocellular carcinoma (HCC) is characterized by rapid progression, high recurrence rate and poor prognosis. Early prediction for the prognosis and immunotherapy efficacy is of great significance to improve the survival of HCC patients. However, there is still no reliable predictor at present. This study is aimed to explore the role of centromere protein L (CENPL) in predicting prognosis and its association with immune infiltration in HCC. Methods The expression of CENPL was identified through analyzing the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data. The association between CENPL expression and clinicopathological features was investigated by the Wilcoxon signed-rank test or Kruskal Wallis test and logistic regression. The role of CENPL in prognosis was examined via Kaplan-Meier method and Log-rank test as well as univariate and multivariate Cox regression analysis. Besides, in TIMER and GEPIA database, we investigated the correlation between CENPL level and immunocyte and immunocyte markers, and the prognostic-related methylation sites in CENPL were identified by MethSurv. Results CENPL had a high expression in HCC samples. Increased CENPL was prominently associated with unfavorable survival, and maybe an independent prognostic factor of worse overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), progression-free interval (PFI). Additionally, CENPL expression was significantly correlated with immune cell infiltration and some markers. CENPL also contained a methylation site that was notably related to poor prognosis. Conclusions Elevated CENPL may be a promising prognostic marker and associate with immune infiltration in HCC.

PURPOSE Flat-panel detector (FPD) based dual-energy cone-beam computed tomography (DE-CBCT) is a promising imaging technique for dedicated clinical applications. In this paper, we proposed a fully analytical method for fast and effective single-scan DE-CBCT image reconstruction and decomposition. METHODS A rotatable Mo filter was inserted between an x-ray source and imaged object to alternately produce low and high-energy x-ray spectra. First, filtered-backprojection (FBP) method was applied on down-sampled projections to reconstruct low and high-energy images. Then, the two images were converted into a vectorized form represented with an amplitude and an argument image. Using amplitude image as a guide, a joint bilateral filter was applied to denoise the argument image. Then, high-quality dual-energy images were recovered from the amplitude image and the denoised argument image. Finally, the recovered dual-energy images were further used for low-noise material decomposition and electron density synthesis. Imaging was conducted on a Catphan® 600 phantom and an anthropomorphic head phantom. The proposed method was evaluated via comparison with the traditional two-scan method and a commonly used filtering method (HYPR-LR). RESULTS On the Catphan® 600 phantom, the proposed method successfully reduced streaking artifacts and preserved spatial resolution and noise-power-spectrum (NPS) pattern. In the electron density image, the proposed method increased contrast-to-noise ratio (CNR) by more than 2.5 times and achieved

Huntingtin-associated protein 1 (HAP1) is the first identified protein whose function is affected by its abnormal interaction with mutant huntingtin (mHTT), which causes Huntington disease. However, the expression patterns of Hap1 and Htt in the rodent brain are not correlated. Here we found that the primate HAP1, unlike the rodent Hap1, is correlatively expressed with HTT in the primate brains. CRISPR/Cas9 targeting revealed that HAP1 deficiency in the developing human neurons did not affect neuronal differentiation and gene expression as seen in the mouse neurons. However, deletion of HAP1 exacerbated neurotoxicity of mutant HTT in the organotypic brain slices of adult monkeys. These findings demonstrate differential HAP1 expression and function in the mouse and primate brains, and suggest that interaction of HAP1 with mutant HTT may be involved in mutant HTT-mediated neurotoxicity in adult primate neurons.

To investigate the prognostic value of interimA total of 97 patients with pathologically diagnosed DLBCL at Sichuan Cancer Hospital and Institute from March 2015 to June 2020 were enrolled in this retrospective study. Receiver operating characteristic analysis (ROC) was used to calculate the optimum maximum standard uptake value reduction ratio (△SUVmax%) cut-off value. The prognostic value of △SUVmax% and Deauville five-point scale (5-PS) in patients with DLBCL was compared, and the determined prognostic factors were analyzed.ROC curve indicated that the optimum △SUV max% cut-off value was 74.9%. Patients with △SUVmax%≥74.9% had a lower rate of progression or recurrence than those with △SUVmax%74.9% (both P0.001). Meanwhile, patients with 5-PS score4 also had a lower rate of progression or recurrence than those with 5-PS score≥4 (both P0.001). △SUVmax% and 5-PS had high specificity (83.7% vs 83.7%) and negative predictive value (87.3% vs 84.9%), while low sensitivity (56.0% vs 52.2%) and positive predictive value (53.8% vs 50.0%). △SUVmax% was more sensitive than 5-PS for the corresponding parameters (78.3% vs 76.2%). Univariate analysis showed that Ann Arbor stage, international prognostic index of National Comprehensive Cancer Network (NCCN-IPI), △SUVmax% and 5-PS were associated with TTP and PFS (all P0.001). Multivariate analysis showed that △SUVmax% was an independent predictor of TTP and PFS (P=0.031, P=0.023).Both 5-PS and △SUVmax% can be used to evaluate the prognosis of DLBCL patients, but the predictive value of △SUVmax% is superior to that of 5-PS.中期探讨中期回顾性分析2015年3月至2020年6月在四川省肿瘤医院就诊的97例DLBCL患者资料，使用ROC曲线计算SUVmax缩减率（△SUVmax%）预测预后的最佳截断值，比较△SUVmax%和Deauville五分法（5-PS）诊断效能差异，分析影响预后的因素。.根据ROC曲线，△SUVmax%评估患者预后的最佳截断值为74.9%，△SUVmax%≥74.9%患者的复发或进展率低于△SUVmax%74.9%患者（均P0.001）；同时，5-PS4分患者复发或进展率低于5-PS≥4分的患者（均P0.001）。△SUVmax%与5-PS预测预后的特异度（83.7% vs 83.7%）和阴性预测值（87.3% vs 84.9%）均较高，敏感度（56.0% vs 52.2%）和阳性预测值均较低（53.8% vs 50.0%），△SUVmax%预测预后的准确率绝对值较5-PS高（78.3% vs 76.2%）。单因素分析结果显示，Ann Arbor分期、NCCN国际预后指数、△SUVmax%及5-PS与TTP及PFS相关（均P0.001）；进一步行多因素分析显示仅△SUVmax%是TTP及PFS的独立预测因子（均P0.05）。.△SUVmax%与5-PS均能准确评估DLBCL患者治疗后的预后情况，但△SUVmax%在预后评估方面有更高的预测价值。.

To explore the clinical effect of warming-needle moxibustion with different lengths of moxa stick for asthenospermia with kidney deficiency and liver depression.A total of 240 patients with asthenospermia of kidney deficiency and liver depression were randomly divided into a 4-cm group (moxibustion with 4-cm moxa stick, 60 cases, 3 cases dropped off), a 3-cm group (moxibustion with 3-cm moxa stick, 60 cases, 4 cases dropped off), a 2-cm group (moxibustion with 2-cm moxa stick, 60 cases, 2 cases dropped off) and an acupuncture group (60 cases, 3 cases dropped off). All patients were treated with warming-needle moxibustion with different lengths of moxa stick or conventicnal acupuncture at Zhongwan (CV 12), Guanyuan (CV 4), Zhongji (CV 3), Guilai (ST 29), Yaoyangguan (GV 3), Guanyuanshu (BL 26), etc., once a day, five times a week; 4-week treatment was taken as one course, a total of two courses of treatment were given. The semen routine indexes, seminal plasma biochemical indexes, sex hormone levels and TCM syndrome score were compared before and after treatment among the 4 groups.After treatment, the sperm density, sperm viability, ratio of grade A sperm, ratio of grade A and B sperm, seminal plasma fructose and neutral α-glucosidase were higher than those before treatment (The warming-needle moxibustion with 4-cm moxa stick could effectively improve quality and motility of sperm and clinical symptoms in patients with asthenospermia of kidney deficiency and liver depression, which is superior to moxibustion with 3-cm, 2-cm moxa sticks and conventional acupuncture.

Hypersampones A-C (

MPDZ is involved in signal transduction mediated by the formation of protein complexes. However, the expression regulation, clinical significance, potential function and mechanism of this gene in lung cancer remain unclear. Methylation status of MPDZ was measured by methylation-specific PCR and bisulfite genomic sequencing. Kaplan-Meier and Cox regression analyses were performed to identify the prognostic value of MPDZ. The tumor suppressing effects of MPDZ were determined in vitro and in vivo. The target molecules and signaling pathway that mediated the function of MPDZ were also identified. MPDZ methylation was identified in 61.2% of primary lung cancer tissues and most lung cancer cell lines but not in normal lung tissues. MPDZ expression was significantly downregulated in lung cancer tissues and negatively associated with DNA hypermethylation, and attenuated MPDZ expression predicted a poor outcome. Furthermore, MPDZ overexpression prominently dampened cell growth, migration and invasion of tumor cells. Conversely, MPDZ knockdown promoted cell proliferation, migration and invasion in vitro and in vivo. Importantly, MPDZ promotes tumor suppressor ability depends on the Hippo pathway-mediated repression of YAP. MPDZ activates the phosphorylation of YAP (Ser127) and inhibits YAP expression through interaction with MST1/LATS/YAP complex. Moreover, MPDZ deficiency promotes tumor metastasis and reduces the survival of MPDZ knock-out mice. We first identified and validated that MPDZ methylation and expression could be a good diagnostic marker and independent prognostic factor for lung cancer. MPDZ functions as a tumor suppressor by inhibiting cell proliferation, migration and invasion through regulating the Hippo-YAP signaling pathway. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No. 81573179 and 81573114). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was approved by the Clinical Research Ethics Committee of the Third Military Medical University, and informed consent was obtained from all patients. All experimental animal procedures were approved by the Institutional Animal Care and Use Committee of Third Military Medical University, China.

Background Cholesterol plays vital roles in human physiology; abnormal levels have deleterious pathological consequences. In cancer, elevated or reduced expression of cholesterol biosynthesis is associated with good or poor prognosis, but the underlying mechanisms are largely unknown. The limonoid compounds A1542 and A1543 stimulate ERK/MAPK by direct binding, leading to leukemic cell death and suppression of leukemia in mouse models. In this study, we investigated the downstream consequences of these ERK/MAPK agonists in leukemic cells. Methods We employed RNAseq analysis combined with Q-RT-PCR, western blot and bioinformatics to identify and confirm genes whose expression was altered by A1542 and A1543 in leukemic cells. ShRNA lentiviruses were used to silence gene expression. Cell culture and an animal model (BALB/c) of erythroleukemia induced by Friend virus were utilized to validate effects of cholesterol on leukemia progression. Results RNAseq analysis of A1542-treated cells revealed the induction of all 18 genes implicated in cholesterol biosynthesis. Expression of these cholesterol genes was blocked by cedrelone, an ERK inhibitor. The cholesterol inhibitor lovastatin diminished ERK/MAPK activation by A1542, thereby reducing leukemic cell death induced by this ERK1/2 agonist. Growth inhibition by cholesterol was observed both at the intracellular level, and when orally administrated into a leukemic mouse model. Both HDL and LDL also suppressed leukemogenesis, implicating these lipids as important prognostic markers for leukemia progression. Mechanistically, knockdown experiments revealed that the activation of SREBP1/2 by A1542-A1543 was responsible for induction of only a sub-set of cholesterol biosynthesis genes. Induction of other regulatory factors by A1542-A1543 including EGR1, AP1 (FOS + JUN) LDLR, IER2 and others may cooperate with SREBP1/2 to induce cholesterol genes. Indeed, pharmacological inhibition of AP1 significantly inhibited cholesterol gene expression induced by A1542. In addition to leukemia, high expression of cholesterol biosynthesis genes was found to correlate with better prognosis in renal cancer. Conclusions This study demonstrates that ERK1/2 agonists suppress leukemia and possibly other types of cancer through transcriptional stimulation of cholesterol biosynthesis genes.

The purpose of this work is to develop and evaluate a novel cycle-contrastive unpaired translation network (cycleCUT) for synthetic computed tomography (sCT) generation from T1-weighted magnetic resonance images (MRI).The cycleCUT proposed in this work integrated the contrastive learning module from contrastive unpaired translation network (CUT) into the cycle-consistent generative adversarial network (cycleGAN) framework to effectively achieve unsupervised CT synthesis from MRI. The diagnostic MRI and radiotherapy planning CT images of 24 brain cancer patients were obtained and reshuffled to train the network. For comparison, the traditional cycleGAN and CUT were also implemented. The sCT images were then imported into a treatment planning system to verify their feasibility for radiotherapy planning. The mean absolute error (MAE), peak signal-to-noise ratio (PSNR), and structural similarity index (SSIM) between the sCT and the corresponding real CT images were calculated. Gamma analysis between sCT- and CT-based dose distributions was also conducted.Quantitative evaluation of an independent test set of six patients showed that the average MAE was 69.62 ± 5.68 Hounsfield Units (HU) for the proposed cycleCUT, significantly (p-value 0.05) lower than that for cycleGAN (77.02 ± 6.00 HU) and CUT (78.05 ± 8.29). The average PSNR was 28.73 ± 0.46 decibels (dB) for cycleCUT, significantly larger than that for cycleGAN (27.96 ± 0.49 dB) and CUT (27.95 ± 0.69 dB). The average SSIM for cycleCUT (0.918 ± 0.012) was also significantly higher than that for cycleGAN (0.906 ± 0.012) and CUT (0.903 ± 0.015). Regarding gamma analysis, cycleCUT achieved the highest passing rate (97.95 ± 1.24% at the 2%/2 mm criteria and 10% dose threshold) but was not significantly different from the others.The proposed cycleCUT could be effectively trained using unaligned image data, and could generate better sCT images than cycleGAN and CUT in terms of HU number accuracy and fine structural details.

BACKGROUND Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed data for children (aged 0-14 years) and adults (aged 15-99 years) diagnosed with a haematological malignancy during 2000-14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and morphology, in young patients (aged 0-24 years). METHODS We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3 that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0-14 years), adolescents (15-19 years), and young adults (20-24 years). We categorised leukaemia subtypes according to the International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs, using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age survival estimates were standardised to the marginal distribution of young people with leukaemia included in the analysis. FINDINGS 164 563 young people were included in this analysis: 121 328 (73·7%) children, 22 963 (14·0%) adolescents, and 20 272 (12·3%) young adults. In 2010-14, the most common subtypes were lymphoid leukaemia (28 205 [68·2%] patients) and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and young adults for all leukaemias combined during 2010-14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better age-standardised survival (from 43% in Ecuador to ≥80% in parts of Europe, North America, Oceania, and Asia) than those with acute myeloid leukaemia (from 32% in Peru to ≥70% in most high-income countries in Europe, North America, and Oceania). Throughout 2000-14, survival from all leukaemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries. INTERPRETATION This study offers the first worldwide picture of population-based survival from leukaemia in children, adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators of the quality of cancer management in this age group. FUNDING Children with Cancer UK, the Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, US National Cancer Institute, and the American Cancer Society.

Background. Head and neck squamous cell carcinoma (HNSCC) is a significant health problem and related to poor long-term outcomes, indicating more research to be done to deeply understand the underlying pathways. Objective. This current study aimed in the assessment of the viral- (especially human papilloma virus [HPV]) and carcinogen-driven head and neck squamous cell carcinoma (HNSCC) microenvironment based on single-cell sequencing analysis. Methods. Data were downloaded from GEO database (GSE139324), including 131224 cells from 18 HP- HNSCC patients and 8 HPV+ HNSCC patients. Following data normalization, all highly variable genes in single cells were identified, and batch correction was applied. Differentially expressed genes were identified using Wilcoxon rank sum test. A gene enrichment analysis was performed in each cell cluster using KEGG analysis. Single-cell pseudotime trajectories were constructed with MONOCLE (version 2.6.4). Cell-cell interactions were analyzed with CellChat R package. Additionally, cell-cell communication patterns in key signal pathways were compared in different tissue groups. A hidden Markov model (HMM) was used to predict gene expression states (on or off) throughout pseudotime. Five-year overall survival outcomes were compared in both HPV+ and HPV- subsets. Results. 20,978 high-quality individual cells passed quality control. RNA-seq data were used from 522 HNSCC primary tumor samples. 1,137 differentially expressed genes between HPV+ and HPV- HNSCC patients were investigated. 96 differentially expressed genes were associated with overall survival and highly enriched in B cell associated biological process. Cell composition differed between types of samples. MHC-I, MHC-II, and MIF signaling pathways were found to be most relevant. Within these pathways, some cells were either signal receiver or signal sender, depending on sample type, respectively. Six genes were obtained, AREG and TGFBI (upregulation), CD27, CXCR3, MS4A1, and CD19 (downregulation), whose expression and HPV types were highly associated with worse overall survival. AREG and TGFBI were pDC marker genes, CXCR3 and CD27 were significantly expressed in T cell-related cells, while MS4A1 and CD19 were mainly expressed in B naïve cells. Conclusions. This study revealed dynamic changes in cell percentage and heterogeneity of cell subtypes of HNSCC. AREG, TGFBI, CD27, CXCR3, MS4A1, and CD19 were associated with worse overall survival in HPV-related HNSCC. Especially B-cell related pathways were revealed as particularly relevant in HPV-related HNSCC. These findings are a basis for the development of biomarkers and therapeutic targets in respective patients.

To identify differentially expressed lncRNA, miRNA, and mRNA during the pathogenesis of gout, explore the ceRNA network regulatory mechanism of gout, and seek potential therapeutic targets.First, gout-related chips were retrieved by GEO database. Then, the analysis of differentially expressed lncRNAs and mRNAs was conducted by R language and other software. Besides, miRNA and its regulated mRNA were predicted based on public databases, the intersection of differentially expressed mRNA and predicated mRNA was taken, and the lncRNA-miRNA-mRNA regulatory relationships were obtained to construct the ceRNA regulatory network. Subsequently, hub genes were screened by the STRING database and Cytoscape software. Then the DAVID database was used to illustrate the gene functions and related pathways of hub genes and to mine key ceRNA networks.Three hundred and eighty-eight lncRNAs and 758 mRNAs were identified with significant differential expression in gout patient, which regulates hub genes in the ceRNA network, such as JUN, FOS, PTGS2, NR4A2, and TNFAIP3. In the ceRNA network, lncRNA competes with mRNA for miRNA, thus affecting the IL-17 signaling pathway, TNF signaling pathway, Oxytocin signaling pathway, and NF-κB signaling pathway through regulating the cell's response to chemical stress. The research indicates that five miRNAs (miR-429, miR-137, miR-139-5p, miR-217, miR-23b-3p) and five lncRNAs (SNHG1, FAM182A, SPAG5-AS1, HNF1A-AS1, UCA1) play an important role in the formation and development of gout.The interaction in the ceRNA network can affect the formation and development of gout by regulating the body's inflammatory response as well as proliferation, differentiation, and apoptosis of chondrocytes and osteoclasts. The identification of potential therapeutic targets and signaling pathways through ceRNA network can provide a reference for further research on the pathogenesis of gout.

Aim. To identify the critical genetic and epigenetic biomarkers by constructing the long noncoding RNA- (lncRNA-) related competing endogenous RNA (ceRNA) network involved in irreversible pulp neural inflammation (pulpitis). Materials and Methods. The public datasets regarding irreversible pulpitis were downloaded from the gene expression omnibus (GEO) database. The differential expression analysis was performed to identify the differentially expressed genes (DEGs) and DElncRNAs. Functional enrichment analysis was performed to explore the biological processes and signaling pathways enriched by DEGs. By performing a weighted gene coexpression network analysis (WGCNA), the significant gene modules in each dataset were identified. Most importantly, DElncRNA-DEmRNA regulatory network and DElncRNA-associated ceRNA network were constructed. A transcription factor- (TF-) DEmRNA network was built to identify the critical TFs involved in pulpitis. Result. Two datasets (GSE92681 and GSE77459) were selected for analysis. DEGs involved in pulpitis were significantly enriched in seven signaling pathways (i.e., NOD-like receptor (NLR), Toll-like receptor (TLR), NF-kappa B, tumor necrosis factor (TNF), cell adhesion molecules (CAMs), chemokine, and cytokine-cytokine receptor interaction pathways). The ceRNA regulatory relationships were established consisting of three genes (i.e., LCP1, EZH2, and NR4A1), five miRNAs (i.e., miR-340-5p, miR-4731-5p, miR-27a-3p, miR-34a-5p, and miR-766-5p), and three lncRNAs (i.e., XIST, MIR155HG, and LINC00630). Six transcription factors (i.e., GATA2, ETS1, FOXP3, STAT1, FOS, and JUN) were identified to play pivotal roles in pulpitis. Conclusion. This paper demonstrates the genetic and epigenetic mechanisms of irreversible pulpitis by revealing the ceRNA network. The biomarkers identified could provide research direction for the application of genetically modified stem cells in endodontic regeneration.

Background Decellularized adipose tissue (DAT) has attracted much attention due to its wide range of sources and adipose regeneration capacity. However, the lipogenic efficiency of DAT is still controversial due to its unclear mechanism. To this point, it is crucial to clarify the mechanism of DAT in promoting adipose regeneration Objective: This study aims to explore the mechanism of DAT promoting adipose regeneration and survival mechanism of DAT transplantation in vivo. Methods DAT preparation by repeated freeze-thaw, enzymatic digestion, and isopropanol degreasing. Histology, DAPI, immunohistochemistry, immunofluorescence and scanning electron microscopy confirmed the efficacy and reproducibility of these approaches. BM-MSCs, ADSCs and UCMSCs were cocultured with DAT for 14 days and then stained with oil red O. Adipogenic genes of three MSCs were detected by RT-PCR. DAT and adipose tissue were transplanted subcutaneously into the back of nude mice to observe medium and long-term morphological changes, vascularization, and lipid-forming efficiency. Mass spectrometry (MS)-based proteomic to analyze the adipogenic protein contents of DAT and adipose tissue. Results The DAT without any cellular components but with an abundance of collagen; neither DNA nor lipids were detected. Seeding experiments with MSCs indicated that the DAT provided an inductive microenvironment for adipogenesis, supporting the expression of the master regulators PPARγ. Within four months after transplantation, HE morphology of DAT was identical to adipose cells. Immunofluorescence markers CD31 and perilipin were increased in DAT, while the retention rate gradually decreased over time, eventually accounting for 33.7% of the original volume. MS-based proteomic analyses identified 1013 types of proteins in adipose tissue and 29 proteins in the DAT. Analyses of GO and KEGG databases suggested that DAT contained a variety of proteins involved in fat metabolism. Conclusions DAT can interact with different types of MSCs and ultimately achieve adipose regeneration. The presence of multiple adipogenic proteins in DAT make it play a vital role in adipose regeneration. DAT is expected to be an ideal bio-derived scaffold for adipose tissue engineering.

Background Gastric outlet obstruction (GOO) is a late complication of advanced gastric cancer, and it is controversial how to select the therapeutic strategies: gastrojejunostomy and palliative gastrectomy? Therefore, this study was to compare the surgical and survival outcomes of gastrojejunostomy and palliative gastrectomy. Methods In total, 199 gastric cancer patients with outlet obstruction treated by surgery between January 2000 and December 2015 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Patients were divided into gastrojejunostomy group and palliative gastrectomy group. Propensity score matching (PSM) was performed to balance the selection bias. Results After 1:1 PSM, a total of 104 patients were included for final analysis. The median overall survival (OS) times in the gastrojejunostomy group and palliative gastrectomy group were 8.50 and 11.87 months, respectively (P = 0.243). The postoperative complication rates in the gastrojejunostomy group and palliative gastrectomy group were 19.23% (10/52) and 17.31% (9/52), respectively (P = 0.800), and no treatment-related death was observed. Multivariate analysis showed that periton0eal seeding (P = 0.014) and chemotherapy (P Conclusions Our results indicated that although the surgical complications of palliative gastrectomy were manageable, it showed no survival benefit. Therefore, relieving obstruction symptom, improving patients’ quality of life and creating better conditions for chemotherapy appear to be the main therapeutic strategies for advanced gastric cancer with GOO.

Circular RNAs (circRNA) are a new member of endogenously produced noncoding RNAs that have been characterized as key regulators of gene expression in a variety of malignances. However, the role of circRNA in oral squamous cell carcinoma (OSCC) remains largely unknown. In this study, we identified unique circRNA that regulate OSCC progression and metastasis and pave roads for future research in early diagnosis, prevention, and treatment of OSCC. Transcriptomic analyses identified a circRNA derived from IGHG locus (circIGHG) as significantly upregulated in OSCC and positively associated with poor prognosis of OSCC. circIGHG directly bound miR-142-5p and consequently elevated IGF2BP3 activity. Knockdown of circIGHG led to impaired expression of IGF2BP3 and attenuated aggressiveness of OSCC cells. Epithelial–mesenchymal transition was the main mechanism through which circIGHG/IGF2BP3 promotes metastasis of OSCC. Overall, these results demonstrate that circIGHG plays a pivotal role in OSCC development and metastasis and has potential to serve as a biomarker and therapeutic target for early-stage diagnosis and treatment of OSCC. Significance: These findings broaden our insights regarding regulation of OSCC progression by circular RNA and serve as a reference for future clinical research in OSCC diagnosis and treatment.

Rectal cancer is a life‑threatening disease worldwide. Chemotherapy resistance is common in rectal adenocarcinoma patients and has unfavorable survival outcomes; however, its related molecular mechanisms remain unknown. To identify genes related to the initiation and progression of rectal adenocarcinoma, three datasets were obtained from the Gene Expression Omnibus database. In total, differentially expressed genes were analyzed from 294 tumor and 277 para-carcinoma samples from patients with rectal cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functions were investigated. Cytoscape software and MicroRNA Enrichment Turned Network were applied to construct a protein-protein interaction network of the dependent hub genes and related microRNAs. The Oncomine database was used to identify hub genes. Additionally, Gene Expression Profiling Interactive Analysis was applied to determine the RNA expression level. Tumor immune infiltration was assessed using the Tumor Immune Estimation Resource database. The expression profiles of hub genes between stages, and their prognostic value, were also evaluated. During this study, data from The Cancer Genome Atlas were utilized. In rectal adenocarcinoma, four hub genes including CXCL1, CXCL2, CXCL3, and GNG4 were highly expressed at the gene and RNA levels. The expression of CXCL1, CXCL2, and CXCL3 was regulated by has-miR-1-3p and had a strong positive correlation with macrophage and neutrophil. CXCL2 and CXCL3 were differentially expressed at different tumor stages. High expression levels of CXCL1 and CXCL3 predicted poor survival. In conclusion, the CXCL1 and CXCL3 genes may have potential for prognosis and molecular targeted therapy of rectal adenocarcinoma., Graphical abstract

INTRODUCTION The efficacy of vitamin D for migraine remains controversial. We conduct a systematic review and meta-analysis to explore the influence of vitamin D versus placebo on treatment in migraine patients. METHODS We search PubMed, EMbase, Web of Science, EBSCO, and Cochrane library databases through April 2020 for randomized controlled trials assessing the effect of vitamin D versus placebo on treatment efficacy in migraine patients. This meta-analysis is performed using the random-effect model. RESULTS Five randomized controlled trials are included in the meta-analysis. Overall, compared with control group in migraine patients, vitamin D treatment is associated with substantially reduced number of headache days (standard mean difference [SMD], -0.53; 95% confidence interval [CI], -0.83 to -0.23; P = 0.0006), frequency of headache attacks (SMD, -1.09; 95% CI, -1.86 to -0.32; P = 0.006), headache severity (SMD, -0.55; 95% CI, -0.91 to -0.19; P = 0.0003), and Migraine Disability Assessment score (SMD, -0.76; 95% CI, -1.11 to -0.40; P < 0.0001). CONCLUSIONS Vitamin D treatment is effective to alleviate migraine.

Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion: In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.

Adipose-derived stem cells (ADSCs) have been documented as possible candidates for skin rejuvenation. However, the effects of ADSC-derived exosomes on photoaged skin remain to be fully elucidated. This study was aimed at determining the antiaging effects of ADSC-derived exosomes on photoaged skin. Human ADSCs were isolated from the adipose tissue of healthy women and cultured in vitro. Then, exosomes were extracted from the cultured ADSCs, purified by ultracentrifugation, and verified by examination of cell morphology using transmission electron microscopy and the identification of specific biomarkers. Meanwhile, the optimal exosome concentration and treatment time were selected. The photoaged skin model was created by subjecting Sprague-Dawley rats to ultraviolet B radiation. Exosomes were injected into the photoaged skin in a single therapeutic dose. The thickness of the epidermis and dermis was observed by HE staining. The relative mRNA expression of type I collagen, type III collagen, and matrix metalloproteinases (MMP-1 and MMP-3) was determined by real-time PCR. In the rat model of photoaged skin, the injected exosomes markedly decreased the epidermal thickness and increased the dermal thickness of the photoaged skin 7 days after treatment. Moreover, the proportion of the stratum corneum of the epidermis was decreased. Furthermore, real-time RT-PCR showed that the mRNA expression of type I collagen was increased and that of type III collagen, MMP-1, and MMP-3 was decreased. Our results demonstrate that ADSC-derived exosome treatment could significantly improve skin photodamage and that ADSC-derived exosomes may be a potential agent for photoaged skin treatment.

Objectives. Recent trials have shown an overall survival (OS) benefit in 10-40% advanced cancer patients treated with programmed cell death 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors. Here, we aimed to evaluate the relationship between PD-L1 expression and the therapeutic efficacy of PD-1 or PD-L1 inhibitors in patients with cancer with recurrent or metastatic disease, compared with control treatments. Methods. We systematically searched Medline (PubMed), Embase, and Cochrane Library databases up to Jan 2019 and pooled the treatment effects (hazard ratio or relative ratio) of PD-1/PD-L1 inhibitors in patients with different PD-L1 expression. Results. Overall, twenty-four qualifying trials with over 14,860 subjects were eligible in this study. Compared with conventional agents, anti-PD/PD-L1 drugs significantly reduced the risk of death (hazard ratio 0.72, 95% CI 0.66 to 0.78), irrespective of the tumor type. Additionally, when PD-L1 expression ≥1% was defined as positive, anti-PD-1/PD-L1 monotherapy correlated with prolonged overall survival in patients with nonsmall cell lung cancer (NSCLC) (0.72, 0.61 to 0.86) and other cancer types (0.66, 0.57 to 0.76) patients with PD-L1 positive, rather than those with PD-L1 negative (hazard ratio for NSCLC and other cancer types: 0.84 and 0.87, respectively; all P > 0.05 ). The subgroup analyses to experimental agents, PD-1/PD-L1 inhibitors, PD-L1 antibody clone, and type of IHC scoring method validated the robustness of these findings. However, anti-PD-1/PD-L1 combination therapies can reduce the risk of death for patients with different cancer types, regardless of PD-L1 expression ( P < 0.05 for all PD-L1 expression status). Conclusions. We recommend PD-L1 expression as a predictive biomarker in patient selection for anti-PD-1/PD-L1 monotherapy, but not for combination therapies.

Heavy-metal pollution has increasingly jeopardized the habitats of marine organisms including the sea cucumber, a seafloor scavenger vital to seawater bio-decontamination, ocean de-acidification and coral-reef protection. Normal physiology including immune functions of sea cucumbers is toxicologically modulated by marine metal pollutants such as cadmium (Cd). The processes underpinning Cd's toxic effects on immune systems in the sea cucumber

Background Radiation-induced lung fibrosis (RILF) is a common complication of thoracic radiotherapy. Alveolar epithelial cells play a crucial role in lung fibrosis via epithelial-mesenchymal transition (EMT). Exosomes derived from mesenchymal stem cells own the beneficial properties to repair and regeneration of damaged tissues, however the underlying mechanisms remain poorly understood. Methods Mouse mesenchymal stem cells-derived exosomes (mMSCs-Exo) were isolated by differential centrifugation, and their protective effects were assessed in vivo and in vitro, respectively. EMT-associated proteins were measured via western blot assay and/or immunofluorescence staining. The miRNA expression was measured by microarray assay and qPCR. Furthermore, bioinformatics prediction with KEGG analysis, luciferase assay, and rescue experiments were performed to explore the molecular mechanism underlying miR-466f-3p. Results mMSCs-Exos were efficiently isolated ranging from 90-150 nm with high expression of exosomal markers (CD63, TSG101, and CD9). mMSCs-Exos administration efficiently relieved radiation-induced lung injury with less collagen deposition and lower levels of IL-1β and IL-6. Meanwhile, in vitro results showed mMSCs-Exos treatment obviously reversed EMT process induced by radiation. Among enriched miRNA cargo in exosomes, miR-466f-3p was primarily responsible for the protective effects via inhibition of AKT/GSK3β pathway. Our mechanistic study further demonstrated that c-MET was the direct target of miR-466f-3p, whose restoration partially abrogated mMSCs-Exo-mediated inhibition in both EMT process and AKT/GSK3β signaling activity induced by radiation. Conclusions Our findings indicated that exosomal miR-466f-3p derived from mMSCs may possess anti-fibrotic properties and prevent radiation-induced EMT through inhibition of AKT/GSK3β via c-MET, providing a promising therapeutic modality for radiation-induced lung fibrosis.

Background Liposuction has become one of the most popular cosmetic surgeries in China. However, few studies have discussed infectious shock caused by C. perfringens as one of the causes of death after liposuction. Case presentation A 24-year-old woman was brought to the emergency department (ED) of Guangzhou Chinese Overseas Hospital for treatment. The patient had undergone liposuction in her bilateral lower limbs two days prior. At the ED, the patient was unconscious, and had bilateral equal-sized (diameter, 6 mm) round pupils, no light reflex, a blood pressure (BP) of 71/33 mmHg, a heart rate of 133 bpm, and an SpO2 of 70%. She had bilateral limb swelling, extensive ecchymoses in her lower abdomen and bilateral thighs, local crepitus, blisters, weak pulses on her femoral artery and dorsalis pedis, high skin tension, and hemoglobin of 32 g/L. The patient was diagnosed with Clostridium perfringens infection, and she underwent debridement surgery and supportive treatment. But the patient’s BP could not improve. At 8:28 pm on the day of admission, the patient was declared clinically dead after the electrocardiograph showed a horizontal line and spontaneous respiration ceased. Conclusions Failure to meet surgical disinfection and environmental standards may be the cause of infection of C. perfringens through wounds. Therefore, it is necessary to strengthen the environmental disinfection of the operating room, and standardize the sterile conditions of the operation staff and patients before and during operation. Liposuction surgery necrotizing fasciitis is a rare but fatal complications, especially if diagnosis delay, therefore it is critical for early diagnosis and treatment of gas gangrene.

Background We aimed to assess whether disease-free survival (DFS) could serve as a reliable surrogate endpoint for overall survival (OS) in adjuvant trials of pancreatic cancer. Methods We systematically reviewed adjuvant randomized trials for non-metastatic pancreatic cancer after curative resection that reported a hazard ratio (HR) for DFS and OS. We assessed the correlation between treatment effect (HR) on DFS and OS, weighted by sample size or precision of hazard ratio estimate, assuming fixed and random effects, and calculated the surrogate threshold effect (STE). We also performed sensitivity analyses and a leave-one-out cross validation approach to evaluate the robustness of our findings. Results After screening 450 relevant articles, we identified a total of 20 qualifying trails comprising 5170 patients for quantitative analysis. We noted a strong correlation between the treatment effects for DFS and OS, with coefficient of determination of 0.82 in the random effect model, 0.82 in the fixed effect model, and 0.80 in the sample size weighting; the robustness of this finding was further verified by the leave-one-out cross-validation approach. Sensitivity analyses with restriction to phase 3 trials, large trials, trials with mature follow-up periods, and trials with adjuvant therapy versus adjuvant therapy strengthened the correlation (0.75 to 0.88) between DFS and OS. The STE was 0.96 for DFS. Conclusions Therefore, DFS could be regarded as a surrogate endpoint for OS in adjuvant trials of pancreatic cancer. In future similar adjuvant trials, a hazard ratio for DFS of 0.96 or less would predict a treatment impact on OS.

Objective To investigate the efficiency of anterior decompression on the proximal‐type cervical spondylotic amyotrophy patients. Methods This was a retrospective analysis. From January 2014 to November 2017, 21 patients with proximal‐type cervical spondylotic amyotrophy (CSA) underwent anterior decompression. There were 15 males and 6 females, aged 35–73 years with an average of 51.62 years. All the patients underwent surgery of anterior decompression (ACDF or ACCF). Among them, 12 patients underwent C4/5 single level ACDF, eight patients underwent C4/5 and C5/6 double level ACDF, and one patient underwent C5 anterior cervical corpectomy decompression and fusion surgery. Preoperative and postoperative clinical and radiologic parameters were assessed. The clinical examinations were reviewed, including muscle strength, neck disability index (NDI) score, cervical Japanese Orthopaedic Association (JOA) score, and improvement rate of manual muscle test (MMT) at the last follow‐up. Preoperative spinal cord or nerve impingement was assessed by magnetic resonance imaging (MRI) or computed tomography (CT) myelography. Postoperative lateral X‐ray radiographs were performed every 3 months after the surgery. Results Severe preoperative muscle atrophy of the deltoid or biceps muscles occurred in 21 patients included in the study. All of them involve impingements of the ventral nerve root and/or the anterior horn according to MRI and CT myelography. The preoperative duration of symptoms averaged 8.4 months. The average follow‐up for all patients was 13.2 months. At the final follow‐up, all patients showed statistically significant improvements in muscle strength and NDI scores (P

Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology., It is not yet clear how ubiquitously-expressed proteins can cause the selective degeneration of particular populations of neurons, such as in spinocerebellar ataxia type 17, SCA17, which results from a CAG trinucleotide repeat expansion in the ubiquitously expressed transcription factor TBP. Here, the authors show that mutant TBP suppresses the cerebellum-enriched transcription of Inpp5a and link altered levels of INPP5A to the selective degeneration of cerebellar neurons.

Background Glomerular IgG deposition in patients with IgA nephropathy (IgAN) has been shown to be associated with poor renal survival; however, most published studies to date are too small-scale and inconsistent to provide guidance for clinical practice. Methods Based on renal biopsy findings, 742 patients were divided into the following groups: (i) IgA deposition alone (IgA) vs IgA + IgG deposition (IgA + IgG) and (ii) IgG co-deposition confined to the mesangium vs mesangium + capillary loops (CLs). The clinicopathological variables at biopsy and renal outcome were assessed. Results Of the 742 patients, 182 had IgG co-deposition and 51 had IgG deposits in the mesangium + CLs. Patients with IgG co-deposition were associated with severe clinical and pathological lesions, especially those with a location of IgG deposits in the mesangium +CLs. Kaplan–Meier analysis revealed that a lower renal cumulative survival rate was present in both patients with IgG co-deposition and those with a location of IgG deposits in the mesangium + CLs (all p

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing, as is research on the molecular mechanisms underlying cellular infection by coronaviruses, with the hope of developing therapeutic agents against this pandemic. Other important respiratory viruses such as 2009 pandemic H1N1 and H7N9 avian influenza virus (AIV), influenza A viruses, are also responsible for a possible outbreak due to their respiratory susceptibility. However, the interaction of these viruses with host cells and the regulation of post-transcriptional genes remains unclear. In this study, we detected and analyzed the comparative transcriptome profiling of SARS-CoV-2, panH1N1 (A/California/07/2009), and H7N9 (A/Shanghai/1/2013) infected cells. The results showed that the commonly upregulated genes among the three groups were mainly involved in autophagy, pertussis, and tuberculosis, which indicated that autophagy plays an important role in viral pathogenicity. There are three groups of commonly downregulated genes involved in metabolic pathways. Notably, unlike panH1N1 and H7N9, SARS-CoV-2 infection can inhibit the m-TOR pathway and activate the p53 signaling pathway, which may be responsible for unique autophagy induction and cell apoptosis. Particularly, upregulated expression of IRF1 was found in SARS-CoV-2, panH1N1, and H7N9 infection. Further analysis showed SARS-CoV-2, panH1N1, and H7N9 infection-induced upregulation of lncRNA-34087.27 could serve as a competitive endogenous RNA to stabilize IRF1 mRNA by competitively binding with miR-302b-3p. This study provides new insights into the molecular mechanisms of influenza A virus and SARS-CoV-2 infection.

Apoptosis, also known as programmed cell death, is a biological process that is critical for embryonic development, organic differentiation, and tissue homeostasis of organisms. As an essential mitochondrial flavoprotein, the apoptosis-inducing factor (AIF) can directly mediate the caspase-independent mitochondrial apoptotic pathway. In this study, we identified and characterized a novel AIF-2 (

Functional brain graph (FBG), by describing the interactions between different brain regions, provides an effective representation of fMRI data for identifying mild cognitive impairment (MCI), an early stage of Alzheimer's Disease (AD). Prior to the identification task, selecting features from the estimated FBG is a necessary step for reducing computational cost, alleviating the risk of overfitting, and finding potential biomarkers of brain diseases. In practice, either node-based features (e.g., local clustering coefficients) or edge-based features (e.g., adjacency weights) are generally considered in current studies. Despite their popularity, these schemes can only capture one granularity (node or edge) of information in the FBG, which might be insufficient for the classification task and the interpretation of the classification result.To address this issue, in this paper, we propose to jointly select nodes and edges from the estimated FBGs. Specifically, we first assign the edges to different node groups. Then, sparse group least absolute shrinkage and selection operator (sgLASSO) is used to select groups (nodes) and edges in the groups towards a better classification performance. Such a technique enables us to simultaneously locate discriminative brain regions, as well as connections between these brain regions, making the classification results more interpretable.Experimental results show that the proposed method achieves better classification performance than state-of-the-art methods. Moreover, by exploring brain network "features" that contributed most to MCI identification, we discover potential biomarkers for MCI diagnosis.A novel method for jointly selecting nodes and edges from the estimated functional brain graphs (FBGs) is proposed.

Excessive neutrophil extracellular trap (NET) formation may contribute to polymyositis (PM)‐associated interstitial lung diseases (ILD), but the underlying mechanism is not fully revealed. In this study, we found that NET accelerated the progression of ILD and promoted pulmonary fibrosis (PF) in vivo. miR‐7 expression was down‐regulated in lung tissue of PM group than control group, and NETs further decreased miR‐7 expression. TLR9 and Smad2 were up‐regulated in lung tissue of PM group than control group, and NETs further increased TLR9 and Smad2 expressions. In vitro experiments showed that PMA‐treated NETs accelerated the proliferation of LF and their differentiation into myofibroblast (MF), whereas DNase I decreased the promotion effect of NETs. Neutrophil extracellular trap components myeloperoxidase (MPO) and histone 3 also promoted the proliferation and differentiation of LF. In addition, we demonstrated that TLR9 involved in the regulation of NETs on LF proliferation and differentiation, and confirmed the interaction between miR‐7 and Smad2 in LF. Finally, miR‐7‐Smad2 pathway was confirmed to be involved in the regulation of TLR9 on LF proliferation and differentiation. Therefore, NETs promote PM‐related ILD, and TLR9‐miR‐7‐Smad2 signalling pathway is involved in the proliferation of LFs and their differentiation into MFs.

Three new aglain derivatives (1-3), one known aglain derivative (4), two known rocaglamide derivatives (5 and 6), four known triterpenoids (7-10), and three steroids (11-13) were isolated from Aglaia odorata Lour. Their structures were established through the analysis of detailed spectroscopic data and electronic circular dichroism calculations. Five compounds (1 and 4-7) exhibited cytotoxic activities on human leukemia cells (HEL) and human breast cancer cells with IC

To explore the application value of staged urethroplasty by tubularization of the reconstructed urethral plate using the preputial island flap in the treatment of severe hypospadias.From May 2014 to February 2019, 91 children with severe hypospadias received one- or two-stage urethroplasty by tubularization of the reconstructed urethral plate with the preputial island flap. We compared the patients' age, glans diameter, length of the straightened urethral defect, and incidence rates of postoperative urethral fistula, urethral diverticulum, glans dehiscence and urethral stricture between the two groups of patients.The 56 patients in the one-stage group were aged 7－144 (21.92 ± 13.37) months old, the urethral defect 3－5 (3.565 ± 0.528) cm in length and the glans 1.0－1.4 (1.195 ± 0.083) cm in diameter, and the 35 in the two-stage group aged 7 －153 (24.78 ± 13.59) months, the urethral defect 3－5 (3.857 ± 0.696) cm in length and the glans 0.8－2.5 (1.206 ± 0.389) cm in diameter. There were no statistically significant differences in age, glans diameter and the length of urethral defect between the two groups. In the one-stage group were found 18 cases of postoperative urinary fistula, 1 case of glans dehiscence, 1 case of urethral diverticulum, and 1 case of both urethral diverticulum and glans dehiscence, all cured by repeated urinary fistula repair/urethroplasty. No urinary fistula occurred in the two-stage group postoperatively except 4 cases of glans dehiscence, of which 2 were cured by repeated repair and the other 2 refused reoperation. The success rate was significantly higher in the two-stage than in the one-stage urethroplasty group (88.57% vs 62.50%, P0.05).Two-stage urethroplasty by tubularization of the reconstructed urethral plate with the preputial island flap can significantly reduce the incidence of urethral fistula in patients with severe hypospadias, but may increase the number of operations in those who do not need staged surgery. The necessity of two-stage urethroplasty can be determined according to the development of the glans, the degree of penile curvature, and the length of urethra defect.

Huntington's disease (HD) is an autosomal dominantly-inherited neurodegenerative disease, which is caused by CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. Although HD is a rare disease, its monogenic nature makes it an ideal model in which to understand pathogenic mechanisms and to develop therapeutic strategies for neurodegenerative diseases. Clustered regularly-interspaced short palindromic repeats (CRISPR) is the latest technology for genome editing. Being simple to use and highly efficient, CRISPR-based genome-editing tools are rapidly gaining popularity in biomedical research and opening up new avenues for disease treatment. Here, we review the development of CRISPR-based genome-editing tools and their applications in HD research to offer a translational perspective on advancing the genome-editing technology to HD treatment.

Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

Fourteen sesquiterpene lactones were isolated from the whole plant of

Twenty-one new schisanhenol derivatives were synthesized, and their hepatoprotective effects against liver injury induced by concanavalin A (Con A) were evaluated in vitro using an MTT assay. The data indicated that most derivatives exhibited equivalent or better protective activity than the positive control (dimethyl dicarboxylate biphenyl, DDB) under the same conditions. Among them, compound 1b showed the most potent hepatoprotective activity against Con A-induced immunological injury. Mechanistic studies in vitro revealed that 1b inhibited cell apoptosis and inflammatory responses caused by Con A treatment via IL-6/JAK2/STAT3 signaling pathway. Consistently, it also exhibited significant hepatoprotective activity in mice with Con A-induced immunological liver injury. These results clearly indicated that 1b might be a highly potent hepatoprotective agent targeting IL-6/STAT3 signaling pathway.

Clonorosins A (

Objectives To investigate the diagnostic value of accessible fingertip mean corpuscular volume (MCV) combined with a visible “beefy red” patch in the diagnosis of vitamin B12 (VB12) deficiency in local clinics and hospitals without in-house clinical laboratories, especially in remote areas. Materials and methods The medical history data of patients complaining of oral mucosal pain at the Stomatological Hospital of Southern Medical University were reviewed. All included patients underwent fingertip blood routine examination, specific serological test (serum VB12, folic acid, iron, and ferritin), and detailed oral clinical examinations. According to the results of the serum VB12 test patients were divided into case and control groups. In diagnostic test, the diagnostic value of the “beefy red” patch and elevated MCV in VB12 deficiency was evaluated by the receiver operator characteristic curve. Results There were more female patients than male patients in the case group (serum VB12 level 100fL” and “folic acid P 100 fL” has high specificity (0.933) but low specificity (0.815), and “MCV > 100 fL combined with beefy red patch” has maximal specificity (0.950), and area under the curve (0.949). Conclusions Visible oral “beefy red” patch combined with accessible fingertip blood MCV could improve the rate of diagnosis in VB12 deficiency, especially in the elderly in local clinics and hospitals without in-house clinical laboratories in China, which is conducive to early disease detection and treatment.

Brain functional network (BFN), usually estimated from blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), has been proven to be a powerful tool to study the organization of the brain and discover biomarkers for diagnosis of brain disorders. Prior to BFN estimation and classification, extracting representative BOLD signals from brain regions of interest (ROIs) is a critical step. Traditional extraction methods include averaging, peaking operation and dimensionality reduction, often leading to signal cancellation and information loss. In this paper, we propose a novel method, namely time-constrained multiset canonical correlation analysis (TMCCA), to extract representative BOLD signals for subsequent BFN estimation and classification. Different from traditional methods that equally treat all BOLD signals in a ROI, the proposed method assigns weights to different BOLD signals, and learns the optimal weights to make the extracted representative signals jointly maximize the multiple correlations between ROIs. Importantly, time-constraint is incorporated into our proposed method, which can effectively encode nonlinear relationship among BOLD signals. To evaluate the effectiveness of the proposed method, the extracted BOLD signals is used to estimate BFN and, in turn, identify brain disorders, including mild cognitive impairment (MCI) and autistic spectrum disorder (ASD). Experimental results demonstrate that our proposed TMCCA can lead to better performance than traditional methods.

Previous studies have separately linked either perfluoroalkyl acid (PFAA) or heavy metal exposure with kidney dysfunction. However, the relationships of co-exposure to PFAAs and heavy metals with kidney function are still unclear.To explore the associations between exposure to PFAAs and heavy metals mixtures and kidney function in adults.We conducted a cross-sectional community-based population study in Guangzhou, China, enrolling 1312 adults from November 2018 to August 2019. We quantified 13 PFAAs in serum and 14 heavy metals in plasma. We chose estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) as outcomes of interest. Distributed lag non-linear models (DLNMs) were used to check nonlinearity of individual pollutant with kidney function. Joint associations of pollutant mixtures on kidney function were assessed by Bayesian Kernel Machine Regression (BKMR) models. We further explored modification effects of gender.Most individual PFAA and heavy metal were associated with declined kidney function in single-pollutant models. We also observed significant dose-response relationships of pollutant mixtures with reduced eGFR levels and increased odds of CKD in BKMR models. Perfluoroheptanesulfonic acid (PFHpS), arsenic (As) and strontium (Sr) were the predominant contributors among pollutant mixtures. A change in log PFHpS, As and Sr concentrations from the 25th to the 75th percentile were associated with a decrease in eGFR of -5.42 (95% confidence interval (CI): -6.86, -3.98), -2.14 (95% CI: -3.70, -0.58) and -1.87 (95% CI: -3.03, -0.72) mL/min/1.73 mWe provided new evidence that co-exposure to PFAAs and heavy metals mixtures was associated with reduced kidney function in adults and PFHpS, As and Sr appeared to be the major contributors. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms.

Laparoscopic inguinal hernia repair has developed rapidly as an important surgical method for inguinal hernia repair; however, postoperative complications, especially postoperative seroma, are becoming an important factor hindering its development. Many studies have shown that placing a negative-pressure drainage tube in the preperitoneal space can effectively reduce postoperative seromas. Accordingly, this study aimed to compare differences in postoperative seroma between surgical procedures with drainage tubes (DRG) and those without drainage tubes (nonDRG).PubMed/Medline, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from the establishment of the database to May 1, 2021. Odds ratio (OR), mean difference (MD), standardized mean difference (SMD), and 95% confidence interval (CI) were selected as the effect scale indices for the evaluation of the difference in seroma, operation time, hospital stay time, blood loss, and recovery time. All of these were compared using RevMan 5.3 Software.Sixteen studies involving 4369 patients, 2856 in the DRG group and 1513 in the nonDRG group, were included. The incidence of seroma in the DRG group was lower than that in the nonDRG group (OR = 0.16, 95% CI: 0.07-0.35, P.001). Additionally, the operation time (min) in the DRG group was longer than that in the nonDRG group (MD = 3.67, 95% CI: 2.18-5.17, P.001). Nevertheless, no significant differences were found in hospital stay (days) (SMD = 0.22, 95% CI: -0.10-0.54, P = .17), blood loss (mL) (MD = 0.28, 95% CI: -0.14-0.69, P = .19), and recovery time (h) (SMD = 0.54, 95% CI: -0.60-1.69, P = .35) between the 2 groups.Despite the slightly prolonged operation time, negative pressure drainage in the preperitoneal space during laparoscopic inguinal hernia repair can significantly reduce the occurrence of postoperative seroma without increasing blood loss, recovery, and hospital stay.