Approximate estimation of cell-type resolution transcriptome in bulk tissue through matrix completion.

Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for uncovering cellular heterogeneity. However, the high costs associated with this technique have rendered it impractical for studying large patient cohorts. We introduce ENIGMA (Deconvolution based on Regularized Matrix Completion), a method that addresses this limitation through accurately deconvoluting bulk tissue RNA-seq data into a readout with cell-type resolution by leveraging information from scRNA-seq data. By employing a matrix completion strategy, ENIGMA minimizes the distance between the mixture transcriptome obtained with bulk sequencing and a weighted combination of cell-type-specific expression. This allows the quantification of cell-type proportions and reconstruction of cell-type-specific transcriptomes. To validate its performance, ENIGMA was tested on both simulated and real datasets, including disease-related tissues, demonstrating its ability in uncovering novel biological insights.

Tripartite motif-containing protein 11 promotes hepatocellular carcinogenesis through ubiquitin-proteasome-mediated degradation of pleckstrin homology domain leucine-rich repeats protein phosphatase 1.

BACKGROUND AND AIMS: HCC is one of the main types of primary liver cancer, with high morbidity and mortality and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC remain open for study. APPROACH AND RESULTS: Through clinical analysis, we found that the expression of TRIM11 was up-regulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade, and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with pleckstrin homology domain leucine-rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1 and thus promoted activation of the protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. CONCLUSIONS: Our study confirmed that TRIM11 plays an oncogenic role in HCC through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of HCC.

Distributions and trends of the global burden of COPD attributable to risk factors by SDI, age, and sex from 1990 to 2019: a systematic analysis of GBD 2019 data.

BACKGROUND: Global distributions and trends of the risk-attributable burdens of chronic obstructive pulmonary disease (COPD) have rarely been systematically explored. To guide the formulation of targeted and accurate strategies for the management of COPD, we analyzed COPD burdens attributable to known risk factors. METHODS: Using detailed COPD data from the Global Burden of Disease study 2019, we analyzed disability-adjusted life years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), and deaths attributable to each risk factor from 1990 to 2019. Additionally, we calculated estimated annual percentage changes (EAPCs) during the study period. The population attributable fraction (PAF) and summary exposure value (SEV) of each risk factor are also presented. RESULTS: From 1990 to 2019, the age-standardized DALY and death rates of COPD attributable to smoking and household air pollution, occupational particles, secondhand smoke, and low temperature presented consistently declining trends in almost all socio-demographic index (SDI) regions. However, the decline in YLD was not as dramatic as that of the death rate. In contrast, the COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure showed undesirable increasing trends in the low- and low-middle-SDI regions. In addition, the age-standardized DALY and death rates attributable to each risk factor except household air pollution and low temperature were the highest in the low-middle-SDI region. In 2019, the COPD burden attributable to smoking ambient particulate matter, ozone, occupational particles, low and high temperature was obviously greater in males than in females. Meanwhile, the most important risk factors for female varied across regions (low- and low-middle-SDI regions: household air pollution; middle-SDI region: ambient particles; high-middle- and high-SDI region: smoking). CONCLUSIONS: Increasing trends of COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure in the low-middle- and low-SDI regions call for an urgent need to implement specific and effective measures. Moreover, considering the gender differences in COPD burdens attributable to some risk factors such as ambient particulate matter and ozone with similar SEV, further research on biological differences between sexes in COPD and relevant policy-making of disease prevention are required.

Surgery to the primary tumor is associated with improved survival of patients with metastatic esophageal cancer: propensity score-matched analyses of a large retrospective cohort.

The survival advantage of surgery to the primary tumor for patients with distant metastatic esophageal cancer has not been adequately evaluated. This study aims to investigate the role of surgery to the primary tumor in distant metastatic esophageal cancer and to evaluate possible different effects of surgery on survival of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). This study included a cohort of 4,367 metastatic esophageal cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database, registered from January 2004 to December 2014. Kaplan-Meier and Cox proportional hazardous models were used to evaluate the overall survival (OS) and corresponding 95% confidence interval (CI). Propensity score matching (PSM) was used to adjust for potential baseline confounding. Both EAC (median OS for surgery group vs. no-surgery group-14.0 vs. 9.0 months, P < 0.001) and ESCC (median OS for surgery vs. no-surgery group-11.0 vs. 7.0 months, P = 0.002) experienced survival benefits from surgery. We found that surgery to the primary tumor, when combined with chemotherapy, was associated with improved survival for patients with M1b disease, both EAC and ESCC, with a greater benefit observed in younger patients, and those with EAC. While the present data indicate a potential survival benefit from surgery for some patients with metastatic esophageal cancer, it is possible that performance status and metastatic disease burden impacted patient selection, influencing these results. Further studies are needed to determine the role of surgery for patients with metastatic esophageal cancer.

Carnosol Inhibits the Proliferation, Migration, and Invasion of Hepatocellular Carcinoma Cells in vitro by Regulating the AMPK Signaling Pathway.

Background: Hepatocellular carcinoma (HCC) is one of the most malignant cancers in the world, and its 5- year survival rate is low. At present, for advanced primary liver cancer, the clinical treatment often adopts the systemic method, but there is no effective targeted treatment. The average survival time of patients with liver cancer after drug treatment is only 3-5 months. Therefore, it is of great clinical significance to find new and effective drugs for the treatment of HCC. Carnosol (CA) is a bioactive diterpene compound present in Lamiaceae spp., which has been demonstrated to have antioxidant, anti-inflammatory, and anticancer properties. Aim: In this study, we aimed to reveal the effect of carnosol on HCC and provide new possibilities for the drug therapy of HCC. Obejective: The objective of this study is to observe the effect of carnosol on the tumor phenotype and signaling pathway of HCC cells. Methods: We treated two different human HCC cells, HepG2 and Huh7, with carnosol. The cells were analyzed using the CCK-8 assay for viability and proliferation. The cell migration and invasion were detected by Transwell assay. The molecular markers of cell proliferation, apoptosis, migration, invasion, and signaling pathways were detected by RTPCR and WB. In addition, we performed rescue experiments with inhibitors to verify the affected signaling pathway. Results: The results showed that carnosol could significantly inhibit HCC cell viability, effort, colony formation, migration, and invasion. Moreover, Carnosol promoted the apoptosis of HCC cells. Mechanically, carnosol activated the AMPK-p53 pathway. Conclusion: To conclude, our study demonstrated that carnosol could inhibit proliferation, migration, invasion, and promote apoptosis via activating AMPK-p53 in HCC cells.

Immune features of COVID-19 convalescent individuals revealed by a single-cell RNA sequencing.

It remains unclear whether immune responses following natural infection can be sustained or potentially prove critical for long-term immune protection against SARS-CoV-2 reinfection. Here, we systematically mapped the phenotypic landscape of SARS-CoV-2-specific immune responses in peripheral blood samples of convalescent patients with COVID-19 by single-cell RNA sequencing. The relative percentage of the CD8 + effector memory subset was increased in both convalescent moderate and severe cases, but NKT-CD160 and marginal zone B clusters were decreased. Innate immune responses were attenuated reflected by decreased expression of genes involved in interferon-gamma, leukocyte migration and neutrophil mediated immune response in convalescent COVID-19 patients. Functions of T cell were strengthened in convalescent COVID-19 patients by clear endorsement of increased expression of genes involved in biological processes of regulation of T cell activation, differentiation and cell-cell adhesion. In addition, T cell mediated immune responses were enhanced with remarkable clonal expansions of TCR and increased transition of CD4 + effector memory and CD8 + effector-GNLY in severe subjects. B cell immune responses displayed complicated and dualfunctions during convalescence of COVID-19, providing a novel mechanism that B cell activation was observed especially in moderate while humoral immune response was weakened. Interestingly, HLA class I genes displayed downregulation while HLA class II genes upregulation in both T and B cell subsets in convalescent individuals. Our results showed that innate immunity was declined but SARS-CoV-2-specific T cell responses were retained even strengthened whereas complicated and dualfunctions of B cells, including declined humoral immunity were presented at several months following infections.

Pan-cancer analyses reveal multi-omics and clinical characteristics of RIO kinase 2 in cancer.

RIO kinase 2 has emerged as a critical kinase for ribosome maturation, and recently it has also been found to play a fundamental role in cancer, being involved in the occurrence and progression of glioblastoma, liver cancer, prostate cancer, non-small cell lung cancer, and acute myeloid leukemia. However, our knowledge in this regard is fragmented and limited and it is difficult to determine the exact role of RIO kinase 2 in tumors. Here, we conducted an integrated pan-cancer analysis comprising 33 cancer-types to determine the function of RIO kinase 2 in malignancies. The results show that RIO kinase 2 is highly expressed in all types of cancer and is significantly associated with tumor survival, metastasis, and immune cell infiltration. Moreover, RIO kinase 2 alteration via DNA methylation, and protein phosphorylation are involved in tumorigenesis. In summary, RIO kinase two serves as a promising target for the identification of cancer and increases our understanding of tumorigenesis and cancer progression and enhancing the ultimate goal of improved treatment for these diseases.

Notoginsenoside R1 induces oxidative stress and modulates LPS induced immune microenvironment of nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor with high incidence. Notoginsenoside R1 (NGR1) is the main active compound of total Panax notoginseng saponin, and has multiple anti-tumor effects. This study aimed to investigate the effect and mechanism of NGR1 in NPC. MATERIALS: NPC cells were treated with different doses of NGR1. The NGR1 function in NPC was evaluated using Cell Counting Kit-8, Transwell, Western blot, flow cytometry, immunofluorescence assay, and quantitative real-time PCR. Meanwhile, the NGR1 mechanism in NPC was assessed by rescue experiments. Furthermore, the NGR1 function in vivo was determined by constructing an NPC xenotransplantation model, TUNEL, and immunohistochemistry assays. RESULTS: NGR1 repressed NPC cell growth and invasion but facilitated NPC cell apoptosis and oxidative stress. Also, NGR1 alleviated inflammation in NPC cells. Mechanistically, NGR1 restrained NPC cell growth and induced oxidative stress in NPC cells, while these effects were abolished after lipopolysaccharide (an activator of the TRAF6/NF-κB pathway) treatment, implying that NGR1 reduced NPC cell growth and induced oxidative stress in NPC cells by the inactivation of TRAF6/NF-κB axis. Moreover, in vivo studies further proved the palliative effect of NGR1 on NPC. CONCLUSION: NGR1 inhibited NPC cell growth and induced oxidative stress in NPC cells by inactivating TRAF6/NF-κB axis.

Moxibustion therapy for treating psoriasis vulgaris: A protocol for systematic review and meta-analysis.

BACKGROUND: Psoriasis vulgaris (PV) is an immune-mediated skin disease, which has seriously affected the quality of life of patients. At present, moxibustion therapy has been widely used in the treatment of PV. The purpose of this study is to provide high-quality evidence-based medicine to evaluate the effectiveness and safety of moxibustion for PV. METHODS: We will search the following Electronic databases from their inceptions to February 2021 without any language limitation: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, WangFang Database, Chinese Science Journal Database, Chinese Biomedical Literature Database. What's more, the grey literature and the references of all included literature will also be retrieved manually. Any clinical randomized controlled trials (RCTs) related to moxibustion therapy for PV will be taken into. In order to complete data synthesis and assess the risk of bias, we will use the RevMan V.5.3 software. RESULTS: This systematic review will provide an assessment of the current state of moxibustion for PV, aiming to assess the efficacy and safety of moxibustion for patients with PV. CONCLUSION: This systematic review will establish convincing evidence to prove the effectiveness and safety of moxibustion for PV. INPLASY REGISTRATION NUMBER: INPLASY202120008.

Fire needle therapy for blood stasis syndrome of plaque psoriasis: A protocol for systematic review and meta-analysis.

BACKGROUND: Plaque psoriasis (PSO) is a common clinical chronic inflammatory skin disease. The incidence rate is increasing year by year due to the fast pace of work and unhealthy diet. Fire needle has been widely used in the treatment of PSO. However, the efficacy of fire needle for PSO is uncertain. Thus, the purpose of this systematic review is to evaluate the effectiveness and safety of fire needle for PSO (blood stasis syndrome). METHODS: The following electronic databases will be searched from inception to October 2020:PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, WangFang Database, Chinese Science Journal Database, Chinese Biomedical Literature Database. In addition, other documents that meet the requirements will be manually searched, including conference papers, dissertations, etc. All randomized controlled trials using fire needle to treat PSO (blood stasis syndrome) that meet the criteria for inclusion will be included. The primary outcomes are clinical efficacy, Psoriasis area and severity index. Secondary outcomes include Itchy, TCM evaluation standard syndrome score, Dermatological quality of life index, and adverse events. To complete data synthesis and assess the risk of bias, we will use the RevMan V.5.3 software. RESULTS: The review results will be published in a peer-reviewed journal. CONCLUSION: This study will provide high-quality evidence based medicine to evaluate the effectiveness and safety of fire needle for PSO (blood stasis syndrome), and further seek its scientific and effective chinese medicine treatment methods. INPLASY REGISTRATION NUMBER: INPLASY202120007.

MYST1/KAT8 contributes to tumor progression by activating EGFR signaling in glioblastoma cells.

With short survival time, glioblastoma (GBM) is the most malignant tumor in the central nervous system. Recently, epigenetic enzymes play essential roles in the regulation of tumorigenesis and cancer development of GBM. However, little is known about MYST1/KAT8/MOF, a histone acetylation enzyme, in GBM. The present study shows that MYST1 promotes GBM progression through activating epidermal growth factor receptor (EGFR) signaling. MYST1 expression was increased in GBM and was negatively correlated with prognosis in patients with glioma and GBM. Knockdown of MYST1 reduced cell proliferation and BrdU incorporation in LN229, U87, and A172 GBM cells. Besides, MYST1 downregulation also induced cell cycle arrest at G2M phase, as well as the reduced expression of CDK1, Cyclin A, Cyclin B1, and increased expression of p21CIP1/Waf1 . Meanwhile, Self-renewal capability in vitro and tumorigenecity in vivo were also impaired after MYST1 knockdown. Importantly, MYST1 expression was lowly expressed in mesenchymal subtype of GBM and was positively correlated with EGFR expression in a cohort from The Cancer Genome Atlas. Western blot subsequently confirmed that phosphorylation and activation of p-Try1068 of EGFR, p-Ser473 of AKT and p-Thr202/Tyr204 of Erk1/2 were also decreased by MYST1 knockdown. Consistent with the results above, overexpression of MYST1 promoted GBM growth and activated EGFR signaling in vitro and in vivo. In addition, erlotinib, a US Food and Drug Administration approved cancer drug which targets EGFR, was able to rescue MYST1-promoted cell proliferation and EGFR signaling pathway. Furthermore, the transcription of EGF, an EFGR ligand, was shown to be positively regulated by MYST1 possibly via H4K16 acetylation. Our findings elucidate MYST1 as a tumor promoter in GBM and an EGFR activator, and may be a potential drug target for GBM treatment.

Palliative Gastrectomy and Survival in Patients With Metastatic Gastric Cancer: A Propensity Score-Matched Analysis of a Large Population-Based Study.

OBJECTIVES: The role of palliative gastrectomy in the management of metastatic gastric cancer remains inadequately clarified. METHODS: We analyzed patients with metastatic gastric cancer enrolled in the Surveillance, Epidemiology, and End Results registry from January 2004 to December 2012. Propensity score (PS) analysis with 1:1 matching and the nearest neighbor matching method was performed to ensure well-balanced characteristics of the groups of patients who undergone gastrectomy and those without gastrectomy. Data were analyzed by Kaplan-Meier and Cox proportional hazards regression models to evaluate the overall survival and cancer-specific survival rates with corresponding 95% confidence intervals (CIs). RESULTS: In general, receiving any kind of gastrectomy was associated with an improvement in survival in the multivariate analyses (hazard ratio [HR]os = 0.64, 95% CI = 0.59-0.70, HRcss = 0.63, 95% CI = 0.57-0.68) and PS matching (PSM) analyses (HRos = 0.63, 95% CI = 0.56-0.70, HRcss = 0.62, 95% CI = 0.55-0.70). After PSM, palliative gastrectomy was found to be associated with remarkably improved survival for patients with stage M1 with only 1 metastasis but not associated with survival of patients with stage M1 with extensive metastasis (≥2 metastatic sites). DISCUSSION: The results obtained from the Surveillance, Epidemiology, and End Results database suggest that patients with metastatic gastric cancer might benefit from palliative gastrectomy on the basis of chemotherapy. However, a PSM cohort study of this kind still has a strong selection bias and cannot replace a properly conducted randomized controlled trial.

Globally Asymptotic Stability Analysis for Genetic Regulatory Networks with Mixed Delays: An M-Matrix-Based Approach.

This paper deals with the problem of globally asymptotic stability for nonnegative equilibrium points of genetic regulatory networks (GRNs) with mixed delays (i.e., time-varying discrete delays and constant distributed delays). Up to now, all existing stability criteria for equilibrium points of the kind of considered GRNs are in the form of the linear matrix inequalities (LMIs). In this paper, the Brouwer's fixed point theorem is employed to obtain sufficient conditions such that the kind of GRNs under consideration here has at least one nonnegative equilibrium point. Then, by using the nonsingular M-matrix theory and the functional differential equation theory, M-matrix-based sufficient conditions are proposed to guarantee that the kind of GRNs under consideration here has a unique nonnegative equilibrium point which is globally asymptotically stable. The M-matrix-based sufficient conditions derived here are to check whether a constant matrix is a nonsingular M-matrix, which can be easily verified, as there are many equivalent statements on the nonsingular M-matrices. So, in terms of computational complexity, the M-matrix-based stability criteria established in this paper are superior to the LMI-based ones in literature. To illustrate the effectiveness of the approach proposed in this paper, several numerical examples and their simulations are given.

The Hippo transducer TAZ promotes cell proliferation and tumor formation of glioblastoma cells through EGFR pathway.

TAZ, a WW-domain-containing transcriptional co-activator, is important for development of various tissues in mammals. Recently, TAZ has been found to be overexpressed in some types of human cancers. However, the role of TAZ in glioblastoma remains unclear. In this study, we found that TAZ was overexpressed in prognostically poor glioblastoma patients. Through knocking down or overexpressing TAZ in U87 and LN229 cells, the expression level of TAZ was found to be positively related to cell proliferation in vitro and tumor formation in vivo. Further investigation indicated that TAZ could significantly promote the acceleration of cell cycle. Moreover, the western blot for p-EGFR, p-AKT, p-ERK1/2, p21, cyclin E and CDK2 proteins, target genes of the EGFR pathway, indicated that TAZ significantly activated EGFR/AKT/ERK signaling. Additionally, the blockage of EGFR pathway resulted in a significantly inhibition of cell proliferation induced by TAZ. Taken together, these results demonstrate that TAZ can promote proliferation and tumor formation in glioblastoma cells by potentiating the EGFR/AKT/ERK pathway, and provide the evidence for promising target for the treatment of glioblastoma.

Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-ß.

Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial event in the pathogenesis of neuroblastoma is to promote proliferation of neuroblasts, which is closely related to poor survival. However, mechanisms for regulation of cell proliferation and tumorigenicity in neuroblastoma are not well understood. Here, we report that overexpression of TAZ in neuroblastoma BE(2)-C cells causes increases in cell proliferation, self renewal and colony formation, which was restored back to its original levels by knockdown of TAZ in TAZ-overexpression cells. Inhibition of endogenous TAZ attenuated cell proliferation, colony formation and tumor development in neuroblastoma SK-N-AS cell, which could be rescued by re-introduction of TAZ into TAZ-knockdown cells. In addition, we found that overexpressing TAZ-mediated induction of CTGF and PDGF-ß expression, cell proliferation and colony formation were inhibited by knocking down CTGF and PDGF-ß with siRNA in TAZ-overexpressing cell. Overall, our findings suggested that TAZ plays an essential role in regulating cell proliferation and tumorigenesis in neuroblastoma cells. Thus, TAZ seems to be a novel and promising target for the treatment of neuroblastoma.

HDAC9 promotes glioblastoma growth via TAZ-mediated EGFR pathway activation.

Histone deacetylase 9 (HDAC9), a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions. We found that HDAC9 is over-expressed in prognostically poor glioblastoma patients. Knockdown HDAC9 decreased proliferation in vitro and tumor formation in vivo. HDAC9 accelerated cell cycle in part by potentiating the EGFR signaling pathway. Also, HDAC9 interacted with TAZ, a key downstream effector of Hippo pathway. Knockdown of HDAC9 decreased the expression of TAZ. We found that overexpressed TAZ in HDAC9-knockdown cells abrogated the effects induced by HDAC9 silencing both in vitro and in vivo. We demonstrated that HDAC9 promotes tumor formation of glioblastoma via TAZ-mediated EGFR pathway activation, and provide the evidence for promising target for the treatment of glioblastoma.