Rationale: Coronavirus disease 2019 (COVID-19) has caused a global pandemic. A classifier combining chest X-ray (CXR) with clinical features may serve as a rapid screening approach. Methods: The study included 512 patients with COVID-19 and 106 with influenza A/B pneumonia. A deep neural network (DNN) was applied, and deep features derived from CXR and clinical findings formed fused features for diagnosis prediction. Results: The clinical features of COVID-19 and influenza showed different patterns. Patients with COVID-19 experienced less fever, more diarrhea, and more salient hypercoagulability. Classifiers constructed using the clinical features or CXR had an area under the receiver operating curve (AUC) of 0.909 and 0.919, respectively. The diagnostic efficacy of the classifier combining the clinical features and CXR was dramatically improved and the AUC was 0.952 with 91.5% sensitivity and 81.2% specificity. Moreover, combined classifier was functional in both severe and non-serve COVID-19, with an AUC of 0.971 with 96.9% sensitivity in non-severe cases, which was on par with the computed tomography (CT)-based classifier, but had relatively inferior efficacy in severe cases compared to CT. In extension, we performed a reader study involving three experienced pulmonary physicians, artificial intelligence (AI) system demonstrated superiority in turn-around time and diagnostic accuracy compared with experienced pulmonary physicians. Conclusions: The classifier constructed using clinical and CXR features is efficient, economical, and radiation safe for distinguishing COVID-19 from influenza A/B pneumonia, serving as an ideal rapid screening tool during the COVID-19 pandemic.

Although germline mutations in BRCA1 highly predispose women towards breast and ovarian cancer, few substantial improvements in preventing or treating such cancers have been made. Importantly, BRCA1 function is closely associated with DNA damage repair, which is required for genetic stability. Here, we examined the efficacy of radiotherapy, assessing the accumulation of genetic instabilities, in the treatment of BRCA1-associated breast cancer using a Brca1-mutant mouse model. Treatment of Brca1-mutant tumor-engrafted mice with X-rays reduced tumor progression by 27.9% compared with untreated controls. A correlation analysis of irradiation responses and biomarker profiles in tumors at baseline identified differences between responders and non-responders at the protein level (pERα, pCHK2, p53, and EpCAM) and at the SOX2 target expression level. We further demonstrated that combined treatment of Brca1-mutant mammary tumors with irradiation and AZD2281, which inhibits PARP, significantly reduced tumor progression and extended survival. Our findings enhance the understanding of DNA damage and biomarker responses in BRCA1-associated mammary tumors and provide preclinical evidence that radiotherapy with synthetic DNA damage is a potential strategy for the therapeutic management of BRCA1-associated breast cancer.

Visualization of cell-cycle G1 phase for monitoring the early response of cell cycle specific drug remains challenging. In this study, we developed genetically engineered bioluminescent reporters by fusing full-length cyclin E to the C-terminal luciferase (named as CycE-Luc and CycE-Luc2). Next, HeLa cell line or an ER-positive breast cancer cell line MCF-7 was transfected with these reporters. In cellular assays, the bioluminescent signal of CycE-Luc and CycE-Luc2 was accumulated in the G1 phase and decreased after exiting from the G1 phase. The expression of CycE-Luc and CycE-Luc2 fusion protein was regulated in a cell cycle-dependent manner, which was mediated by proteasome ubiquitination and degradation. Next, our in vitro and in vivo experiment confirmed that the cell cycle arrested by anti-cancer agents (palbociclib or 5-FU) was monitored quantitatively and dynamically by bioluminescent imaging of these reporters in a real-time and non-invasive manner. Thus, these optical reporters could reflect the G1 phase alternation of cell cycle, and might become a future clinically translatable approach for predicting and monitoring response to palbociclib in patients with ER-positive breast cancer.

Tight junction (TJ) is a "zippering up" junction structure located at the uppermost portion of adjacent epithelial/endothelial cells in organs and tissues. TJs maintain the relative stability of intracellular substances and functions by closing or opening intercellular pathways, coordinating the entry and exit of molecules of different sizes and charges, and regulating the permeability of paracellular barrier. TJs also prevent microbial invasion, maintain epithelial/endothelial cell polarity, and regulate cell proliferation. TJs are widely present in the skin and mucosal epithelial barriers, intestinal epithelial barrier, glomerular filtration barrier, bladder epithelial barrier, blood-brain barrier, brain-blood tumor barrier, and blood-testis barrier. TJ dysfunction in different organs can lead to a variety of diseases. In addition to signal pathways, transcription factors, DNA methylation, histone modification, TJ proteins can also be regulated by a variety of non-coding RNAs, such as micro-RNAs, long-noncoding RNAs, and circular RNAs, directly or indirectly. This review summarizes the structure of TJs and introduces the functions and regulatory mechanisms of TJs in different organs and tissues. The roles and mechanisms of non-coding RNAs in the regulation of TJs are also highlighted in this review.

Background: Head and neck squamous cell carcinoma (HNSCC) are head and neck cancers. On the other hand, ferroptosis is a novel iron-dependent and ROS reliant type of cell death observed various disease conditions. Method: We constructed a prognostic multilncRNA signature based on ferroptosis-related differentially expressed lncRNAs in HNSCC. Results: We identified 25 differently expressed lncRNAs associated with prognosis of HNSCC. Kaplan-Meier analyses revealed the high-risk lncRNAs signature associated with poor prognosis of HNSCC. Moreover, the AUC of the lncRNAs signature was 0.782, underscoring their utility in prediction HNSCC prognosis. Indeed, our risk assessment model was superior to traditional clinicopathological features in predicting HNSCC prognosis. GSEA revealed the immune and tumor-related pathways in the low risk group individuals. Moreover, TCGA revealed T cell functions including cytolytic activity, HLA, regulation of inflammationp, co-stimulation, co-inhibition and coordination of type II INF response were significantly different between the low-risk and high-risk groups. Immune checkpoints such as PDCD-1 (PD-1), CTLA4 and LAG3, were also expressed differently between the two risk groups. Conclusion: A novel ferroptosis-related lncRNAs signature impacts on the prognosis of HNSCC.

This was a national survey that determined the prevalence of depressive symptoms (depression thereafter) and its relationship with quality of life (QOL) in frontline clinicians working in psychiatric hospitals in China during the COVID-19 pandemic. Depression and QOL were assessed using the Patient Health Questionnaire nine items (PHQ-9) and the World Health Organization Quality of Life Questionnaire-brief version (WHOQOL-BREF), respectively. Multivariable logistic regression analyses and analysis of covariance were used. A total of 10,516 frontline clinicians participated in this study, of which, 28.52% (n=2,999) met screening criteria for depression. Compared to those without depression, clinicians with depression had a lower quality of life (F(1, 10515) =2874.66, P<0.001). Higher educational level (OR=1.225, P=0.014), if the number of COVID-19 patients in the hospital catchment area surpassed 500 (OR=1.146, P=0.032), having family/friends/colleagues who were infected (OR=1.695, P<0.001), being a current smoker (OR=1.533, P<0.001), and longer working hours (OR=1.020, P=0.022) were independently associated with higher risk of depression. Living with family members (OR=0.786, P<0.001), and being junior clinicians (OR=0.851, P=0.011) were independently associated with lower odds of depression. The results showed that depression was common in frontline psychiatric clinicians during the COVID-19 pandemic. Timely assessment and effective interventions of depression for frontline clinicians in psychiatric hospitals were warranted.

Basal-like breast cancer (BLBC) is a type of high-grade invasive breast cancer with high risk of recurrence, metastases, and poor survival. Immune activation in BLBC is a key factor that influences both cancer progression and therapeutic response, although its molecular mechanisms are not well clarified. In this study, we examined five cancer immunity-related pathways (IFNα, IFNγ, STAT3, TGFβ and TNFα) in four large independent breast cancer cohorts (n = 6,381) and their associations with the prognosis of breast cancer subtypes. Activities of the 5 pathways were calculated based on corresponding pathway signatures and associations between pathways and clinical outcomes were examined by survival analysis. Among the five PAM50-based subtypes, BLBC had the highest IFNα, IFNγ, TNFα pathway activities, and the lowest TGFβ activity. The IFNα, IFNγ, TNFα pathway activities were negatively correlated with BLBC recurrence. In contrast, positive association and no association with BLBC recurrence were observed for TGFβ and STAT3 pathways, respectively. TNFα/TGFβ pathway combination improved the prediction of recurrence and chemotherapy response of BLBCs. Immune cell subset analysis in BLBC showed that M0, M1 and M2 macrophage levels were associated with either TNFα or TGFβ pathways, whereas the level of activated memory CD4 T cells were associated with both pathways. Moreover, this T cell subset was most abundant in BLBCs with low TGFβ and high TNFα pathway activities. These results suggested that cooperation of TNFα and TGFβ signaling may be involved in the regulation of memory T cells and anti-cancer immunity in BLBCs. Our data also demonstrate that TNFα/TGFβ pathway combination may represent a better biomarker for BLBC prognosis and clinical management.

Prostate cancer (PC) is the most common carcinoma among men worldwide which results in 26% of leading causes of cancer-related death. However, the ideal and effective molecular marker remains elusive. CircRNA, initially observed in plant-infected viruses and Sendai virus in 1979, is generated from pre-mRNA back-splicing and comes in to play by adequate expression. The differential expression in prostate tissues compared with the control reveals the promising capacity in modulating processes including carcinogenesis and metastasis. However, the biological mechanisms of regulatory network in PC needs to systemically concluded. In this review, we enlightened the comprehensive studies on the definite mechanisms of circRNAs affecting tumor progression and metastasis. What's more, we validated the potential clinical application of circRNAs serving as diagnostic and prognostic biomarker. The discussion and analysis in circRNAs will broaden our knowledge of the pathogenesis of PC and further optimize the current therapies against different condition.

Objectives: Radiotherapy has played a limited role in the treatment of non-small cell lung cancer (NSCLC) due to the risk of tumour radioresistance. We previously established the radioresistant non-small cell lung cancer (NSCLC) cell line H460R. In this study, we identified differentially expressed genes between these radioresistant H460R cells and their radiosensitive parent line. We further evaluated the role of a differentially expressed gene, ITGB1, in NSCLC cell radioresistance and as a potential target for improving radiosensitivity. Materials and Methods: The radiosensitivity of NSCLC cells was evaluated by flow cytometry, colony formation assays, immunofluorescence, and Western blotting. Bioinformatics assay was used to identify the effect of ITGB1 and YAP1 expression in NSCLC tissues. Results: ITGB1 mRNA and protein expression levels were higher in H460R than in the parental H460 cells. We observed lower clonogenic survival and cell viability and a higher rate of apoptosis of ITGB1-knockdown A549 and H460R cells than of wild type cells post-irradiation. Transfection with an ITGB1 short hairpin (sh) RNA enhanced radiation-induced DNA damage and G2/M phase arrest. Moreover, ITGB1 induced epithelial-mesenchymal transition (EMT) of NSCLC cells. Silencing ITGB1 suppressed the expression and intracellular translocation of Yes-associated protein 1 (YAP1), a downstream effector of ITGB1. Conclusions: ITGB1 may induce radioresistance via affecting DNA repair and YAP1-induced EMT. Taken together, our data suggest that ITGB1 is an attractive therapeutic target to overcome NSCLC cell radioresistance.

Background: Long non-coding RNAs (lncRNAs) are deemed to be relevant to the tumorigenesis and development of a variety of tumors, containing gastric cancer (GC). The purpose of our investigations is to explore the character of HCP5 in GC. Methods: HCP5 expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in 62 matched GC tissues and corresponding para-carcinoma tissues. In vitro and in vivo functional assays were subjected to verify the biological effects of HCP5 after alteration of HCP5. Chromatin immunoprecipitation assay (CHIP) assays were conducted to confirm that myocyte enhancer factor 2A (MEF2A) could bind to HCP5 promoter regions and thereby induce HCP5 expression. Analysis of the latent binding of miR-106b-5p to HCP5 and p21 was made by bioinformatics prediction and luciferase reporter assays. Results: Significant downregulation of HCP5 was detected in GC tissues. Negative correlation was determined between HCP5 expression level and tumor size and overall survival in GC patients. HCP5 depletion had a facilitating impact on proliferation, migration and invasion of GC cells. Consistently, overexpression of HCP5 came into an opposite effect. Moreover, we demonstrated that MEF2A could combine with the promoter region of HCP5 and thereby induce HCP5 transcription. Luciferase reporter assays revealed that HCP5 could compete with miR-106b-5p as a competing endogenous RNA (ceRNA) and upregulated p21 expression in GC. Conclusions: MEF2A-mediated HCP5 could exert an anti-tumor effect among the development of GC via miR-106b-5p/p21 axis, which provides a novel target for GC therapy.

Dihydroartemisinin (DHA) is an active metabolite of artemisinin and its derivatives (ARTs), and it is an effective clinical drug widely used to treat malaria. Recently, the anticancer activity of DHA has attracted increasing attention. Nevertheless, there is no systematic summary on the anticancer effects of DHA. Notably, studies have shown that DHA exerts anticancer effects through various molecular mechanisms, such as inhibiting proliferation, inducing apoptosis, inhibiting tumor metastasis and angiogenesis, promoting immune function, inducing autophagy and endoplasmic reticulum (ER) stress. In this review, we comprehensively summarized the latest progress regarding the anticancer activities of DHA in cancer. Importantly, the underlying anticancer molecular mechanisms and pharmacological effects of DHA in vitro and in vivo are the focus of our attention. Interestingly, new methods to improve the solubility and bioavailability of DHA are discussed, which greatly enhance its anticancer efficacy. Remarkably, DHA has synergistic anti-tumor effects with a variety of clinical drugs, and preclinical and clinical studies provide stronger evidence of its anticancer potential. Moreover, this article also gives suggestions for further research on the anticancer effects of DHA. Thus, we hope to provide a strong theoretical support for DHA as an anticancer drug.

Several natural products have been demonstrated to both enhance the anti-tumor efficacy and alleviate the side effects of conventional chemotherapy drugs. Rhein, a main constituent of the Chinese herb rhubarb, has been shown to induce apoptosis in various cancer types. However, the exact pharmacological mechanisms controlling the influence of Rhein on chemotherapy drug effects in pancreatic cancer (PC) remain largely undefined. In this study, we found that Rhein inhibited the growth and proliferation of PC cells through G1 phase cell cycle arrest. Moreover, Rhein induced caspase-dependent mitochondrial apoptosis of PC cells through inactivation of the PI3K/AKT pathway. Combination treatment of Rhein and oxaliplatin synergistically enhanced apoptosis of PC cells through increased generation of intracellular reactive oxygen species (ROS) and inactivation of the PI3K/AKT pathway. Pre-treatment with the ROS scavenger N-acetyl-L-cysteine attenuated the combined treatment-induced apoptosis and restored the level of phosphorylated AKT, indicating that ROS is an upstream regulator of the PI3K/AKT pathway. The combination therapy also exhibited stronger anti-tumor effects compared with single drug treatments in vivo. Taken together, these data demonstrate that Rhein can induce apoptosis and enhance the oxaliplatin sensitivity of PC cells, suggesting that Rhein may be an effective strategy to overcome drug resistance in the chemotherapeutic treatment of PC.

Identifying high specificity and sensitivity biomarkers has always been the focus of research in the field of non-invasive cancer diagnosis. Exosomes are extracellular vesicles with a lipid bilayer membrane that can be released by all types of cells, which contain a variety of proteins, lipids, and a variety of non-coding RNAs. Increasing research has shown that the lipid bilayer can effectively protect the nucleic acid in exosomes. In cancers, tumor cell-derived exosomal circRNAs can act on target cells or organs through the transport of exosomes, and then participate in the regulation of tumor development and metastasis. Since exosomes exist in various body fluids and circRNAs in exosomes exhibit high stability, exosomal circRNAs have the potential as biomarkers for early and minimally invasive cancer diagnosis and prognosis judgment. In this review, we summarized circRNAs and their biological roles in cancers, with the emerging value biomarkers in cancer diagnosis, disease judgment, and prognosis observation. In addition, we briefly compared the advantages of exosomal circRNAs as biomarkers and the current obstacles in the exosome isolation technology, shed light to the future development of this technology.

Objective: CA125/MUC16 is an O-glycosylated protein that is expressed on the surfaces of ovarian epithelial cells. This molecule is a widely used tumor-associated marker for diagnosis of ovarian cancer. Recently, CA125 was shown to be involved in ovarian cancer metastasis. The purpose of this study was to investigate the mechanism of CA125 during ovarian cancer metastasis. Methods: We analyzed the Oncomine and CSIOVDB databases to determine the expression levels of DKK1 in ovarian cancer. DKK1 expression levels were upregulated or downregulated and applied with CA125 to Transwell and Western blot assays to ascertain the underlying mechanism by which CA125 stimulates cell migration via the SGK3/FOXO3 pathway. Anti-mesothelin antibodies (anti-MSLN) were used to block CA125 stimulation. Then the expression levels of DKK1were tested by enzyme-linked immunosorbent assay (ELISA) to eliminate the blocking effect of anti-MSLN to CA125 stimulation. Xenograft mouse models were used to detect the effects of CA125 and anti-MSLN on ovarian cancer metastasis in vivo. Results: DKK1 levels were downregulated in ovarian tumor tissues according to the analyses of two databases and significantly correlated with FIGO stage, grade and disease-free survival in ovarian cancer patients. DKK1 levels were downregulated by CA125 stimulation in vitro. Overexpression of DKK1 reversed the ability of exogenous CA125 to mediate cell migration by activating the SGK3/FOXO3 signaling pathway. Anti-MSLN abrogated the DKK1 reduction and increased the apoptosis of ovarian cancer cells. The use of anti-MSLN in xenograft mouse models significantly reduced tumor growth and metastasis accelerated by CA125. Conclusions: These experiments revealed that the SGK3/FOXO3 pathway was activated, wherein decreased expression of DKK1 was caused by CA125, which fuels ovarian cancer cell migration. Mesothelin is a potential therapeutic target for the treatment of ovarian cancer metastasis.

Comprehensive reviews and large population-based cohort studies have played an important role in the diagnosis and treatment of pancreatitis and its sequelae. The incidence and mortality of pancreatitis have been reduced significantly due to substantial advancements in the pathophysiological mechanisms and clinically effective treatments. The study of extracellular vesicles (EVs) has the potential to identify cell-to-cell communication in diseases such as pancreatitis. Exosomes are a subset of EVs with an average diameter of 50~150 nm. Their diverse and unique constituents include nucleic acids, proteins, and lipids, which can be transferred to trigger phenotypic changes of recipient cells. In recent years, many reports have indicated the role of EVs in pancreatitis, including acute pancreatitis, chronic pancreatitis and autoimmune pancreatitis, suggesting their potential influence on the development and progression of pancreatitis. Plasma exosomes of acute pancreatitis can effectively reach the alveolar cavity and activate alveolar macrophages to cause acute lung injury. Furthermore, upregulated exosomal miRNAs can be used as biomarkers for acute pancreatitis. Here, we summarized the current understanding of EVs in pancreatitis with an emphasis on their biological roles and their potential use as diagnostic biomarkers and therapeutic agents for this disease.

With the continuous development of medical image informatics technology, more and more high-throughput quantitative data could be extracted from digital medical images, which has resulted in a new kind of omics-Radiomics. In recent years, in addition to genomics, proteomics and metabolomics, radiomic has attracted the interest of more and more researchers. Compared to other omics, radiomics can be perfectly integrated with clinical data, even with the pathology and molecular biomarker, so that the study can be closer to the clinical reality and more revealing of the tumor development. Mass data will also be generated in this process. Machine learning, due to its own characteristics, has a unique advantage in processing massive radiomic data. By analyzing mass amounts of data with strong clinical relevance, people can construct models that more accurately reflect tumor development and progression, thereby providing the possibility of personalized and sequential treatment of patients. As one of the cancer types whose treatment and diagnosis rely on imaging examination, radiomics has a very broad application prospect in head and neck cancers (HNC). Until now, there have been some notable results in HNC. In this review, we will introduce the concepts and workflow of radiomics and machine learning and their current applications in head and neck cancers, as well as the directions and applications of artificial intelligence in the treatment and diagnosis of HNC.

Endometrial carcinoma (EnCa) is one of the deadliest gynecological malignancies. The purpose of the current study was to develop an immune-related lncRNA prognostic signature for EnCa. In the current research, a series of systematic bioinformatics analyses were conducted to develop a novel immune-related lncRNA prognostic signature to predict disease-free survival (DFS) and response to immunotherapy and chemotherapy in EnCa. Based on the newly developed signature, immune status and mutational loading between high‑ and low‑risk groups were also compared. A novel 13-lncRNA signature associated with DFS of EnCa patients was ultimately developed using systematic bioinformatics analyses. The prognostic signature allowed us to distinguish samples with different risks with relatively high accuracy. In addition, univariate and multivariate Cox regression analyses confirmed that the signature was an independent factor for predicting DFS in EnCa. Moreover, a predictive nomogram combined with the risk signature and clinical stage was constructed to accurately predict 1-, 2-, 3-, and 5-year DFS of EnCa patients. Additionally, EnCa patients with different levels of risk had markedly different immune statuses and mutational loadings. Our findings indicate that the immune-related 13-lncRNA signature is a promising classifier for prognosis and response to immunotherapy and chemotherapy for EnCa.

Traumatic brain injury (TBI) is recognized as the disease with high morbidity and disability around world in spite of the work ongoing in neural protection. Due to heterogeneity among the patients, it's still hard to acquire satisfying achievements in clinic. Neuroinflammation, which exists since primary injury occurs, with elusive duality, appear to be of significance from recovery of injury to neurogenesis. In recent years, studied have revealed that communication in neurogenic niche is more than "cell to cell" communication, and study on NSCs represent it as central role in the progress of neural regeneration. Hence, the neuroinflammation-affecting crosstalk after TBI, and clarifying definitive role of NSCs in the course of regeneration is a promising subject for researchers, for its great potential in overcoming the frustrating status quo in clinic, promoting welfare of TBI patient.

Mediator complex subunit 13 (MED13, previously known as THRAP1 and TRAP240) is a subunit of the cyclin-dependent kinase 8 (CDK8) kinase module in the eukaryotic mediator complex. MED13 has been known to play critical roles in cell cycle, development, and growth. The purpose of this review is to comprehensively discuss its newly identified potential roles in myocardial energy metabolism and non-metabolic cardiovascular diseases. Evidence indicates that cardiac MED13 mainly participates in the regulation of nuclear receptor signaling, which drives the transcription of genes involved in modulating cardiac and systemic energy homeostasis. MED13 is also associated with several pathological conditions, such as metabolic syndrome and thyroid disease-associated heart failure. Therefore, MED13 constitutes a potential therapeutic target for the regulation of metabolic disorders and other cardiovascular diseases.

Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.

The 'epitranscriptome', a collective term for chemical modifications that influence the structure, metabolism, and functions of RNA, has recently emerged as vitally important for the regulation of gene expression. N6-methyladenosine (m6A), the most prevalent mammalian mRNA internal modification, has been demonstrated to have a pivotal role in almost all vital bioprocesses, such as stem cell self-renewal and differentiation, heat shock or DNA damage response, tissue development, and maternal-to-zygotic transition. Hepatocellular carcinoma (HCC) is prevalent worldwide with high morbidity and mortality because of late diagnosis at an advanced stage and lack of effective treatment strategies. Epigenetic modifications including DNA methylation and histone modification have been demonstrated to be crucial for liver carcinogenesis. However, the role and underlying molecular mechanism of m6A in liver carcinogenesis are mostly unknown. In this review, we summarize recent advances in the m6A region and how these new findings remodel our understanding of m6A regulation of gene expression. We also describe the influence of m6A modification on liver carcinoma and lipid metabolism to instigate further investigations of the role of m6A in liver biological diseases and its potential application in the development of therapeutic strategies.

Esophageal squamous cell carcinoma (ESCC) causes aggressive and lethal malignancies with extremely poor prognoses, and accounts for about 90% of cases of esophageal cancer. Neuropilin and tolloid-like 2 (NETO2) protein coding genes have been associated with various human cancers. Nevertheless, little information is reported about the phenotypic expression and its clinical significance in ESCC progression. Here, our study found that NETO2 expression in ESCC patients was associated with tumor clinical stage and lymph node metastasis status. Gain-of-function and loss-of-function analyses showed that NETO2 stimulated ESCC cell proliferation while suppressing apoptosis in vitro and enhanced tumor growth in vivo. Moreover, knockdown of NETO2 significantly inhibited migration and invasion in combination with regulation of epithelial-mesenchymal transition (EMT) related markers. Mechanistically, overexpression of NETO2 increased the phosphorylation of ERK, PI3k/AKT, and Nuclear factor erythroid-2-related factor 2(Nrf2), whereas silencing NETO2 decreased the phosphorylation of these targets. Our data suggest that Nrf2 was a critical downstream event responsible for triggering the PI3K/AKT and ERK signaling pathways and plays a crucial role in NETO2-mediated tumorigenesis. Taken together, NETO2 acts as an oncogene and might serve as a novel therapeutic target or prognostic biomarker in ESCC patients.

The intestine serves as an important digestive and the largest immune organ in the body. Interleukin-6(IL-6), an important mediator of various pathways, participates in the interactions between different kinds of cells and closely correlates with intestinal physiological and pathological condition. In this review we summarize the signaling pathways of IL-6 and its functions in maintaining intestinal homeostasis. We also explored its relation with nervous system and highlight its potential role in Parkinson's disease. Based on its specialty of the double-side influences on intestinal tumors and inflammation, we summarize how they are done through distinctive process.

Androgen receptor (AR) and its variants play vital roles in development and progression of prostate cancer. To clarify the mechanisms involved in the enhancement of their actions would be crucial for understanding the process in prostate cancer and castration-resistant prostate cancer transformation. Here, we provided the evidence to show that pre-mRNA processing factor 6 (PRPF6) acts as a key regulator for action of both AR full length (AR-FL) and AR variant 7 (AR-V7), thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited to cis-regulatory elements in AR target genes and associates with JMJD1A to enhance AR-induced transactivation. PRPF6 also promotes expression of AR-FL and AR-V7. Moreover, PRPF6 depletion reduces tumor growth in prostate cancer-derived cell lines and results in significant suppression of xenograft tumors even under castration condition in mouse model. Furthermore, PRPF6 is obviously highly expressed in human prostate cancer samples. Collectively, our results suggest PRPF6 is involved in enhancement of oncogenic AR signaling, which support a previously unknown role of PRPF6 during progression of prostate cancer and castration-resistant prostate cancers.

Because of their relatively short lifespan (<4 years), rats have become the second most used model organism to study health and diseases in humans who may live for up to 120 years. First-, second- and third-generation sequencing technologies and platforms have produced increasingly greater sequencing depth and accurate reads, leading to significant advancements in the rat genome assembly during the last 20 years. In fact, whole genome sequencing (WGS) of 47 strains have been completed. This has led to the discovery of genome variants in rats, which have been widely used to detect quantitative trait loci underlying complex phenotypes based on gene, haplotype, and sweep association analyses. DNA variants can also reveal strain, chromosome and gene functional evolutions. In parallel, phenome programs have advanced significantly in rats during the last 15 years and more than 10 databases host genome and/or phenome information. In order to discover the bridges between genome and phenome, systems genetics and integrative genomics approaches have been developed. On the other hand, multiple level information transfers from genome to phenome are executed by differential usage of alternative transcriptional start (ATS) and polyadenylation (APA) sites per gene. We used our own experiments to demonstrate how alternative transcriptome analysis can lead to enrichment of phenome-related causal pathways in rats. Development of advanced genome-to-phenome assays will certainly enhance rats as models for human biomedical research.

In recent years, a vast number of potential cancer therapeutic targets have emerged. However, developing efficient and effective drugs for the targets is of major concern. Hydrogen sulfide (H2S), one of the three known gasotransmitters, is involved in the regulation of various cellular activities such as autophagy, apoptosis, migration, and proliferation. Low production of H2S has been identified in numerous cancer types. Treating cancer cells with H2S donors is the common experimental technique used to improve H2S levels; however, the outcome depends on the concentration/dose, time, cell type, and sometimes the drug used. Both natural and synthesized donors are available for this purpose, although their effects vary independently ranging from strong cancer suppressors to promoters. Nonetheless, numerous signaling pathways have been reported to be altered following the treatments with H2S donors which suggest their potential in cancer treatment. This review will analyze the potential of H2S donors in cancer therapy by summarizing key cellular processes and mechanisms involved.

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global infection, and is seriously threatening human life, especially cancer patients. Thus, we sought to determine the clinical roles of ACE2 (the cell entry receptor of SARS-CoV-2) in ccRCC (clear cell renal cell carcinoma). TCGA, GEO and TIP datasets, and immunohistochemistry and western blot results were used to determine the prognostic and clinicopathological characteristics of ACE2. ACE2 expression was down-regulated in ccRCC tissues and cell lines. The multivariate Cox regression analysis results indicated that increased ACE2 expression was independent predictor of longer OS (HR: 0.8259, 95%CI: 0.7734-0.8819, P<0.0001) and RFS (HR: 0.8023, 95%CI: 0.7375-0.8729, P<0.0001) in ccRCC patients. Lower ACE2 expression was also associated with advanced tumor stage, higher histological grade and pathological stage, and metastasis. Besides, ACE2 expression was significantly positively and negatively correlated with CD4 Naïve infiltration and CD4 Memory infiltration, respectively. Moreover, higher CD4 Naïve and lower CD4 Memory infiltration levels were associated with better pathological features and longer OS and RFS. Furthermore, high ACE2 expression group in decreased CD4 Naïve, enriched CD4 Naïve and enriched CD4 memory cohort had favorable prognosis. These findings identified that AEC2 was significantly reduced in ccRCC, and decreased ACE2 was related to worse pathological features and poor prognosis. Low ACE2 expression in ccRCC may partially affect the prognosis due to altered immune cells infiltration levels.

Proliferation is one of the significant hallmarks of gallbladder cancer, which is a relatively rare but fatal malignance. Aim of this study was to examine the biological impact and molecular mechanism of the candidate hub-gene on the proliferation and tumorigenesis of gallbladder cancer. We analyzed the differentially expressed genes and the correlation between these genes with MKI67, and showed that KIF11 is one of the major upregulated regulators of proliferation in gallbladder cancer (GBC). The Gene Ontology, Gene Sets Enrichment Analysis and KEGG Pathway analysis indicated that KIF11 may promote GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. Gain-of-function and loss-of-function assay demonstrated that KIF11 regulated GBC cell cycle and cancer cell proliferation in vitro. GBC cells exhibited G2M phase cell cycle arrest, cell proliferation and clone formation ability reduction after treatment with Monastrol, a specific inhibitor of KIF11. Xenograft model showed that KIF11 promotes GBC growth in vivo. Rescue experiments showed that KIF11-induced GBC cell proliferation dependented on ERBB2/PI3K/AKT pathway. Moreover, we found that H3K27ac signals are enriched among the promoter region of KIF11 in the UCSC Genome Browser Database. Differentially expressed analysis showed that EP300, a major histone acetyltransferase modifying H3K27ac signal, is highly expressed in gallbladder cancer and correlation analysis illustrated that EP300 is positively related with KIF11 in almost all the cancer types. We further found that KIF11 was significantly downregulated in a dose-dependent and time-dependent manner after histone acetylation inhibitor treatment. The present results highlight that high KIF11 expression promotes GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. The findings may help deepen our understanding of mechanism underlying GBC cancer development and development of novel diagnostic and therapeutic target.

MicroRNAs are major post-transcriptional regulators responsible for the development of human cancers, including OSCC. The specific role of miR-619-5p in OSCC, however, is rarely reported. Cisplatin is one of the mostly applied chemotherapy drugs of OSCC. Nevertheless, drug resistance of cisplatin following the initial chemotherapy largely restricts its clinical benefits, and the mechanism of cisplatin resistance is unclear. This study intends to explore the biological function of miR-619-5p in the development of cisplatin resistance in OSCC cell lines and a xenograft model, as well as the potential molecular mechanism. Our results showed that miR-619-5p was down-regulated in OSCC samples and cisplatin-resistant OSCC cells. Ectopically expressed miR-619-5p inhibited proliferative, migratory and invasive abilities of OSCC cisplatin-resistant cells. The putative target gene ATXN3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Importantly, ATXN3 was responsible for the regulatory effects of miR-619-5p on biological behaviors of cisplatin-resistant OSCC cells. Moreover, miR-619-5p mimics and ATXN3-siRNA significantly enhanced ATXN3 knockdown in both HN6/CDDPR and CAL27/CDDPR cells and inhibited expression of PI3K and AKT. In vivo evidences demonstrated that intratumoral injection of miR-619-5p agomir remarkably slowed down the growth of OSCC in xenograft mice. Collectively, microRNA-619-5p was the vital regulator for regulating cisplatin resistance of OSCC, which may be served as a potential therapeutic target.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, characterized by phosphorylated TDP-43 (pTDP-43)-positive inclusions in neurons and glial cells. However, the pathogenic mechanism that underlies ALS remains largely unknown. To investigate the effects of autophagy deficiency in the formation and spreading of pathological TDP-43 along corticospinal tract axons, TDP-43 preformed fibrils (PFFs) were prepared and unilaterally injected into the fifth layer of the left primary motor cortex (M1) or the left anterior horn of the seventh cervical spinal cord segment (C7) of Atg5+/- mice. After the injection of TDP-43 PFFs, the elevated levels of pTDP-43 were present in several pyramidal tract-associated regions of Atg5+/- mice. Additionally, the occurrence of spontaneous potentials detected by electromyography demonstrates evidence of lower motor neuron dysfunction in M1-TDP-43 PFFs-injected Atg5+/- mice, and prolonged central motor conduction time detected by motor evoked potentials provides evidence of upper motor neuron dysfunction in C7-TDP-43 PFFs-injected Atg5+/- mice. These results show that injection of TDP-43 PFFs into the M1 or C7 of Atg5+/- mice induces the spreading of pathological TDP-43 along corticospinal tract axons in both an anterograde and retrograde manner. Importantly, TDP-43 PFFs-injected Atg5+/- mice also display ALS-like motor dysfunction. Taken together, our findings provide direct evidence that TDP-43 PFFs-injected Atg5+/- mice exhibited ALS-like neuropathology and motor phenotypes, suggesting that autophagy deficiency promotes the formation and spreading of pathological TDP-43 in vivo.

Cellular communication can be mediated by the exchange of biological information, mainly in the form of proteins and RNAs. This can occur when extracellular vesicles, such as exosomes, secreted by a donor cell are internalized by an acceptor cell. Exosomes bear specific repertoires of proteins and RNAs, indicating the existence of mechanisms that control the sorting of molecules into them. Knowledge about loadings and processes and mechanisms of cargo sorting of exosomes is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. In this review, we will discuss the molecular mechanisms associated with exosome secretion and their specific cargo sorting, with special attention to the sorting of RNAs and proteins, and thus the outcome and the emerging therapeutic opportunities of the communication between the exosome-producer and recipient cells.

As a systemic syndrome characterized by age-associated degenerative skeletal muscle atrophy, sarcopenia leads to a risk of adverse outcomes in the elderly. Age-related iron accumulation is found in the muscles of sarcopenia animal models and patients, but the role of iron in sarcopenia remains poorly understood. It has been recently found that iron overload in several diseases is involved in ferroptosis, an iron- dependent form of programmed cell death. However, whether this excess iron can result in ferroptosis in muscles is still unclear. In our present study, we found that ferric citrate induced ferroptosis in C2C12 cells, as well as impaired their differentiation from myoblasts to myotubes. Due to the decreased muscle mass and fiber size, 40-week-old senescence accelerated mouse prone 8 (SAMP8) mice were used as a sarcopenia model, in whose muscles the iron content and markers of ferroptosis were found to increase, compared to 8-week- old SAMP8 controls. Moreover, our results showed that iron overload upregulated the expression of P53, which subsequently repressed the protein level of Slc7a11 (solute carrier family 7, member 11), a known ferroptosis-related gene. The downregulation of Slc7a11 then induced the ferroptosis of muscle cells through the accumulation of lipid peroxidation products, which may be one of the causes of sarcopenia. The findings in this study indicate that iron plays a key role in triggering P53- Slc7a11-mediated ferroptosis in muscles, and suggest that targeting iron accumulation and ferroptosis might be a therapeutic strategy for treating sarcopenia.

Autophagy is a conserved catabolic process involving the degradation and recycling of damaged biomacromolecules or organelles through lysosomal-dependent pathways and plays a crucial role in maintaining cell homeostasis. Consequently, abnormal autophagy is associated with multiple diseases, such as infectious diseases, neurodegenerative diseases and cancer. Currently, autophagy is considered to be a dual regulator in cancer, functioning as a suppressor in the early stage while supporting the growth and metastasis of cancer cells in the later stage and may also produce therapeutic resistance. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level by silencing targeted mRNA. MiRNAs have great regulatory potential for several fundamental biological processes, including autophagy. In recent years, an increasing number of studies have linked miRNA dysfunction to the growth, metabolism, migration, metastasis, and responses of cancer cells to therapy. Therefore, the study of autophagy-related miRNAs in cancer will provide insights into cancer biology and lead to the development of novel anti-cancer strategies. In the present review, we summarise the current knowledge of miRNA dysregulation during autophagy in cancer, focusing on the relationship between autophagy and miRNAs, and discuss their involvement in cancer biology and cancer treatment.

βII spectrin, the most common isoform of non-erythrocyte spectrin, is a cytoskeleton protein present in all nucleated cells. Interestingly, βII spectrin is essential for the development of various organs such as nerve, epithelium, inner ear, liver and heart. The functions of βII spectrin include not only establishing and maintaining the cell structure but also regulating a variety of cellular functions, such as cell apoptosis, cell adhesion, cell spreading and cell cycle regulation. Notably, βII spectrin dysfunction is associated with embryonic lethality and the DNA damage response. More recently, the detection of altered βII spectrin expression in tumors indicated that βII spectrin might be involved in the development and progression of cancer. Its mutations and disorders could result in developmental disabilities and various diseases. The versatile roles of βII spectrin in disease have been examined in an increasing number of studies; nonetheless, the exact mechanisms of βII spectrin are still poorly understood. Thus, we summarize the structural features and biological roles of βII spectrin and discuss its molecular mechanisms and functions in development, homeostasis, regeneration and differentiation. This review highlight the potential effects of βII spectrin dysfunction in cancer and other diseases, outstanding questions for the future investigation of therapeutic targets. The investigation of the regulatory mechanism of βII spectrin signal inactivation and recovery may bring hope for future therapy of related diseases.

Germline specification is a fundamental step for human reproduction and this biological phenomenon possesses technical challenges to study in vivo as it occurs immediately after blastocyst implantation. The establishment of in vitro human primordial germ cell-like cells (hPGCLCs) induction system allows sophisticated characterization of human primordial germ cells (hPGCs) development. However, the underlying molecular mechanisms of hPGCLC specification are not fully elucidated. Here, we observed particularly high expression of the histone demethylase KDM2B in male fetal germ cells (FGCs) but not in male somatic cells. Besides, KDM2B shared similar expression pattern with hPGC marker genes in hPGCLCs, suggesting an important role of KDM2B in germ cell development. Although deletion of KDM2B had no significant effects on human embryonic stem cell (hESC)'s pluripotency, loss of KDM2B dramatically impaired hPGCLCs differentiation whereas ectopically expressed KDM2B could efficiently rescue such defect, indicating this defect was due to KDM2B's loss in hPGCLC specification. Mechanistically, as revealed by the transcriptional profiling, KDM2B suppressed the expression of somatic genes thus inhibited somatic differentiation during hPGCLC specification. These data collectively indicate that KDM2B is an indispensable epigenetic regulator for hPGCLC specification, shedding lights on how epigenetic regulations orchestrate transcriptional events in hPGC development for future investigation.

Long noncoding RNA DiGeorge syndrome critical region gene 5 (DGCR5) has been shown to be highly associated with cancer development. However, the biological role and molecular mechanism of DGCR5 in pancreatic cancer (PC) remains largely unknown. This study aimed to explore the role of DGCR5 in PC. It was revealed that DGCR5 was highly expressed in PC tissues compared with adjacent normal tissues and was associated with poor prognosis in PC patients. Furthermore, DGCR5 depletion inhibited the proliferation, migration and invasion by increasing apoptosis and inducing G0/G1 cell cycle arrest in vitro. Moreover, xenograft assay validated that DGCR5 promotes PC tumor growth in vivo. Mechanistically, DGCR5 was found to act as a ceRNA by sponging miR-3163 to regulate DNA topoisomerase 2-alpha (TOP2A) and inhibit Wnt/β-catenin pathway. In addition, it was found that DGCR5 downregulation could enhance the sensitivity of PC cells to gemcitabine, and ChIP assay showed that PAX5 (Paired Box 5) could bind to the promoter region of DGCR5 and increase its transcription. The results of the present study indicated that DGCR5 may be a potential diagnostic biomarker and therapeutic target for PC.

Sepsis is a common serious clinical infectious disease accompanied by more severe injuries and higher mortality rates in men than women. The much higher level of 17β-estradiol (E2) in female is one of the significant reasons for better sepsis resistance ability. Trained immunity is a novel way to fight against infection by improving innate immunity. However, whether β-glucan-induced trained immunity can promote macrophage phagocytosis to clear infections in early sepsis has not been clarified. And whether E2 involved in this process needs further investigation. Symptoms among male, female and ovariectomized (OVX) C57BL/6 mice in early sepsis were detected. The effect of trained immunity on macrophage LC3B-associated phagocytosis (LAP) and the mechanism of E2 functioned in this process have also been explored. We demonstrated compared with male mice, female has significantly more mild symptoms and more reactive oxygen species (ROS) production and stronger NADPH oxidase 2 (NOX2) expression in the macrophage of major organs. In contrary, these characteristics are disappeared in OVX mice. Furthermore, in macrophage cell lines and primary bone marrow- derived macrophages (BMDMs), β-glucan-induced trained immunity can increase ROS production by activating NOX2 to promote macrophage LAP. E2 can up-regulate RUBICON through estrogen receptor α (ERα) to further facilitate macrophage LAP. These results indicated that trained immunity can improve sepsis resistance ability by stimulating macrophage LAP. E2 can boost ROS production and RUBICON expression to further promote macrophage LAP, which can provide a new perspective to recognize the mechanism of trained immunity in gender differences when responding to sepsis.

Glucose and lipids are important nutrients that provide the majority of energy for each organ to maintain homeostasis of the body. With the continuous improvement in living standards, the incidence of metabolic disorder-associated diseases, such as diabetes, hyperlipidemia, and atherosclerosis, is increasing worldwide. Among them, diabetes, which could be induced by both glucose and lipid metabolic disorders, is one of the five diseases with the highest incidence and mortality worldwide. However, the detailed molecular mechanisms underlying glucose and lipid metabolism disorders and target-organ damage are still not fully defined. MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs, which usually affect their target mRNAs in the cytoplasm by post-transcriptional regulation. Previously, we have found that miR-320 contributed to glucose and lipid metabolism via different signaling pathways. Most importantly, we identified that nuclear miR-320 mediated diabetes-induced cardiac dysfunction by activating the transcription of fatty acid metabolic genes to cause lipotoxicity in the heart. Here, we reviewed the roles of miR-320 in glucose and lipid metabolism and target-organ damage.

Rationale: Mechanical stimuli in the microenvironment are considered key regulators of cell function. Clinically, mechanical force (tissue expander) is widely used to regenerate skin for post-burn or trauma repair, implying that mechanical stretching can promote skin cell regeneration and proliferation. However, the underlying mechanism remains unknown. Methods: Microarray analysis was utilized to detect the hub gene. The expression of Cdh1 as examined in cells and tissues by western blot, q-PCR and immunohistochemistry staining respectively. Biological roles of Cdh1 was revealed by a series of functional in vitro and in vivo studies. Results: Microarray analysis identified Cdh1 as a hub gene related to skin regeneration during rat cutaneous mechanical loading. In vitro studies suggested that both mechanical loading and Cdh1 interference induced keratinocyte dedifferentiation and enhanced stemness, promoting cell proliferation and prevent apoptosis. Furthermore, the forkhead box O1/Krüppel-like factor 4 (FOXO1/KLF4) pathway was activated and contributed to the keratinocyte dedifferentiation. In vivo studies showed that mechanical loading and Cdh1 interference facilitated epidermal dedifferentiation and promoted dermal collagen deposition, and that Cdh1 overexpression could block such influence. Conclusions: In this study, we show that E-cadherin (CDH1), a well-known cell-cell adhesion molecule, plays a crucial role in mechanical stretch-induced skin cell regeneration and proliferation. We have shown for the first time the process by which mechanical stress is transmitted to the epidermis and induces a downstream signaling pathway to induce epidermal cells to differentiate. These findings demonstrate that Cdh1-induced keratinocyte dedifferentiation is a crucial event in mechanical stretch-mediated skin regeneration and that Cdh1 may serve as a potential therapeutic target for promoting skin regeneration.

Background: Cervical cancer is a common malignant disease in female patients accompanied by activation of autophagy in tumor cells. However, the exact regulatory factors of autophagy and its effects on the immune response remain unknown. Methods: The induction of autophagy in HeLa and SiHa cells treated with IFN-γ, tryptophan depletion, kynurenine and epacadostat was detected by western blot analysis and by an autophagy detection kit. Following co-culture with pre-treated HeLa and SiHa cells, U937 cells were analyzed by flow cytometry to detect CD80, CD86, CD163 and CD206 expression and the induction of phagocytosis. Results: IFN-γ caused a significant increase in the autophagy levels of HeLa and SiHa cells by promoting indoleamine-2,3-dioxygenase-1 (IDO1) expression. The induction of phagocytosis in HeLa and SiHa cells and the expression levels of CD80 and CD86 in U937 cells were increased significantly following treatment with recombinant human IFN-γ. This effect was associated with the induction of tumor cell autophagy. IFN-γ treatment and IDO1 overexpression promoted tryptophan depletion and kynurenine accumulation in cervical cancer cells. The latter was more potent in inducing autophagy of cervical cancer cells and promoting phagocytosis of macrophages. In vivo, IDO1 overexpression restricted tumor growth in C57 mice and enhanced the induction of phagocytosis in macrophages. Conclusions: IFN-γ promoted induction of autophagy and macrophage phagocytosis in cervical cancer cells possibly via IDO1 expression and kynurenine metabolism.

Postoperative adhesions (PA) are fibrotic tissues that are the most common driver of long-term morbidity after abdominal and pelvic surgery. The optimal drug or material to prevent adhesion formation has not yet been discovered. Comprehensive understanding of cellular and molecular mechanisms of adhesion process stimulates the design of future anti-adhesive strategies. Recently, disruption of peritoneal mesothelial cells were suggested as the 'motor' of PA formation, followed by a cascade of events (coagulation, inflammation, fibrinolysis) and influx of various immune cells, ultimately leading to a fibrous exudate. We showed that a variety of immune cells were recruited into adhesive peritoneal tissues in patients with small bowel obstruction caused by PA. The interactions among various types of immune cells contribute to PA development following peritoneal trauma. Our review focuses on the specific role of different immune cells in cellular and humoral mechanisms underpinning adhesion development.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progression and worse prognosis. Our previous study found that HES1 was overexpressed and promoted invasion in TNBC. However, the role of HES1 in modulating BCSC stemness of TNBC remains unclear. Here, we found that HES1 upregulates Slug both in transcriptional level and in protein level. HES1 also has a positive correlation with Slug expression in 150 TNBC patient samples. TNBC patients with high HES1 and Slug levels show worse prognosis in both progression-free survival and overall survival analyses. Survival analyses indicate that the effects of HES1 on survival prognosis may depend on Slug. Furthermore, we reveal that HES1 is a novel transcriptional activator for Slug through acting directly on its promoter. Meanwhile, HES1 knockdown reduces BCSC self-renewal, BCSC population, and cancer cell proliferation in TNBC, whereas overexpression of Slug restores the oncogenic function of HES1, both in vitro and in vivo, suggesting that HES1 performs its oncogenic role through upregulating Slug. Taken together, HES1 promotes BCSC stemness properties via targeting Slug, highlighting that HES1 might be a novel candidate for BCSC stemness regulation in TNBC and providing new clues for identifying promising prognostic biomarkers and therapeutic targets of TNBC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Increasing studies showed that long non-coding RNAs (lncRNAs), a novel class of RNAs that are greater than 200 nucleotides in length but lack the ability to encode proteins, exert crucial roles in the occurrence and progression of HCC. LncRNAs promote the proliferation, migration, invasion, autophagy, and apoptosis of tumor cells by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can be used as biomarkers to predict the efficacy of HCC treatment strategies, such as surgery, radiotherapy, chemotherapy, and immunotherapy, and as a potential individualized tool for HCC diagnosis and treatment. In this review, we overview up-to-date findings on lncRNAs as potential biomarkers for HCC surgery, radiotherapy, chemotherapy resistance, target therapy, and immunotherapy, and discuss the potential clinical application of lncRNA as tools for HCC diagnosis and treatment.

As a transcription factor and proto-oncogene, MYC is known to be deregulated in a variety of tumors, including breast cancer. However, no consistent conclusion on the role and mechanism of MYC deregulation during breast cancer carcinogenesis has been formed. Here, we used the UALCAN, bc-GenExMiner, TCGA, cBioportal, STRING and Kaplan-Meier Plotter databases to explore the mRNA expression, prognosis, transcriptional profile changes, signal pathway rewiring and interaction with the cancer stem cells of MYC in breast cancer. We found that the expression of MYC varies in different subtypes of breast cancer, with relatively high frequency in TNBC. As a transcription factor, MYC not only participates in the rewiring of cancer signaling pathways, such as estrogen, WNT, NOTCH and other pathways, but also interacts with cancer stem cells. MYC is significantly positively correlated with breast cancer stem cell markers such as CD44, CD24, and ALDH1. Collectively, our results highlight that MYC plays an important regulatory role in the occurrence of breast cancer, and its amplification can be used as a predictor of diagnosis and prognosis. The interaction between MYC and cancer stem cells may play a crucial role in regulating the initiation and metastasis of breast cancer.

Aerobic glycolysis, also known as the Warburg effect, is emerged as a hallmark of most cancer cells. Increased aerobic glycolysis is closely associated with tumor aggressiveness and predicts a poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent genomic aberrations and increased glycolytic phenotype. However, the detailed molecular events implicated in aerobic glycolysis of PDAC are not well understood. In this study, we performed a comprehensive molecular characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis of 89 informative PDAC tumors identified substantial copy number variations (MYC, GATA6, FGFR1, IDO1, and SMAD4) and mutations (KRAS, SMAD4, and RNF43) related to aerobic glycolysis. Moreover, integrated analysis of transcriptional profiles revealed many differentially expressed long non-coding RNAs involved in PDAC aerobic glycolysis. Loss-of-function studies showed that LINC01559 and UNC5B-AS1 knockdown significantly inhibited the glycolytic capacity of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate. Moreover, genetic silencing of LINC01559 and UNC5B-AS1 suppressed tumor growth and resulted in alterations in several signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, and transcriptional misregulation in cancer. Notably, high expression of LINC01559 and UNC5B-AS1 predicted poor patient prognosis and correlated with the maximum standard uptakevalue (SUVmax) in PDAC patients who received preoperative 18F-FDG PET/CT. Taken together, our results decipher the glycolysis-associated copy number variations, mutations, and lncRNA landscapes in PDAC. These findings improve our knowledge of the molecular mechanism of PDAC aerobic glycolysis and may have practical implications for precision cancer therapy.

The outbreak of the coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pandemic apparently started in December 2019 in Wuhan, China, and has since affected many countries worldwide, turning into a major global threat. Chinese researchers reported that SARS-CoV-2 could be classified into two major variants. They suggest that investigating the variations and characteristics of these variants might help assess risks and develop better treatment and prevention strategies. The two variants were named L-type and S-type, in which L-type was prevailed in an initial outbreak in Wuhan, Central China's Hubei Province, and S-type was phylogenetically older than L-type and less prevalent at an early stage, but with a later increase in frequency in Wuhan. There were 149 mutations in 103 sequenced SARS-CoV-2 genomes, 83 of which were nonsynonymous, leading to alteration in the amino acid sequence of proteins. Much effort is currently being devoted to elucidate whether or not these mutations affect viral transmissibility and virulence. In this review, we summarize the mutations in SARS-CoV-2 during the early phase of virus evolution and discuss the significance of the gene alterations in infections.

Multi-system involvement and rapid clinical deterioration are hallmarks of coronavirus disease 2019 (COVID-19) related mortality. The unique clinical phenomena in severe COVID-19 can be perplexing, and they include disproportionately severe hypoxemia relative to lung alveolar-parenchymal pathology and rapid clinical deterioration, with poor response to O2 supplementation, despite preserved lung mechanics. Factors such as microvascular injury, thromboembolism, pulmonary hypertension, and alteration in hemoglobin structure and function could play important roles. Overwhelming immune response associated with "cytokine storms" could activate reactive oxygen species (ROS), which may result in consumption of nitric oxide (NO), a critical vasodilation regulator. In other inflammatory infections, activated neutrophils are known to release myeloperoxidase (MPO) in a natural immune response, which contributes to production of hypochlorous acid (HOCl). However, during overwhelming inflammation, HOCl competes with O2 at heme binding sites, decreasing O2 saturation. Moreover, HOCl contributes to several oxidative reactions, including hemoglobin-heme iron oxidation, heme destruction, and subsequent release of free iron, which mediates toxic tissue injury through additional generation of ROS and NO consumption. Connecting these reactions in a multi-hit model can explain generalized tissue damage, vasoconstriction, severe hypoxia, and precipitous clinical deterioration in critically ill COVID-19 patients. Understanding these mechanisms is critical to develop therapeutic strategies to combat COVID-19.

Eomesodermin (Eomes), a transcription factor, could suppress the Th17 cell differentiation and proliferation through directly binding to the promoter zone of the Rorc and Il17a gene, meanwhile the expression of Eomes is suppressed when c-Jun directly binds to its promoter zone. Ginkgolide K (1,10-dihydroxy-3,14-didehydroginkgolide, GK) is a diterpene lactone isolated from the leaves of Ginkgo biloba. A previous study indicated that GK could decrease the level of phospho JNK (c-Jun N-terminal kinase). Here, we reported the therapeutic potential of Ginkgolide K (GK) treatment to ameliorate experimental autoimmune encephalomyelitis (EAE) disease progression. Methods: EAE was induced in both wildtype and CD4-Eomes conditional knockout mice. GK was injected intraperitoneally. Disease severity, inflammation, and tissue damage were assessed by clinical evaluation, flow cytometry of mononuclear cells (MNCs), and histopathological evaluation. Dual-luciferase reporter assays were performed to measure Eomes transcription activity in vitro. The potency of GK (IC50) was determined using JNK1 Kinase Enzyme System. Results: We revealed that GK could ameliorate EAE disease progression by the inhibition of the Th17 cells. Further mechanism studies demonstrated that the level of phospho JNK was decreased and the level of Eomes in CD4+T cells was dramatically increased. This therapeutic effect of GK was almost completely interrupted in CD4-Eomes conditional knockout mice. Conclusions: These results provided the therapeutic potential of GK treatment in EAE, and further suggested that Eomes expression in CD4+T cells might be essential in this process.

Anaplastic thyroid cancer (ATC) is one of the most aggressive and virulent solid tumors. The ubiquitin proteasome system presents in all eukaryotic cells and is essential for cellular homeostasis. While its underlying role in ATC remains largely unclear. TRIM11 is an E3 ubiquitin ligase and has been reported to act as an oncogene in several human cancers. The present study aims to reveal the oncogenic function of TRIM11 in ATC. Western blot was used to measure the protein expression of TRIM11 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; wound-healing assay and transwell assay were used to measure the migration ability of ATC. The xeno-graft tumor model was used for in vivo study. Immuno-precipitation assay was used to detect the interaction domain between YAP and TRIM11. And the ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. TRIM11 depletion significantly decreases cell proliferation and migration capabilities of ATC cells, and elevates cell sensitivity to chemotherapy, which effect could be further rescued by YAP overexpression. TRIM11 depletion decreases YAP protein level and YAP/TEAD target genes, such as CTGF, ANKRD1 and CYR61 in ATC. Indicating that TRIM11 is a regulator of Hippo signaling pathway. Immuno-precipitation assay shows that the RING domain of TRIM11 is essential for the interaction with WW domain of YAP. Further mechanistic analysis suggests that TRIM11 promotes the mono-ubiquitination of YAP, thus prolongs its protein half. Furthermore, TRIM11 promoter analysis revealed that SOX13 activates TRIM11 transcription by binding to the promoter of TRIM11. In summary, our study describes the oncogenic function of TRIM11 in ATC, which acts as a post-translational modulating factor of Hippo pathway. Targeting TRIM11 may be a potential therapeutic method for ATC treatment.

circular RNA ciRS-7 (ciRS-7) is a type of endogenous circular RNA (circRNA) with a closed circular structure. Since Hansen first demonstrated that ciRS-7 could serve as a microRNA sponge in 2013, researchers have paid increased attention to this circRNA. ciRS-7 plays a crucial role in regulating RNA transcription, downstream gene expression, and protein production. Moreover, ciRS-7 acts as an oncogene and promotes tumor progression through competitively inhibiting miR-7 in various types of cancers. ciRS-7 has been identified to be closely associated with breast cancer, nasopharyngeal carcinoma, lung cancer, hepatocellular carcinoma, cervical cancer, osteosarcoma, melanoma, colorectal cancer, esophageal squamous cell carcinoma, gastric cancer, pancreatic cancer, laryngeal squamous cell carcinoma, and cholangiocarcinoma. In this review, we summarize the biological characteristics, molecular mechanisms, and future challenges of ciRS-7 in multiple tumors.

Melanoma is an aggressive form of skin cancer characterized by rapid invasion and metastasis. CD147 is known to be functioning in cell invasion. In this study, we showed that CD147 was translocated from the cell membrane to the mitochondria in advanced melanoma. Melanoma patients with CD147 localized to the mitochondria confer a worse prognosis. The mitochondrial CD147 levels are correlated with the invasion potential of various melanoma cell lines as well as mitochondrial energy metabolism. Depletion of CD147 decreased the activity of mitochondrial complex V. STRING analysis for protein-protein interaction networks (PPIN) in CD147-depleted melanoma cells showed that mitochondrial proteins HSP60 and ATP5B, a subunit of mitochondrial complex V, were node proteins. HSP60 upregulation was correlated with a worse prognosis of melanoma patients. Co-immunoprecipitation (Co-IP) assay indicates that CD147 interacts with HSP60. These data suggested that mitochondrial CD147 may prompt HSP60 to activate ATP5B, thereby promoting the mitochondrial aerobic oxidation and the invasive abilities of melanoma cells. Correlation analysis of the data acquired from patients was helpful to draw a 5-year survival curve for patients who screened positive and negative for mitochondrial CD147. This study unravels the function of CD147 in tumor invasion and highlights it as a potential tumor therapeutic target.

MicroRNAs (miRNAs) are a class of short non-coding RNAs of approximately 22 nucleotides in length, which function by binding to the 3' UTR sequences of their target mRNAs. It has been reported that dysregulated miRNAs play pivotal roles in numerous diseases, including cancers, such as gastric, breast, colorectal, ovarian, and other cancers. Recent research efforts have been devoted to translating these basic discoveries into clinical applications that could improve the therapeutic outcome in patients with cancer. Early studies have shown that miR-340 may act either as an oncogene or a tumor suppressor by targeting genes related to proliferation, apoptosis, and metastasis, as well as those associated with diagnosis, treatment, chemoresistance, and prognosis. miR-340 has been shown to have a role in other diseases, such as autoimmune diseases, acute stroke, and alcoholic steatohepatitis. Nevertheless, the roles of miR-340 in human malignancies are still unclear, and the associated mechanisms are complex, involving a variety of signaling pathways, such as Wnt/β-catenin and the JAK-STAT pathways. Herein, we review the crucial roles of miR-340 in human cancers through the analysis of the latest research studies, with the aim of clarifying miR-340 function in malignant disease diagnosis, treatment, and prognosis, and to propose further investigations.

The sirtuins family is well known by its unique nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase function. The most-investigated member of the family, Sirtuin 1 (SIRT1), accounts for deacetylating a broad range of transcription factors and coregulators, such as p53, the Forkhead box O (FOXO), and so on. It serves as a pivotal regulator in various intracellular biological processes, including energy metabolism, DNA damage response, genome stability maintenance and tumorigenesis. Although the most attention has been focused on its intracellular functions, the regulatory effect on extracellular microenvironment remodeling of SIRT1 has been recognized by researchers recently. SIRT1 can regulate cell secretion process and participate in glucose metabolism, neuroendocrine function, inflammation and tumorigenesis. Here, we review the advances in the understanding of SIRT1 on remodeling the extracellular microenvironment, which may provide new ideas for pathogenesis investigation and guidance for clinical treatment.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global pandemic that has wreaked havoc globally, which has put a heavy toll on public health, lives, and the world economy. Vaccination is considered as one of the greatest successes in medical history. Based on prior experience with the development of SARS-CoV vaccines, all COVID-19 vaccines must be subjected to the tests for protective effects and harmful risks derived from antibody-dependent enhancement that may contribute to augmented infectivity and/or eosinophilic infiltration. The SARS-CoV-2 vaccine is now being developed urgently in several different ways. China is regarded as one of the world's leading countries in SARS-CoV-2 vaccine development, up to date the last inactivated vaccine international clinical (Phase III) trial was launched in the United Arab Emirates by Sinopharm China National Biotec Group (CNBG). In this review, we outline the current status of vaccine development against clinically relevant SARS-CoV-2 strains, anticipating that such attempts would help create efficacious and sage SARS-CoV-2 vaccines.

Objective: Since December 2019, an outbreak of coronavirus disease 2019 (COVID 19) has been experienced from Wuhan, China to the world. A retrospective cohort study was conducted to summarize the clinical characteristics of patients with COVID-19 and to explore the risk factors affecting the disease duration in Jiangan Fangcang shelter hospital, Wuhan, China. Methods: Clinical characteristics of 409 patients with COVID-19 were retrospectively analyzed. We describe the clinical characteristics and distribution of discharge time or transfer time for each patient. Then we performed univariate and multivariate Cox regression analysis to identify potential risk factors for progression from non-severe to severe COVID-19 or death. Results: The median disease duration of all patients was 23 days (IQR 19-28). The main symptoms of the patient were fever (95.6%), cough (74.3%), tiredness (21.5%), and so on. Comorbidities mainly included hypertension (30.6%) diabetes (17.6%) and heart disease (12.5%). The univariate Cox regression analysis showed that old age, number of symptoms, the combination of hypertension, heart disease and pulmonary disease were associated with the progression of disease. The multivariate Cox regression analysis showed that old age (HR: 7.294; 95% CI: 1.442-36.888; P = 0.016), the combination of hypertension (HR: 2.230; 95% CI: 1.090-4.562; P = 0.028) and heart disease (HR: 2.650; 95% CI: 1.079-6.510; P = 0.034) were independent risk factors for progression of COVID-19. Conclusions: The age of the patient, the combination of hypertension and heart disease were independent risk factors for the progression of COVID-19. Cautions should be raised for patients with these risk factors.

Background: This meta-analysis was aimed to quantitatively assess the associations of metabolic syndrome (MetS) and its components with colorectal cancer (CRC). Methods: PubMed, EMBASE and Web of Science databases were systematically searched for eligible studies. A total of 18 studies for CRC incidence and 12 studies for CRC mortality were identified. Results: MetS was associated with an increased risk of CRC incidence and mortality in male (RR: 1.28, 95 % CI 1.16-1.39, and 1.24, 1.18-1.31, respectively) and correlated with an increased risk of CRC incidence in female (RR: 1.21, 1.13-1.30), but not with CRC mortality in female. MetS increased the risk of cancer-specific mortality (RR: 1.72, 1.03-2.42), but not overall mortality. The risk estimates of CRC incidence changed little depending on age, sex, cancer site, the type of studies, ethnicity, publication year, or definition of MetS. As for CRC mortality, further stratified analyses indicated statistical significance in studies with assessing cancer-specific survival outcome, in male, a cohort design, ethnicity of non-Chinese or with definition of MetS as ≥ 3 metabolic abnormalities. Obesity and hyperglycemia are risk factors of CRC incidence in both male and female. Only dysglycemia is the risk factor for CRC mortality. Conclusions: MetS is associated with an increased risk of CRC incidence and cancer-specific mortality, but not overall mortality. In addition, MetS may increase the CRC mortality in male rather than in female. However, since most of the studies on CRC mortality were conducted in Chinese, further studies are needed to clarify this connection.