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Background: Traditional working procedures requires a lot of clinical processes and processing time. Methods: The orthodontic metal appliances were made by applying oral scanners, digital images, computer-aided design and computer-aided manufacturing (CAD-CAM) printers. Results: The computer digital technology simplified the manufacturing process for dental appliances and shorten the duration for clinical operation and technical processing. Conclusions: The technique described in this paper can guarantee the accuracy of orthodontic appliances and bring revolution the field. Clinical significance: The CAD-CAM technology provides a fully digital workflow for manufacturing metal orthodontic appliances, which saves a considerable amount of labor and material costs, and significantly reduces heavy metal pollution in the working environment of dental technicians.

Abstract Introduction With regard to the esthetics and comfort of orthodontic treatment, the requirement for removable clear aligners (CAs) is increasing. Unlike conventional fixed orthodontic appliances, CAs were made of thermoplastic film by thermoforming on the personalized dental models. The construction of orthodontic thermoplastic is a critical factor for orthodontic tooth movement (OTM). Polyethylene terephthalate glycol-modified (PETG) and thermoplastic polyurethane (TPU) are the most commonly orthodontic thermoplastics; however, the evidence of the differences between different orthodontic thermoplastic are limited to vitro environment and the evidence in vivo environment is not available. Therefore, this trial aims to provide reliable evidence for orthodontists’ personalized treatment plans whether the two most commonly used orthodontic thermoplastics of PETG and TPU have differences in the efficiency of OTM. Methods and analysis This randomized controlled clinical study will recruit 44 orthodontic patients for orthodontic treatment. All the subjects will be randomized into two groups (PETG and TPU, n = 22 for each group). In the first stage (M0 to M1), clear aligners will be made of two orthodontic thermoplastics and move the maxillary first or second premolars 2 mm. In the second stage, patients will take the standard orthodontic treatments. The primary outcome will be the efficiency of clear aligners made of different materials on the digital models. The secondary outcome will be the efficiency of clear aligners made of different materials on the cone-beam computed tomography (CBCT). The efficiency will be calculated through the superimposition of the digital models and CBCT. Discussion The results from this trial will serve as evidence for orthodontists and manufacturers and clarify whether the difference in orthodontic thermoplastics significantly impacts the efficiency of OTM. Trial registration number ChiCTR2300070980. Registered on 27 April 2023. https://www.chictr.org.cn/showproj.html?proj=186253

Abstract Background Gastric cancer patients harboring a TP53 mutation exhibit a more aggressive and chemoresistant phenotype. Unfortunately, efforts to identify the vulnerabilities to overcome these aggressive malignancies have made minimal progress in recent years. Therefore, there is an urgent need to explore the novel therapeutic strategies for this subclass. Histone methylation modulators are critical epigenetic targets for cancer therapies that help maintain the malignancies of cancers harboring TP53 mutations and senescence evasion. Triggering senescence is now considered to benefit multiple cancer therapies. Furthermore, senescence-based “one-two punch” therapy was validated in clinical trials. Therefore, we hypothesized that screening epigenetic modulators might help identify a novel vulnerability to trigger senescence in gastric cancer harboring TP53 mutations. Results We developed a novel efficient approach to identify senescence inducers by sequentially treating cells with drug candidates and senolytic agents. Based on this, we demonstrated that QC6352 (a selective KDM4C inhibitor) efficiently triggered cellular senescence in gastric cancer harboring TP53 mutations. More importantly, the “one-two punch’ therapy consisting of QC6352 and SSK1 eliminates tumor cells harboring TP53 mutations. This finding highlights a potential therapeutic strategy for the aggressive subgroup of gastric cancer. Besides, the functions of QC6352 were totally unknown. We demonstrated that QC6352 might possess far more powerful anti-tumor capacities compared to the traditional genotoxic drugs, 5-Fu and Oxaliplatin. Conclusions This initial investigation to identify a senescence inducer revealed that QC6352 triggers senescence in gastric cancer cells harboring TP53 mutations by regulating the SP1/CDK2 axis through suppressing KDM4C. QC6352 and senolytic agent-SSK1 represent a novel ‘one-two punch’ therapeutic strategy for the more malignant gastric cancer subtypes.

Cloud computing system has the characteristics of large-scale servers and a wide range of users.However, it also consumes a huge number of energy, resulting in high operating costs of cloud providers and high carbon emissions issue.Cloud computing is highly virtualized.How to allocate and manage the virtual resources to ensure efficient physical resource utilization and energy consumption control is a multi-parameter game problem, and it is also a research hotspot in this field.A virtual machine scheduling model and the corresponding SV-GA were proposed, which could calculate the contribution value of the physical machine participating in the work through the Shapley value, and modify the probability parameter of the mutation step in the genetic algorithm through the contribution value, so as to complete the task of virtual machine scheduling.The experimental results show that during the comparison with Max-Min, LrMmt and DE, the SV-GA shows its excellent performance in the multi-parameter game including migration time, times, SLA violation rate and energy consumption in the virtual machine scheduling process.

Background At present, the avoidance of drug shortages mainly relies on expert experience. This study aimed to establish an evaluation index system for the risk of drug shortages in medical institutions in China and to apply the system to guide the graded management of drugs in short supply.Methods A two-round Delphi process was conducted to determine the indicators in the index system. The weight value of each indicator was calculated using analytic hierarchy process (AHP) methods. The data of drugs in short supply from January 1 to December 31, 2020 in Hunan province were collected and evaluated using this index system. The evaluation scores, which ranged from 0 to 100, were calculated.Results A three-level index system with four first-level indicators, 11 second-level indicators, and 36 third-level indicators was constructed by the two rounds of the Delphi process. The expert authority coefficient (Cr) of the first and second rounds of consultation were 0.88 and 0.90, respectively. The Kendall’s coefficients of concordance (Kendall’s W) for the two rounds of consultation were 0.44 and 0.50, respectively (P < .05). For the first-level indicators ‘supply stability,’ ‘causes of shortage,’ ‘medicine availability in medical institution’ and ‘pharmaceutical properties,’ the weight values were 0.3253, 0.2489, 0.2398, and 0.1860, respectively. Based on the risk evaluation score, drugs (dosage strength) at high risk of shortage included sodium thiosulfate (0.64 g), posterior pituitary lobe hormones (1 mL:6 IU), protamine sulfate (5 mL:50 mg), thrombin (500 U), urokinase (10 WU), and rotundine sulfate (2 mL:60 mg).Conclusion An indexed system for the risk assessment of drug shortages in China was established to guide the graded response to drug shortages in medical institutions and the implementation of differential management strategies to address these shortages.

Abstract Aims To examine the effectiveness of D‐dimer values to be used as an independent diagnostic marker for excluding peripherally inserted central catheter‐associated upper extremity deep vein thrombosis and superficial vein thrombosis. Design This was a retrospective case–cohort study. Methods Records were reviewed for 281 patients who underwent peripherally inserted central catheter insertion between 1 October 2017 and 1 October 2019. According to the modified Wells score after peripherally inserted central catheter insertion, the patients who had low vein thrombosis risk underwent a D‐dimer test and colour Doppler ultrasound. Results Among 281 patients, 180 patients (64%, 95% CI: 58.2%–69.4%) had negative D‐dimer results and 39 of 180 patients had vein thrombosis despite having a negative D‐dimer result, resulting in a failure rate of 21.7% (95% CI: 16.3%–28.3%). The negative predictive value of peripherally inserted central catheter‐associated vein thrombosis in the cancer group (80.0%, 95% CI: 73.2%–85.4%) was higher than that of the non‐cancer group (60.0%, 95% CI: 35.7%–80.2%). The negative predictive value of peripherally inserted central catheter‐associated deep venous thrombosis (84.9%, 95% CI: 78.7%–89.6%) was lower than that of the PICC‐associated superficial venous thrombosis (91.0%, 95% CI: 85.4%–94.6%). Conclusion The D‐dimer levels maybe should not be used as a diagnostic index to rule out peripherally inserted central catheter‐associated upper extremity vein thrombosis.

METTL3 catalyzes mRNA m6A deposition. The authors identify an acetylation-mediated regulation of METTL3 subcellular localization and compartment-specific functions, a process that is fine-tuned by anti-inflammatory and pro-inflammatory signals, which ultimately determine breast cancer metastasis.

Introduction Class II treatment with mandibular retrusion often involves the Herbst appliance due to its efficiency and low requirement of cooperation. Despite its advantages, it causes side effects concerning the occlusal plane and pogonion in terms of clockwise rotation that hinder the desired mandibular advancement for hyperdivergent patients. In this study, we will use a newly designed Herbst appliance, and a protocol that is accompanied by TADs for vertical control to avoid maxillary clockwise rotation. We hypothesise that the effect of the Herbst appliance with the vertical control approach will be beneficial for maintaining or even decreasing the skeletal divergence in hyperdivergent class II patients compared with conventional Herbst treatment.Methods and analysis This study is a randomised, parallel, prospective controlled trial that will study the efficacy of Herbst with or without vertical control in children with hyperdivergent skeletal class II malocclusion. A total of 44 patients will be enrolled and randomised in a ratio of 1:1 to either Herbst treatment or Herbst treatment with vertical control. Participants will be recruited at the Shanghai Stomatological Hospital, Shanghai, China. The primary endpoint is the change in the angle indicating the occlusal plane and Sella-Nasion plane from baseline (T0) to the primary endpoint (T2) on cephalometric measurements by lateral X-ray examination. Important secondary outcomes include the root length of the anterior teeth, and the assessment score of the Visual Analogue Scale Questionnaire, etc. Safety endpoints will also be evaluated.Ethics and dissemination This study has been approved by the ethics committee of the Shanghai Stomatological Hospital (Approval No. (2021) 012). Before enrolment, a qualified clinical research assistant will obtain written informed consent from both the participants and their guardians after full explanation of this study. The results will be presented at national or international conferences and published in peer-reviewed journals.Trial registration number ChiCTR2100049860, Chinese Clinical Trial Registry

Artificial intelligence (AI) is a general term that refers to the use of a machine to imitate intelligent behavior for performing complex tasks with minimal human intervention, such as machine learning; this technology is revolutionizing and reshaping medicine. AI has considerable potential to perfect health-care systems in areas such as diagnostics, risk analysis, health information administration, lifestyle supervision, and virtual health assistance. In terms of immunotherapy, AI has been applied to the prediction of immunotherapy responses based on immune signatures, medical imaging and histological analysis. These features could also be highly useful in the management of cancer immunotherapy given their ever-increasing performance in improving diagnostic accuracy, optimizing treatment planning, predicting outcomes of care and reducing human resource costs. In this review, we present the details of AI and the current progression and state of the art in employing AI for cancer immunotherapy. Furthermore, we discuss the challenges, opportunities and corresponding strategies in applying the technology for widespread clinical deployment. Finally, we summarize the impact of AI on cancer immunotherapy and provide our perspectives about underlying applications of AI in the future.

Since most hepatocellular carcinoma (HCC) patients are diagnosed at advanced stages, there is no effective treatment to improve patient survival. Ferroptosis, a regulated cell death driven by iron accumulation and lipid peroxidation, has been reported to play an important role in tumorigenesis. However, the detailed mechanism and biological function of ferroptosis are still incompletely understood in HCC patients. In this study, we analyzed genomic profiles of three HCC datasets, GSE6764, GSE14520, and GSE14323. Venn diagrams were implemented to visualize the overlapping genes between differentially expressed genes and ferroptosis-related gene set. Then, one up-regulated gene, ACSL4, and five down-regulated genes, STEAP3, MT1G, GCH1, HAMP, and CXCL2, were screened. Based on the survival analysis performed by Kaplan-Meier plotter database, ferroptosis-related gene CXCL2 was demonstrated positively-correlated with the patients’ prognosis. Moreover, CXCL2 overexpression significantly inhibited cell growth and improved cellular ROS, Fe2+ and MDA levels in HCC cells Huh7 and MHCC97H, suggesting the roles of CXCL2 in inducing ferroptotic cell death. In addition, aberrantly expressed CXCL2 was negatively associated with malignancy clinical features, such as nodal metastasis and higher grades. The ssGSEA enrichment analysis revealed that CXCL2 co-expressed molecules were mainly involved in inflammation and immune-related pathways, such as acute inflammatory response, humoral immune response, adaptive immune response. TISIDB algorithm indicated the positive correlation between CXCL2 expression and tumor-infiltrating immune cells, including neutrophils and macrophages. Additionally, we also found that CXCL2 was positively correlated with immune infiltration score, and HCC patients with higher score harbored better prognosis. Together, these findings suggested that CXCL2 may enhance ferroptosis sensitivity and regulate immune microenvironment in HCC, and serve as a promising prognosis biomarker for HCC patients.

Abstract Background The purpose of this study is to elucidate the association between peripherally inserted central venous catheter (PICC) in upper extremities and lower extremity deep venous thrombosis (LEDVT) by observing the changes in D-dimer. Methods This was a retrospective cohort study with 3452 patients (104 inserted with PICCs and 3348 without PICC) enrolled at the neurology department from April 1, 2017 to April 1, 2020. The patients underwent color Doppler ultrasound (CDU) and D-dimer examinations. LEDVT-related factors and D-dimer value were analyzed before and after PICC insertion. The predictive value of D-dimer for LEDVT was also evaluated. Results Univariate logistic regression analysis showed that PICC insertion increased the risk of LEDVT by 9 times and promoted the increase of D-dimer by 5 times. After risk adjustment, multivariate logistic regression analysis showed that PICC insertion increased the risk of LEDVT by 4 times and tripled the risk of D-dimer increase. The concentration of D-dimer was significantly increased after PICC insertion. D-dimer was unsuitable for excluding venous thrombosis in patients inserted with PICCs. Conclusions PICC insertion increases the level of D-dimer and the risk of LEDVT. The risks of venous thrombosis need to be assessed in patients inserted with PICCs to ensure the expected clinical outcomes.

Depression has become one of the most common mental diseases in the world, but the understanding of its pathogenesis, diagnosis and treatments remains insufficient. Carnitine is a natural substance that exists in organisms, which can be synthesized in vivo or supplemented by intake. Relationships of carnitine with depression, bipolar disorder and other mental diseases have been reported in different studies. Several studies show that the level of acylcarnitines (ACs) changes significantly in patients with depression compared with healthy controls while the supplementation of acetyl-L-carnitine is beneficial to the treatment of depression. In this review, we aimed to clarify the effects of ACs in depressive patients and to explore whether ACs might be the biomarkers for the diagnosis of depression and provide new ideas to treat depression.

Abstract In the era of the rapid development of cancer immunotherapy, there is a high level of interest in the application of cell-released small vesicles that stimulate the immune system. As cell-derived nanovesicles, exosomes show great promise in cancer immunotherapy because of their immunogenicity and molecular transfer function. The cargoes carried on exosomes have been recently identified with improved technological advances and play functional roles in the regulation of immune responses. In particular, exosomes derived from tumor cells and immune cells exhibit unique composition profiles that are directly involved in anticancer immunotherapy. More importantly, exosomes can deliver their cargoes to targeted cells and thus influence the phenotype and immune-regulation functions of targeted cells. Accumulating evidence over the last decade has further revealed that exosomes can participate in multiple cellular processes contributing to cancer development and therapeutic effects, showing the dual characteristics of promoting and suppressing cancer. The potential of exosomes in the field of cancer immunotherapy is huge, and exosomes may become the most effective cancer vaccines, as well as targeted antigen/drug carriers. Understanding how exosomes can be utilized in immune therapy is important for controlling cancer progression; additionally, exosomes have implications for diagnostics and the development of novel therapeutic strategies. This review discusses the role of exosomes in immunotherapy as carriers to stimulate an anti-cancer immune response and as predictive markers for immune activation; furthermore, it summarizes the mechanism and clinical application prospects of exosome-based immunotherapy in human cancer.

Abstract Extrachromosomal circular DNA was recently found to be particularly abundant in multiple human cancer cells, although its frequency varies among different tumor types. Elevated levels of extrachromosomal circular DNA have been considered an effective biomarker of cancer pathogenesis. Multiple reports have demonstrated that the amplification of oncogenes and therapeutic resistance genes located on extrachromosomal DNA is a frequent event that drives intratumoral genetic heterogeneity and provides a potential evolutionary advantage. This review highlights the current understanding of the extrachromosomal circular DNA present in the tissues and circulation of patients with advanced cancers and provides a detailed discussion of their substantial roles in tumor regulation. Confirming the presence of cancer-related extrachromosomal circular DNA would provide a putative testing strategy for the precision diagnosis and treatment of human malignancies in clinical practice.

Abstract Background Growing evidence has shown that the gut-renal connection and gut microbiota dysbiosis play a critical role in immunoglobulin A nephropathy (IgAN). However, the fecal microbiome profile in Chinese patients with IgAN remains unknown. A cross-sectional study was designed for the first time to investigate the fecal microbiota compositions in patients with primary IgAN in China and to evaluate the relationship between the fecal microbiome and IgAN clinical presentation. Methods Fecal samples were collected from 17 IgAN patients and 18 age-, sex-, and body mass index-matched healthy controls, and bacterial DNA was extracted for 16S ribosomal RNA gene sequencing targeting the V3-V4 region. Results Fecal samples from the IgAN patients and healthy controls showed differences in gut microbiota community richness and compositions. Compared to the healthy controls, IgAN patients at the phylum level had an increased abundance of Fusobacteria, but a decreased abundance of Synergistetes. The significantly increased genera in the IgAN group were Escherichia-Shigella, Hungatella, and Eggerthella, all of which possess pathogenic potential. Furthermore, the genus Escherichia-Shigella was negatively associated with the estimated glomerular filtration rate (eGFR) but was positively associated with the urinary albumin-to-creatinine ratio (uACR). However, the genus rectale_group was present in the IgAN group with a low abundance and was negatively associated with the uACR. Functional analysis disclosed that infection-related pathways were enriched in the IgAN group. Conclusions We demonstrate that gut microbiota dysbiosis occurs in patients with IgAN, and that changes in gut bacterial populations are closely related to IgAN clinical features, suggesting that certain specific gut microbiota may be a potential therapeutic target for IgAN.

Overall, 12% of the global population (800 million) suffers from liver disease, which causes 2 million deaths every year. Liver injury involving characteristic reactive oxygen/nitrogen species (RONS) and inflammation plays a key role in progression of liver disease. As a key metabolic organ of the human body, the liver is susceptible to injury from various sources, including COVID-19 infection. Owing to unique structural features and functions of the liver, most current antioxidants and anti-inflammatory drugs are limited against liver injury. However, the characteristics of the liver could be utilized in the development of nanodrugs to achieve specific enrichment in the liver and consequently targeted treatment. Nanodrugs have shown significant potential in eliminating RONS and regulating inflammation, presenting an attractive therapeutic tool for liver disease through controlling liver injury. Therefore, the main aim of the current review is to provide a comprehensive summary of the latest developments contributing to our understanding of the mechanisms underlying nanodrugs in the treatment of liver injury via harnessing RONS and inflammation. Meanwhile, the prospects of nanodrugs for liver injury therapy are systematically discussed, which provides a sound platform for novel therapeutic insights and inspiration for design of nanodrugs to treat liver disease.

Ferroptosis is an iron-dependent cell death process that plays important regulatory roles in the occurrence and development of cancers, including hepatocellular carcinoma (HCC). Moreover, the molecular events surrounding aberrantly expressed long non-coding RNAs (lncRNAs) that drive HCC initiation and progression have attracted increasing attention. However, research on ferroptosis-related lncRNA prognostic signature in patients with HCC is still lacking. In this study, the association between differentially expressed lncRNAs and ferroptosis-related genes, in 374 HCC and 50 normal hepatic samples obtained from The Cancer Genome Atlas (TCGA), was evaluated using Pearson’s test, thereby identifying 24 ferroptosis-related differentially expressed lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression model were used to construct and validate a prognostic risk score model from both TCGA training dataset and GEO testing dataset (GSE40144). A nine-lncRNA-based signature (CTD-2033A16.3, CTD-2116N20.1, CTD-2510F5.4, DDX11-AS1, LINC00942, LINC01224, LINC01231, LINC01508, and ZFPM2-AS1) was identified as the ferroptosis-related prognostic model for HCC, independent of multiple clinicopathological parameters. In addition, the HCC patients were divided into high-risk and low-risk groups according to the nine-lncRNA prognostic signature. The gene set enrichment analysis enrichment analysis revealed that the lncRNA-based signature might regulate the HCC immune microenvironment by interfering with tumor necrosis factor α/nuclear factor kappa-B, interleukin 2/signal transducers and activators of transcription 5, and cytokine/cytokine receptor signaling pathways. The infiltrating immune cell subtypes, such as resting memory CD4(+) T cells, follicular helper T cells, regulatory T cells, and M0 macrophages, were all significantly different between the high-risk group and the low-risk group as indicated in Spearman’s correlation analysis. Moreover, a substantial increase in the expression of B7H3 immune checkpoint molecule was found in the high-risk group. Our findings provided a promising insight into ferroptosis-related lncRNAs in HCC and a personalized prediction tool for prognosis and immune responses in patients.

Although STK38 (serine-threonine kinase 38) has been proven to play an important role in cancer initiation and progression based on a series of cell and animal experiments, no systemic assessment of STK38 across human cancers is available. We firstly performed a pan-cancer analysis of STK38 in this study. The expression level of STK38 was significantly different between tumor and normal tissues in 15 types of cancers. Meanwhile, a prognosis analysis showed that a distinct relationship existed between STK38 expression and the clinical prognosis of cancer patients. Furthermore, the expression of STK38 was related to the infiltration of immune cells, such as NK cells, memory CD4+ T cells, mast cells and cancer-associated fibroblasts in a few cancers. There were three immune-associated signaling pathways involved in KEGG analysis of STK38. In general, STK38 shows a significant prognostic value in different cancers and is closely associated with cancer immunity.

Abstract Genomic amplification of OTUD7B is frequently found across human cancers. But its role in tumorigenesis is poorly understood. Lysine‐specific demethylase 1 (LSD1) is known to execute epigenetic regulation by forming corepressor complex with CoREST/histone deacetylases (HDACs). However, the molecular mechanisms by which cells maintain LSD1/CoREST complex integrity are unknown. Here, it is reported that LSD1 protein undergoes K63‐linked polyubiquitination. OTUD7B is responsible for LSD1 deubiquitination at K226/277 residues, resulting in dynamic control of LSD1 binding partner specificity and cellular homeostasis. OTUD7B deficiency increases K63‐linked ubiquitination of LSD1, which disrupts LSD1/CoREST complex formation and targets LSD1 for p62‐mediated proteolysis. Consequently, OTUD7B deficiency impairs genome‐wide LSD1 occupancy and enhances the methylation of H3K4/H3K9, therefore profoundly impacting global gene expression and abrogating breast cancer metastasis. Moreover, physiological fluctuation of OTUD7B modulates cell cycle‐dependent LSD1 oscillation, ensuring the G1/S transition. Both OTUD7B and LSD1 proteins are overpresented in high‐grade or metastatic human breast cancer, while dysregulation of either protein is associated with poor survival and metastasis. Thus, OTUD7B plays a unique partner‐switching role in maintaining the integrity of LSD1/CoREST corepressor complex, LSD1 turnover, and breast cancer metastasis.

Background: The aim of this study was to describe the sleep quality and its influencing factors among medical workers of different working statuses and staff types during the coronavirus disease 2019 (COVID-19) epidemic.Methods: Through an online questionnaire survey, all medical staffs in Xiangya Hospital were invited to complete sections on general information, the Self-Rating Scale of Sleep (SRSS), the Depression, Anxiety and Stress Scale (DASS-21), the Social Support Rating Scale (SSRS), and the Simplified Coping Style Questionnaire (CSQ).Results: A total of 4,245 respondents completed the survey. Among them, 38.7% had sleep disturbance. After matching, the SRSS scores in the staffs who were assigned to the intensive care unit (ICU) of Union Hospital in Wuhan and working in the epidemic area of Xiangya Hospital were not significantly different (P > 0.05); the SRSS scores in the battlefront staffs were significantly higher than (P < 0.05) those who were not treating patients infected with COVID-19. The SRSS scores of nurses were significantly higher than those of doctors and hospital administrators (P < 0.01). Anxiety, depression, and coping style were associated with sleep disturbance.Conclusion: The sleep quality of the medical staffs has been impaired during the epidemic period, especially among nurses, doctors, and administrators who are working on the front line. Medical institutions should strengthen psychological services and coping strategies for medical staffs.

Abstract Cancer-associated fibroblasts (CAFs) plays an essential role in cancer cell growth, metabolism and immunoreaction. Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. Targeting autophagy has gained interest with multiple preclinical and clinical trials, such as the pharmacological inhibitor chloroquine or the inducer rapamycin, especially in exploiting its ability to modulate the secretory capability of CAFs to enhance drug delivery or inhibit it to prevent its influence on cancer cell chemoresistance. In this review, we summarize the reports on autophagy in cancer-associated fibroblasts by detailing the mechanism and role of autophagy in CAFs, including the hypoxic-autophagy positive feedback cycle, the metabolic cross-talk between CAFs and tumors induced by autophagy, CAFs secreted cytokines promote cancer survival by secretory autophagy, CAFs autophagy-induced EMT, stemness, senescence and treatment sensitivity, as well as the research of antitumor chemicals, miRNAs and lncRNAs. Additionally, we discuss the evidence of molecules in CAFs that are relevant to autophagy and the contribution to sensitive treatments as a potential target for cancer treatment.

Background: Health literacy is essential to population health, yet few studies have described the geographic variation in health literacy in China. This study aimed to investigate the level of health literacy, its regional heterogeneities, as well as influencing factors of health literacy in 25 provinces or municipalities in China.Methods: The study was conducted among residents aged 15–69 years from 25 provinces or municipalities in China in 2017. Health literacy was measured using the Chinese Health Literacy Scale. MapInfo software was used to map the geographic distribution. Multiple logistic regression was used to adjust for the factors associated with the health literacy level in the overall and regional samples.Results: A total of 3,482 participants were included in the study, comprising 1,792 (51.5%) males and 1,690 (48.5%) females. Notable geographic variation was observed in health literacy levels. The proportion of respondents with adequate health literacy was 22.3% overall, 33.0% in the eastern region, 23.1% in the central region, and 17.6% in the western region. The proportion of adequate health literacy in the different provinces and municipalities ranged from 10.5% (Xinjiang) to 47.0% (Beijing). Being a female [odds ratio (OR) = 1.353; 95% confidence interval (CI): 1.146–1.597], having a high education level [OR ranging from 2.794 (CI: 1.469–5.314) to 9.458 (CI: 5.251–17.036)], having a high economic status [OR ranging from 1.537 (CI: 1.248–1.891) to 1.850 (CI: 1.498–2.284)], having a good self-rated health status [OR ranging from 2.793 (CI: 1.534–5.083) to 3.003 (CI: 1.672–5.395)], and having frequent community health education (OR = 1.588; 95% CI: 1.066–2.365) were independently associated with adequate health literacy.Conclusions: The health literacy level in the 25 provinces or municipalities of China is relatively low compared to the developed countries, and there are heterogeneities among different regions, between urban and rural areas, and among different social groups. Tailored health education and promotion strategies are needed for different subgroups of residents.

Circadian rhythms are physical, behavioral and environmental cycles that respond primarily to light and dark, with a period of time of approximately 24 h. The most essential physiological functions of mammals are manifested in circadian rhythm patterns, including the sleep-wake cycle and nutrient and energy metabolism. Autophagy is a conserved biological process contributing to nutrient and cellular homeostasis. The factors affecting autophagy are numerous, such as diet, drugs, and aging. Recent studies have indicated that autophagy is activated rhythmically in a clock-dependent manner whether the organism is healthy or has certain diseases. In addition, autophagy can affect circadian rhythm by degrading circadian proteins. This review discusses the interaction and mechanisms between autophagy and circadian rhythm. Moreover, we introduce the molecules influencing both autophagy and circadian rhythm. We then discuss the drugs affecting the circadian rhythm of autophagy. Finally, we present the role of rhythmic autophagy in nutrient and energy metabolism and its significance in physiology and metabolic disease.

Intracerebral hemorrhage (ICH) is a disease with a significantly high rate of morbidity, mortality and disability. Inhibition of inflammation is considered a potential strategy for improving the clinical symptoms induced by ICH. The hallmark of neuroinflammation is microglial activation. Microglia can polarize into either the classically activated M1 (proinflammatory) phenotype, exacerbating neuronal damage, or the alternatively activated M2 (antiinflammatory) phenotype, exerting neuroprotection and promoting neuronal recovery. Promoting microglial polarization to the M2 phenotype may be a viable strategy for treating neuroinflammation. Several studies have indicated that promoting blood circulation and removing blood stasis exhibits therapeutic effects on intracerebral hemorrhage. Dahuang Zhechong Pill (DHZCP), a classical recipe that promotes blood circulation and removes blood stasis, has been reported to improve the clinical outcome of ICH. DHZCP has been shown to exert antiinflammatory effects. However, the detailed antiinflammatory mechanism of DHZCP in ICH has rarely been investigated. In this study, DHZCP inhibited lipopolysaccharide (LPS)-induced M1 microglial activation. DHZCP exerted antiinflammatory effects, by inhibiting LPS-induced M1 proinflammatory cytokine (TNF-α and IL-6), and iNOS production and increasing M2 antiinflammatory cytokine (IL-10) production. DHZCP also switched microglial polarization from M1 to M2, as indicated by significantly increased expression of M2 polarization markers (CD209, and CD206) and markedly decreased expression of an M1 polarization marker (CD54). In addition, DHZCP inhibited p38 and TLR4/NF-κB signaling activation, as demonstrated by inhibition of LPS-induced increases in p-p38, TLR4 and nuclear factor kappa B p-65 (NF-κB p-65) protein expression. Taken together, DHZCP modulates microglial M1/M2 polarization via the p38 and TLR4/NF-κB signaling pathways to confer antiinflammatory effects.

Purpose Renin-angiotensin system blockers (RASBs), which include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-2 receptor 1 blockers (ARBs), have been reported to be associated with lung cancer metastasis, radiotherapy and chemotherapy. Until now, very limited clinical data for RASBs’ diagnostic and prognostic effects has existed for lung cancer chemotherapy in Chinese patients. Methods There were a total of 678 lung cancer patients with hypertension, of which 461 (68%) were in the non-RASBs group and 217 (32%) were in the RASBs group. Patients’ gender, age, smoking status, histologic differentiation, tumor size, pathological grade, lymph node metastasis, pathological stage and progression-free survival (PFS) were retrospectively analyzed between these two groups. The clinical effects of ACEIs and ARBs in lung cancer patients were compared via t tests, and χ2 test, and potential prognostic factors for progression-free survival (PFS) were evaluated by Kaplan–Meier analysis. Results Significant differences were observed in lymph node metastasis between the RASBs and non-RASBs groups. The RASBs group (62.8% vs 71.7%, p = 0.037) and ARBs group (60.0% vs 71.7%, p = 0.030) had lower lymph node metastasis, and patients with RASBs had a lower pathological stage than those in non-RASBs groups (67.1% vs 77.4%, p = 0.044 ). The PFS of the RASBs (10.7 vs. 6.7 months, p = 0.040) and ACEIs (12.9 vs 6.7 months, p = 0.021) groups were longer than that of the non-RASBs group, while no statistical difference was shown between the ACEIs and ARBs groups. Moreover, the significant results of PFS were further confirmed in pathological stage III–IV patients. In the non-RASB group, 55% of patients took calcium channel blockers (CCBs), and the ACEIs group have a significantly longer PFS compared to the non-CCBs group (6.4 vs 12.9 months, p = 0.036). Conclusion In this study, we showed that the use of RASBs is a positive factor for pathological stage and prognosis of lung cancer patients. Therefore, it is necessary to actively evaluate medical history, especially the use of anti-hypertension medication, in patients with lung cancer and reflect medical history in the treatment and management plans of these patients.

Abstract Background The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive. Methods Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with γH2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of γH2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models. Results PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clonogenicity, and synergistically induced cell apoptosis and DNA damage, while had no detectable toxicity to normal prostate epithelial cells. Mechanistically, veliparib or SAHA alone reduced BRCA1 or UHRF1 protein levels, co-treatment with veliparib and SAHA synergistically reduced BRCA1 protein levels by targeting the UHRF1/BRCA1 protein complex, the depletion of UHRF1 resulted in the degradation of BRCA1 protein, while the elevation of UHRF1 impaired co-treatment-reduced BRCA1 protein levels. Co-administration of both drugs synergistically decreased the growth of xenografts. Conclusions Our studies revealed that the synergistic lethality of HDAC and PARP inhibitors resulted from promoting DNA damage and inhibiting HR DNA damage repair pathways, in particular targeting the UHRF1/BRCA1 protein complex. The synergistic lethality of veliparib and SAHA shows great potential for future PCa clinical trials.

BackgroundLncRNAs have been shown to play essential roles in cancer therapeutic response. However, the detailed mechanism of lncRNAs in temozolomide (TMZ) resistance in glioblastoma (GBM) remain to be elucidated.MethodsTo elucidate the mechanism maintaining TMZ resistance, we constructed two TMZ-resistant GBM cell lines (T98G-R/U118-R). LncRNAs from four public datasets were reanalyzed, and the candidate lncRNA ADAMTS9-AS2 was evaluated in TMZ-treated GBM patients and in vitro cell lines.ResultsReanalysis of lncRNA expression profiles identified ADAMTS9-AS2 as significantly overexpressed in TMZ-resistant GBM cells and as positively associated with the IC50 of TMZ in GBM cells. Overexpression of ADAMTS9-AS2 was also significantly associated with poor TMZ response and shorter progression-free survival (PFS) in TMZ-treated GBM patients. Knockdown of ADAMTS9-AS2 inhibited proliferation and attenuated the IC50 of TMZ, as well as mitigating invasion and migration in TMZ-resistant GBM cells. Subsequent investigations indicated that reduced expression of ADAMTS9-AS2 significantly suppressed expression of the FUS protein, which was predicted as a direct substrate of ADAMTS9-AS2. Expression trends of FUS were directly correlated with those of ADAMTS9-AS2, as shown by increasing concentrations and prolonged treatment with TMZ. RNA pull-down and RIP assays indicated that both endogenous and exogenous ADAMTS9-AS2 directly binds to the RRM and Znf_RanBP2 domains of FUS, consequently increasing FUS protein expression. Knockdown of ADAMTS9-AS2 reduced the half-life of FUS and decreased FUS protein stability via K48 ubiquitin degradation. Moreover, the E3 ubiquitin-protein ligase MDM2 interacts with and down regulates FUS, while the RRM and Znf_RanBP2 domains of FUS facilitate its binding with MDM2. ADAMTS9-AS2 decreased the interaction between MDM2 and FUS, which mediates FUS K48 ubiquitination. Additionally, knockdown of the ADAMTS9-AS2/FUS signaling axis significantly alleviated progression and metastasis in TMZ-resistant cells.ConclusionADAMTS9-AS2 possessed a novel function that promotes TMZ resistance via upregulating the FUS/MDM2 axis in GBM cells. The RRM or Znf_RanBP2 domains of FUS facilitate the combination of ADAMTS9-AS2 and FUS, competitively inhibiting MDM2-dependent FUS K48 ubiquitination and resulting in enhanced FUS stability and TMZ resistance. Our results suggest that the ADAMTS9-AS2/FUS/MDM2 axis may represent a suitable prognostic biomarker and a potential target in TMZ-resistant GBM therapy.

Nafamostat mesylate (NM), a synthetic serine protease inhibitor first placed on the market by Japan Tobacco in 1986, has been approved to treat inflammatory-related diseases, such as pancreatitis. Recently, an increasing number of studies have highlighted the promising effects of NM in inhibiting cancer progression. Alone or in combination treatments, studies have shown that NM attenuates various malignant tumors, including pancreatic, colorectal, gastric, gallbladder, and hepatocellular cancers. In this review, based on several activating pathways, including the canonical Nuclear factor-κB (NF-κB) signaling pathway, tumor necrosis factor receptor-1 (TNFR1) signaling pathway, and tumorigenesis-related tryptase secreted by mast cells, we summarize the anticancer properties of NM in existing studies both in vitro and in vivo. In addition, the efficacy and side effects of NM in cancer patients are summarized in detail. To further clarify NM's antitumor activities, clinical trials devoted to validating the clinical applications and underlying mechanisms are needed in the future.

Objective Aloperine (ALO), an alkaloid isolated from the leaves of Sophora alopecuroides, has been suggested to exhibit anti-inflammatory and anti-tumor properties and is traditionally used to treat various human diseases, including cancer. However, limited information is available about the mechanisms that determine the anti-tumor activities of ALO. Methods Herein, through comprehensive bioinformatics methods and in vitro functional analyses, we evaluated the detailed anti-tumor mechanisms of ALO. Results Using the databases Bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine and PubChem Project, we identified the potential targets of ALO. A protein–protein interaction network was constructed to determine the relationship among these probable targets. Functional enrichment analysis revealed that ALO is potentially involved in the induction of apoptosis. In addition, molecular docking demonstrated that ALO expectedly docks into the active pocket of the Bcl2 protein, suggesting Bcl2 as a direct target of ALO. Moreover, western blot and qPCR analysis showed that ALO downregulated Bcl2 expression in human glioma cell lines, SK-N-AS and U118. Using flow cytometry methods, we further confirmed that ALO significantly promotes apoptosis in SK-N-AS and U118 cell lines, similar to the effect induced by ABT-737, a well-known Bcl2 inhibitor. In addition, Bcl-2 overexpression could rescue ALO-induced Bcl-2 inhibition and suppress pro-apoptotic effects in glioma cells. Conclusion Taken together, these findings suggest that the natural agent ALO effectively enhances apoptosis by acting as a potential Bcl2 inhibitor in human glioma cells.

Neurotrophic receptor tyrosine kinase 2 (NTRK2) is a member of the tropomyosin receptor kinase family associated with the tumor development. However, the detailed function of NTRK2 in lung cancer, especially in lung adenocarcinoma (LUAD), is still not fully understood. Here, we investigated the effects of NTRK2 on LUAD biology. Through analyzing bioinformatics data derived from several databases, such as Oncomine, Gene Expression Profiling Interactive Analysis and UALCAN, we found that NTRK2 expression was significantly decreased in LUAD tissues. Clinical data acquired from Wanderer database, which is linked to The Cancer Genome Atlas database, demonstrated that the expression and methylation site of NTRK2 were significantly related to the clinical characteristics and prognosis of LUAD. Furthermore, NTRK2 expression was increased remarkably after treatment with the protein kinase B (AKT) inhibitor MK2206 and the anticancer agent actinomycin D. Functional enrichment analysis of NTRK2-associated coexpression genes was further conducted. Together, our results suggested that downregulated NTRK2 might be used in the diagnostic and prognostic evaluation of LUAD patients, or as a potential therapeutic target for the treatment of LUAD.

Adenosine deaminase RNA-specific B1 (ADARB1), an adenosine-to-inosine (A-to-I) RNA-editing enzyme, has been found to play an essential role in the development of cancer. However, the specific function of ADARB1 in lung cancer, especially in lung adenocarcinoma (LUAD), is still not fully understood and requires further study. In our study, integrative bioinformatics were used to analyze the detailed function of ADARB1 in LUAD. By conducting bioinformatics analyses of several public databases, such as Gene Expression Profiling Interactive Analysis (GEPIA), GE-mini, and Oncomine, we found significantly decreased ADARB1 expression in LUAD cells and tissues. Moreover, RT-PCR and Western blot showed lower ADARB1 expression in H358 and A549 LUAD cells compared to human bronchial epithelial Beas-2B cells. Wound Healing Assay indicated that knockdown ADARB1 could promote LUAD cell metastasis. By using the Kaplan-Meier Plotter tool, we found that downregulation of ADARB1 was related to shorter first progression (FP), overall survival time (OS) and post-progression survival time (PPS). The relevant clinical data acquired from the Wanderer database indicated that the expression and methylation values of ADARB1 were significantly associated with the clinical characteristics of LUAD. Using DNA methylation inhibitor, we found DNMT inhibitor 5-aza-2-deoxycytidine (5-azaD) could promote the expression of ADARB1 and reverse the inhibition effect of ADARB1 in migration. In addition, functional enrichment analysis of ADARB1-associated coexpression genes was further conducted. Our investigation demonstrated that low levels of ADARB1 were specifically found in LUAD, and this gene might be a potential target in the diagnostic and prognostic evaluation of LUAD patients.

Zinc level in the body is finely regulated to maintain cellular function. Dysregulation of zinc metabolism may induce a variety of diseases, e.g., diabetes. Zinc participates in insulin synthesis, storage, and secretion by functioning as a “cellular second messenger” in the insulin signaling pathway and glucose homeostasis. The highest zinc concentration is in the pancreas islets. Zinc accumulation in cell granules is manipulated by ZnT8, a zinc transporter expressed predominately in pancreatic α and β cells. A common ZnT8 gene (SLC30A8) polymorphism increases the risk of type 2 diabetes mellitus (T2DM), and rare mutations may present protective effects. In type 1 diabetes mellitus (T1DM), autoantibodies show specificity for binding two variants of ZnT8 (R or W at amino acid 325) dictated by a polymorphism in SLC30A8. In this review, we summarize the structure, feature, functions, and polymorphisms of ZnT8 along with its association with diabetes and explore future study directions.

Marsdenia tenacissima (MT), a traditional Chinese herbal medicine, has long been used for thousands of years to treat asthma, tracheitis, rheumatism, etc. An increasing number of recent studies have focused on the antitumor effects of MT. The effects of MT on cancer are the result of various activated signaling pathways and inhibiting factors and the high expression levels of regulatory proteins. MT can inhibit different cancer types including non-small cell lung cancer (NSCLC), malignant tumors, hepatic carcinoma, and so on. This article mainly focuses on the activities and mechanisms of MT. In addition, the efficacy and toxicity of MT are also discussed. Further studies of MT are required for improved medicinal utilization.

Resistance to temozolomide (TMZ), the standard chemotherapy agent for glioblastoma (GBM), poses a major clinical challenge to GBM prognosis. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. Recent studies suggest that bioenergetic alterations of cancer cells play important roles in drug resistance. In our study, the altered metabolism of cancer cells was observed using a metabolic PCR array. We found that stearoyl-coenzyme A desaturase 1 (SCD1), a key rate-limiting enzyme for synthesis of monounsaturated fatty acids, was significantly upregulated in TMZ-resistant GBM cells compared to their parental counterparts. Overexpression of SCD1 promoted resistance to TMZ in parental GBM cells, whereas SCD1 downregulation by siRNA could re-sensitize TMZ-resistant cells in vitro. Combinational treatment of TMZ and an SCD1-specific inhibitor showed a combined inhibitory effect on TMZ-resistant glioma cells. We also observed that overexpression of SCD1 promoted Akt/GSK3β/β-catenin signaling, while silencing of SCD1 inhibited the signaling. The combination of an Akt activator with exogenous SCD1 or the combined inhibition of Akt and enforced expression of SCD1 resulted in the most significant changes of Akt signaling. Functionally, significantly lower viability and mobility rates were observed in TMZ-resistant cells when treated with Akt inhibitors and an SCD1 inhibitor simultaneously compared to when treated individually. In conclusion, our study identified SCD1 along with its functional pathway as a novel target in the development of TMZ resistance. SCD1 inhibition used alone or in combination with Akt inhibition could effectively overcome TMZ resistance in gliomas.

Natural compound licochalcone A (lico A), a main constituent of flavonoids, has been proved to induce ER stress and apoptosis in cancer cells. However, the underlying anti-tumor mechanism of lico A remains to be clarified in detail. A recently-published report from the journal Frontiers in Pharmacology evaluated the miRNA-based mechanism for lico A on its anti-cancer effect. They found that lico A significantly promoted the tumor-suppressor miR-144-3p expression, so as to up-regulate ER stress-response protein CHOP (CCAAT/-enhancer-binding protein homologous protein) by down-regulating nuclear factor E2-related factor 2 (Nrf2), finally inducing apoptotic cell death in lung cancer. Their findings pave the path toward a more understanding of miRNA-based drugs for cancer treatment in the future. Keywords: Lico A, ER stress, Apoptosis, miR-144-3p, Lung cancer, Anti-cancer therapeutics

Radiotherapy is a powerful tool in the treatment of cancer that has the advantage of preserving normal tissues. However, tumor radioresistance currently remains a major impediment to effective RT. Thus, exploring effective radiation sensitizers is urgently needed. In this study, we have shown that diosmetin, the aglycone of the lavonoid glycoside from olive leaves, citrus fruits and some medicinal herbs, has a promising effect on radiotherapy sensitization. In our results, DIO could induce G1 phase arrest and thus enhance the radiosensitivity of radioresistant A549/IR lung cancer cells. Furthermore, DIO also restrains the IR-induced DNA damage repair by inhibiting the activated Akt signaling pathway. The combination of Akt inhibition (DIO, LY294002 or MK-2206) and radiation potently blocked A549/IR cancer cell proliferation. In summary, these observations suggest that the natural compound DIO could act as a potential drug for the treatment of radioresistant lung cancer cells.

Tigecycline (TIG), the first member of glycylcycline bacteriostatic agents, has been approved to treat complicated infections in the clinic because of its expanded-spectrum antibiotic potential. Recently, an increasing number of studies have emphasized the anti-tumor effects of TIG. The inhibitory effects of TIG on cancer depend on several activating signaling pathways and abnormal mitochondrial function in cancer cells. The aim of this review is to summarize the cumulative anti-tumor evidence supporting TIG activity against different cancer types, including acute myeloid leukemia (AML), glioma, non-small cell lung cancer (NSCLC), among others. In addition, future clinical trials are discussed that will evaluate the security and validate the underlying the tumor-killing properties of TIG.

BACKGROUND: Follicular stimulating hormone (FSH) is a glycoprotein and widely used for the treatment of infertility; FSH action is mediated by FSH receptor (FSHR), SNPs of which determine the ovarian response. Two polymorphisms of the FSHR gene were identified, which caused a change of threonine (T) to alanine (A) at position 307 and asparagine (N) to serine(S) at position 680. Both polymorphic sites give rise to three discrete variants of the FSHR: TT, TA, and AA for position 307; NN, NS, and SS for position 680. METHODOLOGY/PRINCIPAL FINDINGS: 450 Chinese women were recruited in an assisted reproductive technology program from October 2011 to March 2012. FSHR polymorphisms at the positions 307 and 680 were examined by PCR-RFLP. Serum FSH and estradiol level, FSH amount, ovarian response and pregnancy rate were recorded during treatment. The basal FSH levels were higher in AA [7.38 ± 2.07 vs 6.34 ± 1.75, 6.63 ± 1.94, P