Efficacy tumor therapeutic applications of stimuli-responsive block copolymer-based nano-assemblies.

Block copolymers are composed of two or more blocks or segments with different chemical properties via various chemical bonds, which can assemble into nanoparticles with a "core-shell" structure. Due to the benefits of simple functionalization, superior drug-loading capacity, and good biocompatibility, various nano-assemblies based on block copolymers have become widely applied in the treatment of cancers in recent years. These nano-assemblies serve as carriers for anti-tumor bioactive, enhancing drug stability and prolonging their circulation time in vivo, which can reduce the toxic side effects of drugs and improve the therapeutic effect. However, the complex and heterogeneous tumor microenvironment poses challenges to the therapeutic efficacy of these nano-assemblies, having the result in the occurrence of drug resistance and the recurrence of tumors. Consequently, a diverse array of stimuli-responsive nano-assemblies has been devised in order to surmount these obstacles. This article provides a comprehensive overview of the utilization of stimuli-responsive nano-assemblies derived from block copolymers in the context of tumor treatment. The review summarizes block polymers responsive to internal stimuli (like ROS, redox, pH, and enzymes) and external stimuli (like light, and temperature), and discusses current challenges and prospects in this field, aiming to provide novel insights for clinical applications.

Unveiling the complexity of early childhood caries: Candida albicans and Streptococcus mutans cooperative strategies in carbohydrate metabolism and virulence.

Objective: To explore the mechanisms underlying the virulence changes in early childhood caries (ECC) caused by Candida albicans (C. albicans) and Streptococcus mutans (S. mutans), with a focus on carbohydrate metabolism and environmental acidification. Methods: A review of literature was conducted to understand the symbiotic relationship between C. albicans and S. mutans, and their role in the pathogenesis of ECC. The review also examined how their interactions influence carbohydrate metabolism and environmental acidification in the oral cavity. Results: C. albicans and S. mutans play crucial roles in the onset and progression of ECC. C. albicans promotes the adhesion and accumulation of S. mutans, while S. mutans creates an environment favorable for the growth of C. albicans. Their interactions, especially through carbohydrate metabolism, strengthen their pathogenic potential. The review highlights the importance of understanding these mechanisms for the development of effective management and treatment protocols for ECC. Conclusion: The symbiotic relationship between C. albicans and S. mutans, and their interactions through carbohydrate metabolism and environmental acidification, are key factors in the pathogenesis of ECC. A comprehensive understanding of these mechanisms is crucial for developing effective strategies to manage and treat ECC.

Exhaled breath and urinary volatile organic compounds (VOCs) for cancer diagnoses, and microbial-related VOC metabolic pathway analysis: a systematic review and meta-analysis.

BACKGROUND: The gradual evolution of the detection and quantification of volatile organic compounds (VOCs) has been instrumental in cancer diagnosis. The primary objective of this study was to assess the diagnostic potential of exhaled breath and urinary VOCs in cancer detection. As VOCs are indicative of tumor and human metabolism, our work also sought to investigate the metabolic pathways linked to the development of cancerous tumors. MATERIALS AND METHODS: An electronic search was performed in the PubMed database. Original studies on VOCs within exhaled breath and urine for cancer detection with a control group were included. A meta-analysis was conducted using a bivariate model to assess the sensitivity and specificity of the VOCs for cancer detection. Fagan's nomogram was designed to leverage the findings from our diagnostic analysis for the purpose of estimating the likelihood of cancer in patients. Ultimately, MetOrigin was employed to conduct an analysis of the metabolic pathways associated with VOCs in relation to both human and/or microbiota. RESULTS: The pooled sensitivity, specificity and the area under the curve for cancer screening utilizing exhaled breath and urinary VOCs were determined to be 0.89, 0.88, and 0.95, respectively. A pretest probability of 51% can be considered as the threshold for diagnosing cancers with VOCs. As the estimated pretest probability of cancer exceeds 51%, it becomes more appropriate to emphasize the 'ruling in' approach. Conversely, when the estimated pretest probability of cancer falls below 51%, it is more suitable to emphasize the 'ruling out' approach. A total of 14, 14, 6, and 7 microbiota-related VOCs were identified in relation to lung, colorectal, breast, and liver cancers, respectively. The enrichment analysis of volatile metabolites revealed a significant enrichment of butanoate metabolism in the aforementioned tumor types. CONCLUSIONS: The analysis of exhaled breath and urinary VOCs showed promise for cancer screening. In addition, the enrichment analysis of volatile metabolites revealed a significant enrichment of butanoate metabolism in four tumor types, namely lung, colorectum, breast and liver. These findings hold significant implications for the prospective clinical application of multiomics correlation in disease management and the exploration of potential therapeutic targets.

NAD metabolic therapy in metabolic dysfunction-associated steatotic liver disease: Possible roles of gut microbiota.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly named non-alcoholic fatty liver disease (NAFLD), is induced by alterations of hepatic metabolism. As a critical metabolites function regulator, nicotinamide adenine dinucleotide (NAD) nowadays has been validated to be effective in the treatment of diet-induced murine model of MASLD. Additionally, gut microbiota has been reported to have the potential to prevent MASLD by dietary NAD precursors metabolizing together with mammals. However, the underlying mechanism remains unclear. In this review, we hypothesized that NAD enhancing mitochondrial activity might reshape a specific microbiota signature, and improve MASLD progression demonstrated by fecal microbiota transplantation. Here, this review especially focused on the mechanism of Microbiota-Gut-Liver Axis together with NAD metabolism for the MASLD progress. Notably, we found significant changes in Prevotella associated with NAD in a gut microbiome signature of certain MASLD patients. With the recent researches, we also inferred that Prevotella can not only regulate the level of NAD pool by boosting the carbon metabolism, but also play a vital part in regulating the branched-chain amino acid (BCAA)-related fatty acid metabolism pathway. Altogether, our results support the notion that the gut microbiota contribute to the dietary NAD precursors metabolism in MASLD development and the dietary NAD precursors together with certain gut microbiota may be a preventive or therapeutic strategy in MASLD management.

NIR-promoted ferrous ion regeneration enhances ferroptosis for glioblastoma treatment.

Ferroptosis, a unique iron-dependent mode of cell death characterized by lipid peroxide accumulation, holds significant potential for the treatment of glioblastoma (GBM). However, the effectiveness of ferroptosis is hindered by the limited intracellular ferrous ions (Fe2+) and hydrogen peroxide (H2O2). In this study, a novel near-infrared (NIR)-light-responsive nanoplatform (ApoE-UMSNs-GOx/SRF) based on upconversion nanoparticles (UCNPs) was developed. A layer of mesoporous silica and a lipid bilayer were coated on UCNPs sequentially and loaded with glucose oxidase (GOx) and sorafenib, respectively. Further attachment of the ApoE peptide endowed the nanoplatform with BBB penetration and GBM targeting capabilities. Our results revealed that ApoE-UMSNs-GOx/SRF could efficiently accumulated in the orthotopic GBM and induce amplified ferroptosis when combining with NIR irradiation. The UCNPs mediated the photoreduction of Fe3+ to Fe2+ by converting NIR to UV light, and excess H2O2 was produced by the reaction of glucose with the loaded GOx. These processes greatly promoted the production of ROS, which together with inhibition of system Xc- by the loaded sorafenib, leading to enhanced accumulation of lipid peroxides and significantly improved the antiglioma effect both in vitro and in vivo. Our strategy has the potential to enhance the effectiveness of ferroptosis as a therapeutic approach for GBM.

Therapeutic effect and metabolic fingerprinting of triple-negative breast cancer cells following exposure to a novel pH-responsive, gambogic acid-loaded micelle.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and lacks effective therapeutic targets. The use of gambogic acid (GA), a class of active ingredients in traditional Chinese medicine with anti-tumour potential, is limited in tumour therapy owing to its drawbacks and unclear organ toxicity. In this study, we used the pH-responsive amphiphilic block copolymer, PEOz-PCL, to create nanodrugs for GA delivery to MDA-MB-231 cells. The pH-responsive GA-loaded micelles were prepared through nanoprecipitation with a more homogeneous size. The average particle size was 42.29 ± 1.74 nm, and the zeta potential value was 9.88 ± 0.17 mV. The encapsulation rate was 85.06%, and the drug loading rate was 10.63%. The process was reproducible, and sustained release reached 80% in 96 h at acid pH 5.0. Furthermore, cellular tests using CCK-8, TUNEL, and flow cytometry revealed that pH-responsive GA-loaded micelles killed MDA-MB-231 cells more effectively and had much higher activity and targeting compared with free drugs. Metabolomic analysis of the changes in differential metabolites revealed that pH-responsive GA-loaded micelles may inhibit TNBC cells by causing amino acid anabolism, nucleotide metabolism, and glucose metabolism, as well as by affecting their energy sources. The study outcomes will help understand the mechanism of action and the therapeutic efficacy of pH-responsive GA-loaded micellesin vivo.

Recent advances in glucose oxidase-based nanocarriers for tumor targeting therapy.

Glucose oxidase (GOx) can specifically catalyze the conversion of ß-d-glucose into gluconic acid and hydrogen peroxide (H2O2) in the presence of oxygen, making it promising for tumor starvation therapy and oxidative therapy. However, GOx's immunogenicity, poor in vivo stability, short half-life, and potential systemic toxicity, limit its application in cancer therapy. Nanocarriers are capable of improving the pharmacological properties of therapeutic drugs (e.g. stability, circulating half-life, and tumor accumulation) and lower toxicity, hence resolving GOx issues and enhancing its efficacy. Although the application of targeted nanocarriers based on GOx has recently flourished, this field has not yet been reviewed and evaluated. Herein, we initially examined the mechanism of GOx-based nanocarriers for enhanced tumor therapy. Also, we present a comprehensive and up-to-date review that highlights GOx-based nanocarriers for tumor targeting therapy. This review expands on GOx-based nano-targeted combination therapies from both passive and active targeting perspectives, meanwhile, active targeting is further classified into ligand-mediated targeting and physical-mediated targeting. Furthermore, this review also emphasizes the present challenges and promising advancements.

Low acrosin activity is associated with decreased Spam1/acrosin expression and GSH deficiency-caused premature acrosome release of human sperm cells.

Low acrosin activity (LAA) is associated with sperm function anomaly and poor outcomes of in vitro fertilization. In this study, we confirm that 993 semen samples with LAA had a reduced sperm motility and low in vitro fertilization rate in comparison with 1332 normal controls (NC). Proteomic comparison between 11 LAA and 11 NC sperm samples identified 35 upregulated and 99 downregulated proteins in the LAA group. Indeed, proteomic data showed that acrosome enzymes Spam1 and Acrosin were among the downregulated proteins in the LAA group, which was validated by quantitative PCR and immunefluorescent staining of sperm cells. The KEEG pathway analysis revealed a deficiency of GSH and Gln biosynthesis in LAA sperm cells. Immunofluorescent staining of sperms and quantitative PCR verified downregulation of GLUL and GCLC, the key enzymes for GSH and Gln biosynthesis. Moreover, the results of ELISA assay confirmed low levels of GSH and Gln in LAA sperm cells. Mechanistic studies showed that addition of 10 mM H2O2 to semen samples led to a significant reduction of acrosin activity and sperm motility, most possibly by triggering premature acrosome release. In contrast, the presence of 20 mM GSH blocked the oxidative effects of H2O2. Since GSH counteracts the oxidative stress and Gln participates in TCA cycling, their deficiency may affect the redox balance as well as energy production of sperm cells. These findings shed new light on the pathological mechanisms of infertility associated with LAA. Male infertility patients could benefit from GSH supplement by improvement of acrosin activity and other sperm functions.

Effects of Gestational Arsenic Exposures on Placental and Fetal Development in Mice: The Role of Cyr61 m6A.

BACKGROUND: Several epidemiological investigations demonstrated that maternal arsenic (As) exposure elevated risk of fetal growth restriction (FGR), but the mechanism remains unclear. OBJECTIVES: This study aimed to investigate the effects of gestational As exposure on placental and fetal development and its underlying mechanism. METHODS: Dams were exposed to 0.15, 1.5, and 15mg/L NaAsO2 throughout pregnancy via drinking water. Sizes of fetuses and placentas, placental histopathology, and glycogen content were measured. Placental RNA sequencing was conducted. Human trophoblasts were exposed to NaAsO2 (2µM) to establish an in vitro model of As exposure. The mRNA stability and protein level of genes identified through RNA sequencing were measured. N6-Methyladenosine (m6A) modification was detected by methylated RNA immunoprecipitation-quantitative real-time polymerase chain reason (qPCR). The binding ability of insulin-like growth factor 2 binding protein 2 to the gene of interest was detected by RNA-binding protein immunoprecipitation-qPCR. Intracellular S-adenosylmethionine (SAM) and methyltransferase activity were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and colorimetry, respectively. In vitro As+3 methyltransferase (As3MT) knockdown or SAM supplementation and in vivo folic acid (FA) supplementation were used to evaluate the protective effect. A case-control study verified the findings. RESULTS: Sizes of fetuses (exposed to 1.5 and 15mg/L NaAsO2) and placentas (exposed to 15mg/L NaAsO2) were lower in As-exposed mice. More glycogen+ trophoblasts accumulated and the expression of markers of interstitial invasion was lower in the 15mg/L NaAsO2-exposed mouse group in comparison with control. Placental RNA sequencing identified cysteine-rich angiogenic inducer 61 (Cyr61) as a candidate gene of interest. Mechanistically, mice and cells exposed to As had lower protein expression of CYR61, and this was attributed to a lower incidence of Cyr61 m6A. Furthermore, cells exposed to As had lower methyltransferase activity, suggesting that this could be the mechanism by which Cyr61 m6A was affected. Depletion of intracellular SAM, a cofactor for m6A methyltransferase catalytic domain, partially contributed to As-induced methyltransferase activity reduction. Either As3MT knockdown or SAM supplementation attenuated As-induced Cyr61 m6A down-regulation. In mice, FA supplementation rescued As-induced defective trophoblastic invasion and FGR. In humans, a negative correlation between maternal urinary As and plasma CYR61 was observed in infants who were small for gestational age. DISCUSSION: Using in vitro and in vivo models, we found that intracellular SAM depletion-mediated Cyr61 m6A down-regulation partially contributed to As-induced defective trophoblastic invasion and FGR. https://doi.org/10.1289/EHP12207.

Circulating Non-coding RNAs and Exosomes: Liquid Biopsies for Monitoring Preeclampsia.

Preeclampsia (PE) remains a leading cause of maternal and fetal mortality, due to ineffective treatment and diagnostic strategies, compounded by the lack of clarity on the etiology of the disorder. The early prediction or accurate diagnosis of PE is a concern of researchers. Liquid biopsy can be analyzed for cell-free nucleic acids and exosomes. Because circulating non-coding RNAs (ncRNAs) and peripheral blood exosomes can be detected in the peripheral blood of women in early pregnancy, these vesicles and their contents have become the focus of research on early predictive and diagnostic biomarkers for preeclampsia. In this review, we focus on recent studies addressing the roles of circulating ncRNAs and exosomes in PE, with particular attention paid to the potential application value of placenta-derived exosomes and circulating ncRNAs as PE-specific biomarkers.

SeqWiz: a modularized toolkit for next-generation protein sequence database management and analysis.

BACKGROUND: Current proteomic technologies are fast-evolving to uncover the complex features of sequence processes, variations and modifications. Thus, protein sequence database and the corresponding softwares should also be improved to solve this issue. RESULTS: We developed a state-of-the-art toolkit (SeqWiz) for constructing next-generation sequence databases and performing proteomic-centric sequence analyses. First, we proposed two derived data formats: SQPD (a well-structured and high-performance local sequence database based on SQLite), and SET (an associated list of selected entries based on JSON). The SQPD format follows the basic standards of the emerging PEFF format, which also aims to facilitate the search of complex proteoform. The SET format is designed for generating subsets with with high-efficiency. These formats are shown to greatly outperform the conventional FASTA or PEFF formats in time and resource consumption. Then, we mainly focused on the UniProt knowledgebase and developed a collection of open-source tools and basic modules for retrieving species-specific databases, formats conversion, sequence generation, sequence filter, and sequence analysis. These tools are implemented by using the Python language and licensed under the GNU General Public Licence V3. The source codes and distributions are freely available at GitHub ( https://github.com/fountao/protwiz/tree/main/seqwiz ). CONCLUSIONS: SeqWiz is designed to be a collection of modularized tools, which is friendly to both end-users for preparing easy-to-use sequence databases as well as bioinformaticians for performing downstream sequence analysis. Besides the novel formats, it also provides compatible functions for handling the traditional text based FASTA or PEFF formats. We believe that SeqWiz will promote the implementing of complementary proteomics for data renewal and proteoform analysis to achieve precision proteomics. Additionally, it can also drive the improvement of proteomic standardization and the development of next-generation proteomic softwares.

Constructing liquid metal/metal-organic framework nanohybrids with strong sonochemical energy storage performance for enhanced pollutants removal.

With endogenous redox systems and multiple enzymes, the storage and utilization of external energy is general in living cells, especially through photo/ultrasonic synthesis/catalysis due to in-situ generation of abundant reactive oxygen species (ROS). However, in artificial systems, because of extreme cavitation surroundings, ultrashort lifetime and increased diffusion distance, sonochemical energy is rapidly dissipated via electron-hole pairs recombination and ROS termination. Here, we integrate zeolitic imidazolate framework-90 (ZIF-90) and liquid metal (LM) with opposite charges by convenient sonosynthesis, and the resultant nanohybrid (LMND@ZIF-90) can efficiently capture sonogenerated holes and electrons, and thus suppress electron-hole pairs recombination. Unexpectedly, LMND@ZIF-90 can store the ultrasonic energy for over ten days and exhibit acid-responsive release to trigger persistent generation of various ROS including superoxide (O2•-), hydroxyl radicals (•OH), and singlet oxygen (1O2), presenting significantly faster dye degradation rate (short to seconds) than previously reported sonocatalysts. Moreover, unique properties of gallium could additionally facilitate heavy metals removal through galvanic replacement and alloying. In summary, the LM/MOF nanohybrid constructed here demonstrates strong capacity for storing sonochemical energy as long-lived ROS, enabling enhanced water decontamination without energy input.

HE4 overexpression in mice leads to leydig cell hyperplasia and spermatogensis impairment: Pathological implications for oligospermia.

Previous studies have shown that HE4 cancer biomarker promoted cancer cell proliferation and tumor growth in mouse xenograft models. Interestingly, HE4 levels are significantly increased in the seminal plasma of oligoasthenospermia patients, raising a question on HE4 role(s) in spermatogenesis. We constructed an HE4 overexpression mouse model (HE4-OE), and observed that HE4-OE male adult mice had small testes, low sperm counts, and elevated serum/testis testosterone levels. These mice exhibited disorganized seminiferous tubules and impaired spermatogenesis. HE4 overexpression concentrated in Leydig cells, and these cells had hyperplasia and increased testosterone biosynthesis. Mechanistic studies indicated that the impaired spermatogenesis was likely caused by a local and direct action of HE4 in the testis rather than by a hypothalamus/pituitary-initiated dysregulation. The new findings reveal a novel HE4 function in male reproductive system, and suggest the existence of a subtype of primary oligoasthenospermia characterized by HE4 overexpression, Leydig cell hyperplasia, and elevated testosterone levels.

Gestational folic acid supplement prevents vitamin D deficiency-induced depression-like behavior by reversing cortical DNA hypomethylation in adult offspring.

Depression is a common mental disorder with an increasing incidence. Several studies have demonstrated that cortical DNA hypomethylation is associated with depression-like behaviors. This study aims to investigate whether maternal vitamin D deficiency (VDD) induces depression-like behaviors and to explore the effects of folic acid supplement on VDD-induced cortical DNA hypomethylation in adult offspring. Female mice were fed with a VDD diet, beginning at 5 weeks of age and throughout pregnancy. Depression-like behaviors were evaluated, and cortical 5-methylcytosine (5mC) content was detected in adult offspring. Results showed that depression-like behaviors were observed in adult offspring of the VDD group. Cortical Ache and Oxtr mRNAs were upregulated in female offspring of the VDD group. Cortical Cpt1a and Htr1b mRNAs were increased in male offspring of the VDD group. Moreover, cortical 5mC content was reduced in offspring of VDD-fed dams. The additional experiment showed that serum folate and cortical S-adenosylmethionine (SAM) contents were decreased in the offspring of the VDD group. Folic acid supplement attenuated VDD-induced SAM depletion and reversed cortical DNA methylation. Moreover, folic acid supplement attenuated VDD-induced upregulation of depression-related genes. In addition, folic acid supplement alleviated maternal VDD-induced depression-like behaviors in adult offspring. These results suggest that maternal VDD induces depression-like behavior in adult offspring by reducing cortical DNA methylation. The gestational folic acid supplement prevents VDD-induced depression-like behavior by reversing cortical DNA hypomethylation in adult offspring.

Lactobacillus for the treatment and prevention of atopic dermatitis: Clinical and experimental evidence.

Atopic dermatitis (AD) is a chronic inflammatory skin disease, accompanied by itching and swelling. The main pathological mechanism of AD is related to the imbalance between Type 2 helper cells (Th2 cells) and Type 1 helper cells (Th1 cells). Currently, no safe and effective means to treat and prevent AD are available; moreover, some treatments have side effects. Probiotics, such as some strains of Lactobacillus, can address these concerns via various pathways: i) facilitating high patient compliance; ii) regulating Th1/Th2 balance, increasing IL-10 secretion, and reducing inflammatory cytokines; iii) accelerating the maturation of the immune system, maintaining intestinal homeostasis, and improving gut microbiota; and iv) improving the symptoms of AD. This review describes the treatment and prevention of AD using 13 species of Lactobacillus. AD is commonly observed in children. Therefore, the review includes a higher proportion of studies on AD in children and fewer in adolescents and adults. However, there are also some strains that do not improve the symptoms of AD and even worsen allergies in children. In addition, a subset of the genus Lactobacillus that can prevent and relieve AD has been identified in vitro. Therefore, future studies should include more in vivo studies and randomized controlled clinical trials. Given the advantages and disadvantages mentioned above, further research in this area is urgently required.

Relationship between Maternal Vitamin D Levels and Adverse Outcomes.

Vitamin D (VD), a fat-soluble vitamin, has a variety of functions that are important for growth and development, including regulation of cell differentiation and apoptosis, immune system development, and brain development. As such, VD status during pregnancy is critical for maternal health, fetal skeletal growth, and optimal pregnancy outcomes. Studies have confirmed that adverse pregnancy outcomes, such as preeclampsia, low birth weight, neonatal hypocalcemia, poor postnatal growth, skeletal fragility, and increased incidence of autoimmune diseases, can be associated with low VD levels during pregnancy and infancy. Thus, there is growing interest in the role of VD during pregnancy. This review summarizes the potential adverse health outcomes of maternal VD status during pregnancy for both mother and offspring (gestational diabetes mellitus, hypertensive gestational hypertension, intrauterine growth restriction, miscarriage, stillbirth, and preterm birth) and discusses the underlying mechanisms (regulation of cytokine pathways, immune system processing, internal secretion, placental function, etc.) of VD in regulating each of the outcomes. This review aims to provide a basis for public health intervention strategies to reduce the incidence of adverse pregnancies.

Microbiome-metabolome analysis reveals cervical lesion alterations.

Cervical cancer (CC) continues to be one of the most common cancers among females worldwide. It takes a few years or even decades for CC to arise in a minority of women with cervical precancers. An increasing corpus of studies today indicates that local microecology and carcinogenesis are intimately related. To investigate the changes in cericovaginal microecology with the development of cervical cancer, we performed 16S rDNA sequencing and metabolomic analysis in cericovaginal fluid from 10 LSIL patients, 10 HSIL patients, 10 CC patients and 10 healthy controls to reveal the differential flora and metabolites during cervical carcinogenesis. Carcinogenesis is associated with alterations in microbiome diversity, individual taxa, and functions with notable changes in Lactobacillus, Prevotella and Aquabacterium, as well as in cervicovaginal metabolites that correlate with cervicovaginal microbial patterns. Increased bacterial diversity and a decline in the relative abundance of Lactobacillus, the dominant species in the cericovaginal flora, are observed when cervical lesions advance. According to KEGG pathway enrichment analysis, lipids and organic acids change as cervical cancer progresses, and the phenylalanine, tyrosine, and tryptophan biosynthesis pathway is essential for the development of cervical cancer. Our results reveal that microbic and metabolomic profiling is capable of distinguishing CC from precancer and highlights potential biomarkers for the early detection of cervical dysplasia. These differential microorganisms and metabolites are expected to become a potential tool to assist in the diagnosis of cervical cancer.

A pan-cancer analysis of the expression of STAT family genes in tumors and their relationship to the tumor microenvironment.

Background: The signal transducer and activator of transcription (STAT) protein family, a group of seven members (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6), has been widely used to investigate numerous biological functions including cell proliferation, differentiation, apoptosis, and immune regulation. However, not much is known about the role of the STAT family genes in pan-cancer. Methods: Tumor Immune Estimation Resource (TIMER), Sangerbox, cBioPortal, GSCALite, Xena Shiny, GeneMANIA, Gene Expression Profiling Interactive Analysis (GEPIA), and Metascape were used to analyze the relationship between STAT gene expression, clinical outcome, gene variation, methylation status, pathway activity, tumor immune infiltration, and microenvironment in different cancer types and screened drugs that could potentially influence STATs. Results: The Cancer Genome Atlas (TCGA) pan-cancer data showed that most STAT family genes were extensively changed in most tumors compared to the adjacent normal tissues. We also found that STAT gene expression could be used to predict patient survival in various cancers. The STAT gene family formed a network of interaction networks that was associated with several pathways. By mining the of Genomics Drug Sensitivity in Cancer (GDSC) database, we discovered a number of potential drugs that might target STAT regulators. Importantly, the close correlation between STATs and immunocell infiltration suggested the important role of dysregulation of STATs in tumor immune escape. Finally, the relation between STAT gene expression and the tumor microenvironment (TME) indicated that the higher expression of STAT regulators, the higher the degree of tumor stem cells. Conclusion: Considering these genomic alterations and clinical features of STAT family members across cancer types, it will be possible to change the relationship between STATs and tumorigenesis. It was beneficial to treat cancer by targeting these STAT regulators.