Author Correction: Design of amidobenzimidazole STING receptor agonists with systemic activity.

Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mechanism of the Visible-Light-Promoted C(sp3)-H Oxidation via Uranyl Photocatalysis.

Uranyl cation, as an emerging photocatalyst, has been successfully applied to synthetic chemistry in recent years and displayed remarkable catalytic ability under visible light. However, the molecular-level reaction mechanisms of uranyl photocatalysis are unclear. Here, we explore the mechanism of the stepwise benzylic C-H oxygenation of typical alkyl-substituted aromatics (i.e., toluene, ethylbenzene, and cumene) via uranyl photocatalysis using theoretical and experimental methods. Theoretical calculation results show that the most favorable reaction path for uranyl photocatalytic oxidation is as follows: first, hydrogen atom transfer (HAT) from the benzyl position to form a carbon radical ([R•]), then oxygen addition ([R•] + O2 → [ROO•]), then radical-radical combination ([ROO•] + [R•] → [ROOR] → 2[RO•]), and eventually [RO•] reduction to produce alcohols, of which 2° alcohol would further be oxidized to ketones and 1° would be stepwise-oxygenated to acids. The results of the designed verification experiments and the capture of reactive intermediates were consistent with those of theoretical calculations and the previously reported research that the active benzylic C-H would be stepwise-oxygenated in the presence of uranyl. This work deepens our understanding of the HAT mechanism of uranyl photocatalysis and provides important theoretical support for the relevant application of uranyl photocatalysts in organic transformation.

Design of amidobenzimidazole STING receptor agonists with systemic activity.

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.

Tumor cell vaccine combined with Newcastle disease virus promote immunotherapy of lung cancer.

Lung cancer is a fatal disease with the highest worldwide morbidity and mortality rates. Despite recent advances in targeted therapy and immune checkpoint inhibitors for cancer, their efficacy remained limited. Therefore, we designed a Newcastle disease virus (NDV)-modified tumor whole-cell vaccine as a therapeutic vaccine and identified its antigen presentation level to develop effective immunotherapy. Then, we calculated the therapeutic and immune-stimulating effects of NDV-modified lung cancer cell vaccine and intratumoral NDV injection combination on tumor-bearing mice. The results showed that the immunogenic cell death (ICD) expression in NDV-modified lung cancer cell vaccine stimulates dendritic cell maturation and T cell activation in vivo and in vitro. Moreover, NDV-modified lung cancer cell vaccine combined with intratumoral NDV injection could significantly inhibit tumor growth and enhance the differentiation of Th1 cells and Inflammatory cell infiltration in vivo, leading to an excellent immunotherapeutic effect. Therefore, our results revealed that NDV-modified lung cancer cell vaccine combined with intratumoral NDV injection could promote antigen presentation and induce a strong antitumor immune response, which provided a promising combined therapy strategy for tumor immunotherapy.

Daily walking kinematic characteristics of the elderly in different residential settings: experimental study on Chinese community-living elderly and long-term nursing home residents.

BACKGROUND: Long-term nursing home (NH) care helps NH residents with their daily activities and improves their quality of life, but negatively affects their independent physical activities and increases the risk of dangerous events. Dangerous events in the elderly usually occur in the conversion of walking periods when forward striding has already happened, but the body has not yet entered a completely steady walking. OBJECTIVES: Compare the gait characteristics in Chinese long-term NH residents and community-living elderly during the walking Transitional Period (TP) and Stabilization Period (SP). METHODS: 32 long-term NH residents and 33 age- and sex-matched community-living elderly were recruited. The 30-Second Chair Stand Test (30-s CST), Timed Up and Go Test (TUGT), and Modified Falls Efficacy Scale (MFES) were used to assess their body function. The Xsens MVN BIOMECH system was used to collect and analyze the gait parameters of participants. RESULTS: Compared to community-living elderly, NH residents had fewer numbers of 30-s CST, took more time to complete TUGT, and lower MEFS scores. NH residents showed slower gait speed (P < 0.001), less peak hip flexion (P = 0.022) and extension (P = 0.003), knee internal rotation (P = 0.023), and ankle plantarflexion (P = 0.001) and internal rotation (P = 0.007) angles during walking. When walking progressed from TP to SP, NH residents showed increased ankle dorsiflexion (P < 0.001), decreased hip internal rotation (P < 0.001), and community-living elderly had increased hip extension (P = 0.005) angles. CONCLUSIONS: Chinese long-term NH residents had reduced lower extremities strength and postural balance, and higher fear of falling compared to community-living elderly. Their walking performance also showed high fall risk. Besides, long-term NH residents adopted a distal strategy to propel the body forward, which may be a compensatory measure to compensate for inadequate proximal joint control from forward walking to stable walking, and long-term NH residents have reduced postural stability during this process.

An Automated TW3-RUS Bone Age Assessment Method with Ordinal Regression-Based Determination of Skeletal Maturity.

The assessment of bone age is important for evaluating child development, optimizing the treatment for endocrine diseases, etc. And the well-known Tanner-Whitehouse (TW) clinical method improves the quantitative description of skeletal development based on setting up a series of distinguishable stages for each bone individually. However, the assessment is affected by rater variability, which makes the assessment result not reliable enough in clinical practice. The main goal of this work is to achieve a reliable and accurate skeletal maturity determination by proposing an automated bone age assessment method called PEARLS, which is based on the TW3-RUS system (analysis of the radius, ulna, phalanges, and metacarpal bones). The proposed method comprises the point estimation of anchor (PEA) module for accurately localizing specific bones, the ranking learning (RL) module for producing a continuous stage representation of each bone by encoding the ordinal relationship between stage labels into the learning process, and the scoring (S) module for outputting the bone age directly based on two standard transform curves. The development of each module in PEARLS is based on different datasets. Finally, corresponding results are presented to evaluate the system performance in localizing specific bones, determining the skeletal maturity stage, and assessing the bone age. The mean average precision of point estimation is 86.29%, the average stage determination precision is 97.33% overall bones, and the average bone age assessment accuracy is 96.8% within 1 year for the female and male cohorts.

Preparation of a Chitosan/Coal Gasification Slag Composite Membrane and Its Adsorption and Removal of Cr (VI) and RhB in Water.

At present, there are many kinds of pollutants, including dyes and heavy metal ions, in wastewater. It is very important to develop adsorbents that can simultaneously remove heavy metal ions and dyes. In this study, a renewable composite membrane material was synthesized using chitosan and treated coal gasification slag. The Cr (VI) maximum adsorption capacity of the composite membrane was 50.0 mg/L, which was 4.3~8.8% higher than that of the chitosan membrane. For the adsorption of RhB, the removal rate of the chitosan membrane was only approximately 5.0%, but this value could be improved to 95.3% by introducing coal gasification slag. The specific surface area of the chitosan membrane could also be increased 16.2 times by the introduction of coal gasification slag. This is because coal gasification slag could open the nanopores of the chitosan membrane (from 80 µm to 110 µm). Based on the adsorption kinetics and adsorption mechanism analysis, it was found that the adsorption of Cr (VI) occurred mainly through the formation of coordination bonds with the amino groups on the molecular chains of chitosan. Meanwhile, RhB adsorption occurred through the formation of hydrogen bonds with the surface of coal gasification slag. Additionally, coal gasification slag can improve the mechanical properties of the chitosan membrane by 2.2 times, which may facilitate the practical application of the composite membrane. This study provides new insight into the adsorbent design and the resource utilization of coal gasification slag.

Sphingosine 1-phosphate protects against radiation-induced ovarian injury in female rats-impact on mitochondrial-related genes.

The toxic effects of ionizing radiation on the gonads have been widely recognized. Sphingosine 1-phosphate (S1P) has a protective effect on ovarian injury, and although it is known that mitochondria are involved in this process, the specific mechanism is not fully understood. The present study analysed the changes in the serum AMH and ovarian histology in Sprague-Dawley female rats exposed to X-ray radiation only or co-administered with S1P. The mRNA expression profile of ovarian tissue was further analysed via next-generation sequencing and bioinformatics approaches to screen out candidate mitochondria-related genes. Finally, differentially expressed target genes were verified by real-time PCR. The results showed that ionizing radiation could reduce the serum AMH level, destroy ovarian structure and decrease the number of follicles in rats, while S1P administration significantly attenuated the impairment of ovarian function. Gene ontology (GO) and KEGG pathway analysis revealed that a variety of genes related to mitochondrial function were differentially expressed, and the protective effect of S1P on mitochondria was more obvious in the acute phase 24 h after radiation. The differentially expressed mitochondrial function-related genes associated with the protective effect of S1P were UQCRH, MICU2 and GPX4, which were subsequently verified by RT-PCR. Therefore, ionizing radiation has a significant effect on ovarian function, and S1P has a protective effect on radiation-induced ovarian injury, in which mitochondria may play an important role. This study sheds new light on the mechanism of radiation-induced ovarian injury and helps develop a novel potential strategy to control it.

Phenanthrene, but not its isomer anthracene, effectively activates both human and mouse nuclear receptor constitutive androstane receptor (CAR) and induces hepatotoxicity in mice.

Polycyclic aromatic hydrocarbons (PAHs) are a class of pervasive global environmental pollutants and adversely affect human health. Among PAHs, phenanthrene and anthracene are isomers consisting of three benzene rings. In the present study, we have made comparisons of constitutive androstane receptor (CAR) activation and toxic effects on the liver between these two isomers. Phenanthrene, but not anthracene, significantly induced promoter activity and gene expression of human drug metabolizing enzyme CYP2B6 in HepG2 cells and human primary hepatocytes, respectively. Phenanthrene, but not anthracene, significantly increased CYP2B10 expression levels and caused hepatotoxicity in mice. Phenanthrene induced the nuclear accumulation of CAR in the liver of wild-type mice, but not CAR-/- mice. Hepatocellular necrosis, elevated expression levels of some CAR-related genes such as CYP2B10, CYP3A11, UGT1A1, SULT2A1 and GSTM3, and lower hepatic glutathione levels were found in phenanthrene-exposed wild-type mice but not CAR-/- mice. Additionally, phenanthrene and anthracene were detected in both raw and grilled lamb samples. The average concentrations of phenanthrene were much higher than those of anthracene in these samples. This study is the first to demonstrate that phenanthrene, but not its isomer anthracene, effectively activates both human and mouse nuclear receptor CAR, and CAR plays a crucial role in phenanthrene-induced mouse hepatotoxicity. Compared with anthracene, K region may be an important electronic structure of phenanthrene for activation of CAR. Dietary consumption of PAHs-contaminated food is an important exposure route for humans. Exposure to phenanthrene may affect human health especially associated with liver.

Pb2+ modulates ryanodine receptors from the endoplasmic reticulum in rat brain.

Although the neurotoxic mechanism of lead (Pb2+) has been extensively studied, it is not well understood. The effects of Pb2+ on free cytosolic calcium (Ca2+) concentration and calcium-regulated events have been suggested to be major mechanisms in Pb2+ toxicity. Based on our previous findings that Pb2+ changes calcium release through ryanodine receptors (RyRs), the modulation of endoplasmic reticulum (ER) vesicular RyRs by Pb2+ was investigated further in the present study. The results of [3H]ryanodine binding assays showed that in the presence of a free Ca2+ concentration ([Ca2+]f) of 100µM, Pb2+ modulated the equilibrium of [3H]ryanodine binding to brain RyRs, with a U-type dose-response curve, where minimal binding was observed at a free Pb2+ concentration ([Pb2+]f) of 0.39µM. This modulation was also observed over a time course. Scatchard analysis indicated that both an increase in Kd and a possible decrease in Bmax were responsible for the decrease in binding induced by low [Pb2+]f. Moreover, the effects of Pb2+ on the function of ER RyRs in neurons might also be controlled by other RyR modulators. Whole-cell patch-clamp experiments revealed that dynamic calcium oscillations evoked by specific RyR agonists were depressed rapidly and reversibly by exposure to 10µM Pb2+. Our study indicates that RyRs are molecular targets of Pb2+, and this interaction disturbs Ca2+ signals and leads to neurotoxicity.

Lead, cadmium, arsenic, and mercury combined exposure disrupted synaptic homeostasis through activating the Snk-SPAR pathway.

Lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) are among the leading toxic agents detected in the environment, and they have also been detected simultaneously in blood, serum, and urine samples of the general population. Meanwhile early neurologic effects and multiple interactions of Pb, Cd, As, and Hg had been found in children from environmentally polluted area. However, the current studies of these four metals were mostly limited to the interactions between any two metals, whereas the interaction characteristics between any three and four metals were rarely studied. In our study, we firstly explored the characteristics of the neurotoxic interactions among these four elements in nerve cells with factorial designs. The results showed that Pb+Cd+As+Hg co-exposure had a synergistic neurotoxic effect that was more severe than that induced by any two or three metals, when their individual metals were at human environmental exposure (in the blood of U.S. population) relevant levels and below no observed adverse effect levels (NOAELs). Therefore, Pb+Cd+As+Hg co-exposure at human environmental exposure relevant levels were further selected to examine synaptic homeostasis as the cellular and molecular foundation of learning and memory. We reported for the first time that Pb+Cd+As+Hg co-exposure induced dose-dependent decreases of the dendritic lengths and branching, as well as spine density and mature phenotype in primary hippocampal neurons, and the stimulated neurite outgrowths in NGF-differentiated PC12 cells. And the above synaptic homeostasis disruption was associated with serum induced kinase (Snk)-spine associated Rap GTPase activating protein (SPAR) pathway. Our study suggests that human environmental Pb, Cd, As, and Hg co-exposure has the potential to evoke synergistic neurotoxicity even if their individual metals are below NOAELs, which reinforces the need to control and regulate potential sources of metal contamination.

Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats.

Polycyclic aromatic hydrocarbons (PAHs) are a group of persistent organic pollutants primarily formed from the incomplete combustion of carbonaceous materials, and have adverse effects on human health. In this study, we investigated whether pyrene, a PAH consisting of 4 fused benzene rings, has adverse effects on rat. Adult male Sprague-Dawly rats were treated daily by oral gavage with vehicle (corn oil) or pyrene at doses of 375, 750, 1500, or 2200 mg/kg/day for 4 days. The results showed that pyrene caused hepatotoxicity in rats. When compared with the control group, relative liver weights, plasma alanine aminotransferase, and direct bilirubin levels significantly increased after pyrene exposure. Hepatocyte swelling and degeneration and decreased hepatic total glutathione (GSH) levels were also found in pyrene-exposed rats. We further observed that mRNA levels of several hepatic metabolizing enzymes regulated by constitutive androstane receptor (CAR) such as CYP2B1 and CYP2B2 significantly increased in pyrene-exposed rats. These results suggest that decreased GSH levels, elevated hepatic metabolizing enzyme gene expression, and CAR activation are important contributors for pyrene-induced hepatotoxicity in rats. Additionally, we found pyrene significantly induced plasma inflammatory indices including white blood cell and lymphocyte counts. We also observed that pyrene exposure increased relative weight of kidneys and disrupted kidney function with elevated urea and creatinine levels in rats.

dbMDEGA: a database for meta-analysis of differentially expressed genes in autism spectrum disorder.

BACKGROUND: Autism spectrum disorders (ASD) are hereditary, heterogeneous and biologically complex neurodevelopmental disorders. Individual studies on gene expression in ASD cannot provide clear consensus conclusions. Therefore, a systematic review to synthesize the current findings from brain tissues and a search tool to share the meta-analysis results are urgently needed. METHODS: Here, we conducted a meta-analysis of brain gene expression profiles in the current reported human ASD expression datasets (with 84 frozen male cortex samples, 17 female cortex samples, 32 cerebellum samples and 4 formalin fixed samples) and knock-out mouse ASD model expression datasets (with 80 collective brain samples). Then, we applied R language software and developed an interactive shared and updated database (dbMDEGA) displaying the results of meta-analysis of data from ASD studies regarding differentially expressed genes (DEGs) in the brain. RESULTS: This database, dbMDEGA ( https://dbmdega.shinyapps.io/dbMDEGA/ ), is a publicly available web-portal for manual annotation and visualization of DEGs in the brain from data from ASD studies. This database uniquely presents meta-analysis values and homologous forest plots of DEGs in brain tissues. Gene entries are annotated with meta-values, statistical values and forest plots of DEGs in brain samples. This database aims to provide searchable meta-analysis results based on the current reported brain gene expression datasets of ASD to help detect candidate genes underlying this disorder. CONCLUSION: This new analytical tool may provide valuable assistance in the discovery of DEGs and the elucidation of the molecular pathogenicity of ASD. This database model may be replicated to study other disorders.

Vitamin D receptor protects glioblastoma A172 cells against Coxsackievirus A16 infection induced cell death in the pathogenesis of hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD) was one of the most common children illnesses. Coxsackievirus A16 was one of the major pathogens that cause HFMD. However, the role of vitamin D underlying this common illness has not been elucidated. Our study examined that vitamin D levels was significantly lower in 33 HFMD patients, compared to 36 healthy children. Unexpectedly, both mRNA and protein expression of VDR were significantly decreased in CA16 infected glioblastoma A172 cells. And overexpression of VDR or vitamin D treatment in CA16 infected glioblastoma A172 cells could reverse the CA16 infection induced cell death, apoptosis or mitochondrial membrane rupture. Therefore, our study, for the first time, demonstrated that vitamin D and VDR could associate with the pathogenesis of HFMD. Thus might provide useful information for HFMD prevention and treatments.

Upregulation of human CYP2C9 expression by Bisphenol A via estrogen receptor alpha (ERα) and Med25.

Bisphenol A (BPA) is an important industrial chemical, mainly used in the manufacture of polycarbonate plastic and epoxy resins. Due to its widespread use, humans have a high risk of exposure to BPA. BPA has been found to have adverse health effects such as interfering with hormone-related pathways and is well-known to act as an endocrine disruptor. The present study is the first to show the induction effect of BPA on gene expression and enzyme activity of CYP2C9, an important hepatic drug metabolizing enzyme in human. We further identify the mechanism of BPA upregulation of CYP2C9 expression. We show that BPA is able to transcriptionally activate CYP2C9 promoter through ERα and ERE site within the CYP2C9 promoter region in HepG2 cells, and can induce CYP2C9 gene expression and enzyme activity in human primary hepatocytes. Moreover, we demonstrate that Med25, a variable member of the Mediator complex, is a coactivator of ligand-activated ERα that interacts with ERα through its C-terminal LXXLL motif after BPA exposure, and is functionally involved in BPA-induced transcriptional regulation of CYP2C9 expression and enzyme activity. Our findings suggest that BPA exposure has a potential risk for adverse health effects in human liver metabolism by upregulation of CYP2C9 expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 970-978, 2017.

Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction.

Although therapeutic interventions of signal-transduction cascades with targeted kinase inhibitors are a well-established strategy, drug-discovery efforts to identify targeted phosphatase inhibitors have proven challenging. Herein we report a series of allosteric, small-molecule inhibitors of wild-type p53-induced phosphatase (Wip1), an oncogenic phosphatase common to multiple cancers. Compound binding to Wip1 is dependent on a 'flap' subdomain located near the Wip1 catalytic site that renders Wip1 structurally divergent from other members of the protein phosphatase 2C (PP2C) family and that thereby confers selectivity for Wip1 over other phosphatases. Treatment of tumor cells with the inhibitor GSK2830371 increases phosphorylation of Wip1 substrates and causes growth inhibition in both hematopoietic tumor cell lines and Wip1-amplified breast tumor cells harboring wild-type TP53. Oral administration of Wip1 inhibitors in mice results in expected pharmacodynamic effects and causes inhibition of lymphoma xenograft growth. To our knowledge, GSK2830371 is the first orally active, allosteric inhibitor of Wip1 phosphatase.

Assembled collagen films modified using polyacrylic acid with improved mechanical properties via mineralization.

The imperative task of enforcing collagen materials holds paramount significance in the field of hard tissue repair. We hereby present mineralized collagen fiber films via mineralization with improved mechanical properties. Self-extracted collagen was assembled into an array with an aligned fibrous pattern and then modified with polyacrylic acid (PAA) followed by mineralization in cationic polyacrylamide (CPAM)-SBF. Biomineralization occurred at the inner and outer surface of the assembled collagen fiber films. A tensile strength of up to 40.38 ± 3.08 MPa of mineralized collagen was obtained, for the first time, which may be attributed to the synergistic effect of polyanion and polycation on the mineralization process of assembled intrafibrillar collagen fibers. It was argued that PAA may facilitate the intra-fiber interaction of collagen, which extends the elongation at break of collagen fibers. This study introduces a pioneering approach for the preparation of mineralized collagen materials with superior mechanical properties, which would be beneficial for hard tissue repair.

Pregnane X receptor (PXR) deficiency promotes hepatocarcinogenesis via induction of Akr1c18 expression and prostaglandin F2α (PGF2α) levels.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F2α (PGF2α) and aldo-keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH2 to PGF2α, were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF2α levels and the increased PGF2α levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF2α biosynthesis may be a potential and novel therapeutic strategy for HCC.

Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family.

A comprehensive survey was carried out to investigate the genetic etiology of short stature in children by whole exon sequencing of a core family cohort to find and study mutations in multiple genes to assess their potential correlations to low height in children. The study included 56 pediatric patients from the Department of Pediatrics at the Zhangzhou Affiliated Hospital of Fujian Medical University. The participants met strict inclusion criteria, including age, Han Chinese ethnicity, low height standard deviation score, and the absence of known causes for short stature. Core pedigrees were identified using exome sequencing. After sequencing, variations were categorized and interpreted according to a variety of factors, including inheritance, location, type, and disease-causing gene databases. Variants were verified by Sanger sequencing. Most of the 97 gene mutations were missense. ACAN, PHEX, and COL2A1 were the most common gene mutations. Copy number variations were identified, particularly associated with the PHEX gene. Protein functional studies revealed that the mutations had a considerable influence on disease-promoting damage. The chromosomal locations with the highest enrichment of these genes were chr12, chr5, and chr2. In conclusion, the study revealed numerous genetic changes that may substantially impact physiological processes and disease. These findings establish the basis for further investigations into their diagnostic and therapeutic capabilities.

Construction and validation of prognostic signature for transcription factors regulating T cell exhaustion in hepatocellular carcinoma.

In the tumor microenvironment (TME), CD8+ T cells showed stage exhaustion due to the continuous stimulation of tumor antigens. To evaluate the status of CD8+ T cells and reverse the exhaustion is the key to evaluate the prognosis and therapeutic effect of tumor patients. The aim of this study was to establish a prognostic signature that could effectively predict prognosis and response to immunotherapy in patients with hepatocellular carcinoma (HCC). We used univariate Cox analysis to obtain transcription factors associated with CD8+ T cell exhaustion from The Cancer Genome Atlas dataset. Then, the prognostic signature for transcription factors basic leucine zipper ATF-like transcription factor, Eomesodermin, and T-box protein 21 regulating T cell exhaustion was constructed using LASSO Cox regression. The relative expression levels of the mRNA of the 3 transcription factors were detected by reverse transcription-quantitative polymerase chain reaction in 23 pairs of HCC and paracancer tissues, and verified internally in The Cancer Genome Atlas dataset and externally in the International Cancer Genome Consortium dataset. Cox regression analysis showed that risk score was an independent prognostic variable. The overall survival of the high-risk group was significantly lower than that of the low-risk group. The low-risk group had higher immune scores, matrix scores, and ESTIMATE scores, and significantly increased expression levels of most immune checkpoint genes in the low-risk group. Therefore, patients with lower risk scores benefit more from immunotherapy. The combination of the 3 transcription factors can evaluate the exhaustion state of CD8+ T cells in the TME, laying a foundation for evaluating the TME and immunotherapy efficacy in patients with HCC.