Inhibition of hexokinase 2 with 3-BrPA promotes MDSCs differentiation and immunosuppressive function.

The adoptive transfer of ex vivo generated myeloid-derived suppressor cells (MDSCs) may be a promising therapeutic strategy for preventing allograft rejection after solid organ transplantation. Currently, the precise role of immune-metabolic pathways in the differentiation and function of MDSCs is not fully understood. Hexokinase 2 (HK2) is an isoform of hexokinase and is a key enzyme involved in the increased aerobic glycolysis of different immune cells during their activation and function. Here, we demonstrate that the addition of HK2 inhibitor 3-Bromopyruvic acid (3-BrPA) into traditional MDSCs induction system in vitro significantly promoted MDSCs production and enhanced their immunosuppressive function. Treatment with 3-BrPA increased the expression of MDSC-related immunosuppressive molecules, such as iNOS, Arg1, and CXCR2. Moreover, the adoptive transfer of 3-BrPA-treated MDSCs significantly prolonged the survival time of mouse heart allografts. This study provides a novel strategy to solve the problems of harvesting enough autologous cells for MDSC production from sick patients, and producing functionally enhanced MDSCs for preventing graft rejection and inducing tolerance.

The burden of brain and central nervous system cancers in Asia from 1990 to 2019 and its predicted level in the next twenty-five years : Burden and prediction model of CNS cancers in Asia.

BACKGROUND: Primary brain and central nervous system cancer (collectively called CNS cancers) cause a significant burden to society. The purpose of this study was to evaluate the trends in the burden of CNS cancers from 1990 to 2019 and to predict the incidence and mortality rates and the corresponding numbers for the next 25 years to help countries to understand the trends in its incidence and mortality, and to make better adjustments or formulation of policies and allocation of resources thereby reducing the burden of the disease. METHODS: The 2019 Global Burden of Disease Study provided incidence rates, death rates, and disability-adjusted life year (DALY) data in Asia from 1990 to 2019. To reflect the trends in the age-standardized incidence, mortality, and DALY rates, the estimated annual percentage change (EAPC) was determined. The Bayesian age-period cohort (BAPC) model was employed to predict the burden of CNS cancers in the next 25 years. RESULTS: The incidence, death, and DALY rates of CNS cancers all increased from 1990 to 2019. The age-standardized incidence rate (ASIR) for CNS cancers increased from 9.89/100,000 in 1990 to 12.14/100,000 in 2019, with an EAPC of 0.69 (95% confidence interval (CI): 0.65, 0.73). The ASDR and the age-standardized DALY rate both decreased, with EAPCs of - 0.08 and - 0.52, respectively. Before 2005, the age-standardized DALY rate in East Asia was much greater in females than in males, while in Central Asia, the age-standardized death and DALY rates in males both increased sharply after 2000. In contrast to 1990, the caseload increased for the 55-70 years age group. The number of deaths decreased sharply among individuals aged younger than 20 years, especially in East Asia, accounting for only 5.41% of all deaths. The age group with the highest mortality rate was > 60 years, especially in Japan. The ASIR will continue to increase in Asia from 2020 to 2044, and the ASDR will gradually diminish. The incidence and number of deaths from CNS cancers in Asia are expected to increase over the next 25 years, especially among females. CONCLUSIONS: The study identified an increasing trend in morbidity, mortality and disability-adjusted life-years (DALYs), with differences in age-standardized morbidity rates for different population groups. In addition, it is noteworthy that the burden of disease (as measured by disability-adjusted life-years (DALYs)) is higher among women in Central Asia compared with other regions. ASIR will continue to increase over the next 25 years, with the increase in female cases and mortality expected to be more pronounced. This may need to be further substantiated by additional research, on the basis of which health authorities and policymakers can better utilize limited resources and develop appropriate policies and preventive measures.

Cryotherapy Attenuates Inflammation via the lncRNA SNHG1/miR-9-5p/NFKB1 Regulatory Axis in Periodontal Ligament Cells.

Cryotherapy is a common non-pharmacological method to relieve pain and inflammation. Clinical studies have shown that cryotherapy can reduce postoperative pain after root canal therapy, but the mechanism remains unclear. In this study, we aimed to investigate the underlying molecular mechanisms by which cryotherapy reduces inflammation in lipopolysaccharide (LPS)-stimulated periodontal ligament cells through transcriptome sequencing analysis. We found that cryotherapy significantly reduced the expression of multiple proinflammatory cytokines and chemokines, and NFKB1 was the key regulator down-regulated by cryotherapy. Importantly, we discovered that lncRNA SNHG1 expression level significantly decreased after cold treatment. SNHG1 expression was positively related to NFKB1 while negatively correlated with miR-9-5p, which formed a novel ceRNA regulatory pathway. Knockdown of SNHG1 significantly reduced the expression of NFKB1, IL1B, and IL6, while overexpression of SNHG1 significantly increased the expression of these genes. In conclusion, our study demonstrated that cryotherapy can effectively reduce inflammation in LPS-induced periodontal ligament cells by suppressing the lncRNA SNHG1/miR-9-5p/NFKB1 axis.

SRSF3-Mediated Ki67 Exon 7-Inclusion Promotes Head and Neck Squamous Cell Carcinoma Progression via Repressing AKR1C2.

Ki67 is a well-known proliferation marker with a large size of around 350 kDa, but its biological function remains largely unknown. The roles of Ki67 in tumor prognosis are still controversial. Ki67 has two isoforms generated by alternative splicing of exon 7. The roles and regulatory mechanisms of Ki67 isoforms in tumor progression are not clear. In the present study, we surprisingly find that the increased inclusion of Ki67 exon 7, not total Ki67 expression level, was significantly associated with poor prognosis in multiple cancer types, including head and neck squamous cell carcinoma (HNSCC). Importantly, the Ki67 exon 7-included isoform is required for HNSCC cell proliferation, cell cycle progression, cell migration, and tumorigenesis. Unexpectedly, Ki67 exon 7-included isoform is positively associated with intracellular reactive oxygen species (ROS) level. Mechanically, splicing factor SRSF3 could promote exon 7 inclusion via its two exonic splicing enhancers. RNA-seq revealed that aldo-keto reductase AKR1C2 is a novel tumor-suppressive gene targeted by Ki67 exon 7-included isoform in HNSCC cells. Our study illuminates that the inclusion of Ki67 exon 7 has important prognostic value in cancers and is essential for tumorigenesis. Our study also suggested a new SRSF3/Ki67/AKR1C2 regulatory axis during HNSCC tumor progression.

Cytoplasmic Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells.

Acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation is a unique subtype of adult leukemia. Recent studies show that NPM1-mutated AML has high autophagy activity. However, the mechanism for upholding the high autophagic level is still not fully elucidated. In this study, we first identified that tumor protein p53 inducible nuclear protein 2 (TP53INP2) was highly expressed and cytoplasmically localized in NPM1-mutated AML cells. Subsequent data showed that the expression of TP53INP2 was upregulated by fat mass and obesity-associated protein (FTO)-mediated m6A modification. Meanwhile, TP53INP2 was delocalized to the cytoplasm by interacting with NPM1 mutants. Functionally, cytoplasmic TP53INP2 enhanced autophagy activity by promoting the interaction of microtubule-associated protein 1 light chain 3 (LC3) - autophagy-related 7 (ATG7) and further facilitated the survival of leukemia cells. Taken together, our study indicates that TP53INP2 plays an oncogenic role in maintaining the high autophagy activity of NPM1-mutated AML and provides further insight into autophagy-targeted therapy of this leukemia subtype.

CDH4 inhibits ferroptosis in oral squamous cell carcinoma cells.

BACKGROUND: The cadherin-4 gene (CDH4), a member of the cadherin family genes, encodes R-cadherin (R-cad); however, the function of this gene in different types of cancer remains controversial. The function of CDH4 in OSCC (oral squamous cell carcinoma) is unknown. MATERIALS AND METHODS: We use the Cancer Genome Atlas (TCGA) database to find the expression of CDH4 in OSCC is more than normal tissue. Our tissue samples also confirmed that CDH4 gene was highly expressed in OSCC. The related cell function assay detected that CDH4 promotes the ability of cell proliferation, migration, self-renewal and invasion. Cell staining experiment confirmed that the change of CDH4 expression would change the cell mortality. The western blot of GPX4 (glutathione-dependent peroxidase-4), GSH (reduced glutathione) test assay and MDA(Malondialdehyde) test assay show that the expression of CDH4 may resist the sensitivity of ferropotosis in OSCC. RESULTS: CDH4 was upregulated in OSCC samples and was correlation with poor survival of patients. High expression of CDH4 effectively promotes the proliferation, mobility of OSCC cells and reduce the sensitivity of OSCC cells to ferroptosis. CDH4 is positively correlated with EMT pathway genes, negatively correlated with fatty acid metabolism pathway genes and peroxisome pathway genes, and positively correlated with ferroptosis suppressor genes in OSCC. CONCLUSIONS: These results indicate that CDH4 may play a positive role in tumor progression and resistance ferroptosis and may be a potential therapeutic target for OSCC.

Economic policy uncertainty and directors and officers liability insurance: a perspective on capital market pressures.

This study investigates the effects of economic policy uncertainty (EPU) on corporate purchases of directors and officers liability insurance from the perspective of capital market pressures. Using data on A-share Chinese listed firms from 2010 to 2021, our theoretical analysis and empirical tests reveal that higher levels of EPU increase purchases. The theoretical analysis and mediating tests reveal that capital market pressures play a mediating role in the relationship between EPU and purchases. This study also finds that the indirect ways in which EPU increases purchases consider the need for firms to mitigate litigation risks and take advantage of insurance governance. The heterogeneous analysis and tests reveal that EPU increases purchases more significantly in firms that have higher managerial agency costs, have lower corporate transparency, and are in industries with higher competition. The findings are significant for improving the risk management system in China's capital markets.

High expression of Notch2 drives tongue squamous cell carcinoma carcinogenesis.

Tongue squamous cell carcinoma (TSCC) is one of the most common cancers in the oral cavity. Notch signaling is frequently dysregulated in cancer. However, the role of Notch2 in TSCC is not well understood. The aim of this study was to investigate the effect of abnormal expression of Notch2 in TSCC. The expression of Notch2 was tested in 47 pairs of tissues from tongue cancer and normal samples by using immunohistochemical staining. Tongue cancer cells were transfected with siRNA or plasmid. The proliferation of the cells was tested by the CCK8 assay and colony formation assay. Subcutaneous tumor model was established to observe tumor growth. Transwell assay was used to detect the changes of cell migration and invasion ability. A humanized anti-Notch2 antibody was used to TSCC cells. We found that Notch2 was upregulated in tongue carcinoma tissues. Knocking down the expression of Notch2 by siRNA in the TSCC cell lines decreased proliferation ability both in vitro and in vivo. In addition, migration and invasion abilities were inhibited by knockdown of Notch2 in the TSCC cells. However, overexpression of Notch2 increased tongue cancer cell proliferation, invasion and migration. The humanized anti-Notch2 antibody inhibited TSCC cell growth. The results indicated that Notch2 is an oncogene in tongue squamous cell carcinoma and may become the target of a new approach for treating TSCC.

Roles of Regulatory T Cell-Derived Extracellular Vesicles in Human Diseases.

Regulatory T (Treg) cells play crucial roles in maintaining immune self-tolerance and immune homeostasis, and closely associated with many human diseases. Recently, Treg cells-derived extracellular vesicles (Treg-EVs) have been demonstrated as a novel cell-contact independent inhibitory mechanism of Treg cells. Treg-EVs contain many specific biological molecules, which are delivered to target cells and modulate immune responses by inhibiting T cell proliferation, inducing T cell apoptosis, and changing the cytokine expression profiles of target cells. The abnormal quantity or function of Treg-EVs is associated with several types of human diseases or conditions, such as transplant rejection, inflammatory diseases, autoimmune diseases, and cancers. Treg-EVs are promising novel potential targets for disease diagnosis, therapy, and drug transport. Moreover, Treg-EVs possess distinct advantages over Treg cell-based immunotherapies. However, the therapeutic potential of Treg-EVs is limited by some factors, such as the standardized protocol for isolation and purification, large scale production, and drug loading efficiency. In this review, we systematically describe the structure, components, functions, and basic mechanisms of action of Treg-EVs and discuss the emerging roles in pathogenesis and the potential application of Treg-EVs in human diseases.

Development and validation of a flexible DNA extraction (PAN) method for liquid biopsy of multiple sample types.

BACKGROUND: Liquid biopsy is gaining increasing popularity in cancer screening and diagnosis. However, there is no relatively mature DNA isolation method or commercial kit available that is compatible with different LB sample types. This study developed a PAN-sample DNA isolation method (PAN method) for liquid biopsy samples. METHODS: The PAN method has two key steps, including biosample-specific pretreatments for various LB sample types and high concentration guanidine thiocyanate buffer for lysis and denaturation procedure. Subsequently, the performance of PAN method was validated by a series of molecular analyses. RESULTS: The PAN method was used to isolate DNA from multiple sample types related to LB, including plasma, serum, saliva, nasopharyngeal swab, and stool. All purified DNA products showed good quality and high quantity. Comparison of KRAS mutation analysis using DNA purified using PAN method versus QIAamp methods showed similar efficiency. Epstein-Barr virus DNA was detected via Q-PCR using DNA purified from serum, plasma, nasopharyngeal swab, and saliva samples collected from nasopharyngeal carcinoma patients. Similarly, methylation sequencing of swab and saliva samples revealed good coverage of target region and high methylation of HLA-DPB1 gene. Finally, 16S rDNA gene sequencing of saliva, swab, and stool samples successfully defines the relative abundance of microbial communities. CONCLUSIONS: This study developed and validated a PAN-sample DNA isolation method that can be used for different LB samples, which can be applied to molecular epidemiological research and other areas.

Transmission Potential of Asymptomatic and Paucisymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections: A 3-Family Cluster Study in China.

Data concerning the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in asymptomatic and paucisymptomatic patients are lacking. We report a 3-family cluster of infections involving asymptomatic and paucisymptomatic transmission. Eight of 15 (53%) members from 3 families were confirmed with SARS-CoV-2 infection. Of 8 patients, 3 were asymptomatic and 1 was paucisymptomatic. An asymptomatic mother transmitted the virus to her son, and a paucisymptomatic father transmitted the virus to his 3-month-old daughter. SARS-CoV-2 was detected in the environment of 1 household. The complete genomes of SARS-CoV-2 from the patients were > 99.9% identical and were clustered with other SARS-CoV-2 sequences reported from China and other countries.

Synergistic Coupling of Ni Nanoparticles with Ni3 C Nanosheets for Highly Efficient Overall Water Splitting.

Exploring earth-abundant bifunctional electrocatalysts with high efficiency for water electrolysis is extremely demanding and challenging. Herein, density functional theory (DFT) predictions reveal that coupling Ni with Ni3 C can not only facilitate the oxygen evolution reaction (OER) kinetics, but also optimize the hydrogen adsorption and water adsorption energies. Experimentally, a facile strategy is designed to in situ fabricate Ni3 C nanosheets on carbon cloth (CC), and simultaneously couple with Ni nanoparticles, resulting in the formation of an integrated heterostructure catalyst (Ni-Ni3 C/CC). Benefiting from the superior intrinsic activity as well as the abundant active sites, the Ni-Ni3 C/CC electrode demonstrates excellent bifunctional electrocatalytic activities toward the OER and hydrogen evolution reaction (HER), which are superior to all the documented Ni3 C-based electrocatalysts in alkaline electrolytes. Specifically, the Ni-Ni3 C/CC catalyst exhibits the low overpotentials of only 299 mV at the current density of 20 mA cm-2 for the OER and 98 mV at 10 mA cm-2 for the HER in 1 m KOH. Furthermore, the bifunctional Ni-Ni3 C/CC catalyst can propel water electrolysis with excellent activity and nearly 100% faradic efficiency. This work highlights an easy approach for designing and constructing advanced nickel carbide-based catalysts with high activity based on the theoretical predictions.

The oncogenic effects of HES1 on salivary adenoid cystic carcinoma cell growth and metastasis.

BACKGROUND: Our previous study demonstrated a close relationship between NOTCH signaling pathway and salivary adenoid cystic carcinoma (SACC). HES1 is a well-known target gene of NOTCH signaling pathway. The purpose of the present study was to further explore the molecular mechanism of HES1 in SACC. METHODS: Comparative transcriptome analyses by RNA-Sequencing (RNA-Seq) were employed to reveal NOTCH1 downstream gene in SACC cells. Immunohistochemical staining was used to detect the expression of HES1 in clinical samples. After HES1-siRNA transfected into SACC LM cells, the cell proliferation and cell apoptosis were tested by suitable methods; animal model was established to detect the change of growth ability of tumor. Transwell and wound healing assays were used to evaluate cell metastasis and invasion. RESULTS: We found that HES1 was strongly linked to NOTCH signaling pathway in SACC cells. The immunohistochemical results implied the high expression of HES1 in cancerous tissues. The growth of SACC LM cells transfected with HES1-siRNAs was significantly suppressed in vitro and tumorigenicity in vivo by inducing cell apoptosis. After HES1 expression was silenced, the SACC LM cell metastasis and invasion ability was suppressed. CONCLUSIONS: The results of this study demonstrate that HES1 is a specific downstream gene of NOTCH1 and that it contributes to SACC proliferation, apoptosis and metastasis. Our findings serve as evidence indicating that HES1 may be useful as a clinical target in the treatment of SACC.

MicroRNA-30e-5p promotes cell growth by targeting PTPN13 and indicates poor survival and recurrence in lung adenocarcinoma.

Aberrant microRNA expression is involved in the regulation of various cellular processes, such as proliferation and metastasis in multiple diseases including cancers. MicroRNA-30e-5p (miR-30e) was previously reported as an oncogenic or tumour suppressing miRNA in some malignancies, but its function in lung adenocarcinoma (LAC) remains largely undefined. In this study, we found that the expression of miR-30e was increased in LAC tissues and cell lines, associated with tumour size and represented an independent prognostic factor for overall survival and recurrence of LAC patients. Further functional experiments showed that knockdown of miR-30e suppressed cell growth while its overexpression promoted growth of LAC cells and xenografts in vitro and in vivo. Mechanistically, PTPN13 was identified as the direct target of miR-30e in LAC, in which PTPN13 expression was down-regulated in LAC tissues and showed the inverse correlation with miR-30e expression. Overexpression of PTPN13 inhibited cell growth and rescued the proliferation-promoting effect of miR-30e through inhibition of the EGFR signalling. Altogether, our findings suggest that miR-30e could function as an oncogene in LAC via targeting PTPN13 and act as a potential therapeutic target for treating LAC.

Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. METHODS: First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. RESULTS: AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. CONCLUSION: Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

MIF promotes Th17 cell differentiation in Hashimoto's thyroiditis by binding HVEM and activating NF-κB signaling pathway.

Hashimoto's thyroiditis is a typical thyroid autoimmune disease and Th17 cells are crucial in its development. In recent years, MIF (Macrophage Migration Inhibitory Factor) has been found to promote the secretion of IL-17A and the production and differentiation of Th17 cells. However, the specific mechanism of it remains unclear. Here, we found that the expression of MIF, IL-17A and HVEM (Herpes Virus Entry Mediator) were up-regulated in HT patients. The proportion of Th17 cells in peripheral blood mononuclear cells was positively correlated with the serum MIF protein level. We further found that the expression of HVEM and the phosphorylation level of NF-κB in peripheral blood mononuclear cells of HT patients were significantly increased. Therefore, we speculated that MIF promotes Th17 cell differentiation through HVEM and NF-κB signaling pathways. Further mechanism studies showed that MIF could directly bind to HVEM, and the stimulation of rhMIF in vitro could increase the expression of HVEM and activate NF-κB signaling pathways to promote Th17 cell differentiation. After blocking HVEM with HVEM antibody, the effect of MIF on Th17 cell differentiation disappeared. The results above show that the differentiation of Th17 cells is promoted by MIF combined with HVEM through NF-κB signaling pathways. Our research provides a new theory to the regulation mechanism of Th17 cell differentiation and gives hint to new potential therapeutic targets for HT.

Lactate inhibits interferon-α response in ovarian cancer by inducing STAT1 ubiquitin degradation.

The emergence of lactate, produced by lactate dehydrogenase A (LDHA), as an important regulator of the immune response in tumor development has garnered attention in recent research. But, many questions still need to be clarified regarding the relationship between lactate and anti-tumor immunity. Here, we reported that both exogenous and endogenous lactate reduced the protein level and activation of the signal transducer and activator of transcription 1(STAT1) in ovarian cancer cells. As a consequence, the expression of IFNα-STAT1 regulated genes was weakened. This, in turn, weakened the antitumor effect of IFNα by impeding NKT and CD8+T cells recruitment. Strikingly, we found that LDHA knockdown did not result in the downregulation of STAT1 mRNA level in ovarian cancer cells. Instead, we observed that lactate triggered the degradation of STAT1 through the proteasomal pathway. Notably, we identified that lactate reduced the stability of STAT1 by promoting the expression of F-box only protein 40 (Fbxo40). This protein interacts with STAT1 and potentially acts as an E3 ubiquitin ligase, leading to the induction of STAT1 polyubiquitination and degradation. Importantly, ectopic over-expression of the Fbxo40 gene significantly inhibited the expression of ISGs in LDHA knockdown cells. In the TCGA tumor data, we observed that high expression of Fbxo40 negatively correlates with overall survival in ovarian cancer patients. Collectively, our findings reveal lactate as a negative regulator of the IFNα-STAT1 signaling axis in ovarian cancer. This discovery suggests that strategies aimed at targeting lactate for ovarian cancer prevention and treatment should consider the impact on the IFNα-STAT1 response.

Congenitally corrected transposition of the great arteries and implantation of a leadless pacemaker: a case report.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare cardiac anomaly and can lead to abnormal electrical activity of the heart. The implant of a pacemaker in such patients is more complicated than conventional operations. This case report of an adult with ccTGA who had a leadless pacemaker implant will provide a reference for diagnosing and treating such patients. CASE PRESENTATION: A 50-year-old male patient was admitted to hospital having experienced intermittent vision loss for a month. An electrocardiogram and Holter monitoring showed intermittent third-degree atrioventricular block, and echocardiography, cardiac computed tomography and cardiac magnetic resonance imaging confirmed a diagnosis of ccTGA. A leadless pacemaker was successfully implanted into the patient's anatomical left ventricle, and the postoperative parameters were stable. CONCLUSION: Implanting a leadless pacemaker into a patient with a rare anatomical and electrophysiological abnormality, such as ccTGA, is feasible and efficacious, but preoperative imaging evaluation is of considerable importance.

Corrigendum: The m6A-methylated mRNA pattern and the activation of the Wnt signaling pathway under the hyper-m6A-modifying condition in the keloid.

[This corrects the article DOI: 10.3389/fcell.2022.947337.].

Prevalence, distribution, accumulation, and risk of environmental corticosteroids and estrogens in biofilms from the Pearl River Delta.

Biofilms play a significant role in the biogeochemical processing of organic matter and the environmental fate of emerging pollutants. In this study, we investigated the occurrence and distribution of 32 endocrine-disrupting chemicals (EDCs), including 24 environmental corticosteroids (ECs) and 8 environmental estrogens (EEs), in natural biofilms from the Pearl River system. Their association between biofilms and water and environmental risk were assessed. The ECs and EEs ubiquitously occurred in the biofilms, ranging from <0.61-6.57 ng/g and <0.8-2535 ng/g, respectively. Temporally, there was no obvious variance in either ECs or EEs in the biofilms during the winter and summer, and their concentrations exhibited a spatial trend of upward to midstream, descending downstream, and then seaward attenuation at the estuary. For ECs and EEs, the similar levels of field-derived bioconcentration factors (BCFs) (logarithm values: 2.42-2.86 and 2.72-2.98, respectively) and biofilm organic carbon-normalized partitioning coefficients (Kboc) (3.39-3.69 and 3.35-3.95) suggest the comparable potential of accumulation and sorption by biofilms between these two classes of EDCs. In addition, higher values of BCF and Kboc for the EEs were found in winter and were correspondingly comparable to their distribution coefficients (Kd) and Koc derived from suspended particles and sediment, revealing that biofilms are a competitive environmental compartment for capturing EDCs, particularly during the mature period. A positive logKboc-logKow relationship suggests hydrophobic partitioning as a primary interaction mechanism between the biofilm and EEs. Moreover, high risks from biofilm-associated ECs and EEs might have posed to the fluvial ecosystem. This study provides original insights into the occurrence, fate, and risk of ECs in natural biofilms for the first time and demonstrates that biofilms may not only serve as reservoirs but also serve as sentinels for fluvial EDC contamination. These results contribute to the further understanding of the behavior and fate of EDCs in aquatic environments.