The value of ripple mapping in the age of coherent mapping in scar-related atrial tachycardia.

BACKGROUND: An accurate display of scar-related atrial tachycardia (ATs) is a key determinant of ablation success. The efficacy of ripple mapping (RM) in identifying the mechanism and critical isthmus of scar-related ATs during coherent mapping is unknown. METHODS: A total of 97 patients with complex ATs who underwent radiofrequency catheter ablation at our center between October 2018 and September 2022 were included. ATs was mapped using a multielectrode mapping catheter on the CARTO3v7 CONFIDENCE module. Coherent and RM were used to identify the reentrant circuit. RESULTS: The mechanisms of 128 ATs were analyzed retrospectively (84 anatomic-reentrant ATs and 44 non-anatomic reentrant ATs). The median AT cycle length was 264 ± 25ms. The correct diagnosis was achieved in 83 ATs (68%) using only coherent mapping. Through coherent mapping plus RM, 114 ATs (84.2%) were correctly diagnosed (68% vs. 89%, p = .019). In non-anatomical reentrant ATs, 81% of the diagnostic rate was achieved by reviewing both coherent and ripple mapping compared to reviewing coherent mapping alone (81% vs. 52%, p = .03). Reviewing coherent mapping and ripple mapping showed a higher diagnostic rate in patients who underwent cardiac surgery than those with Coherent mapping alone (64% vs. 88%, p = .04). CONCLUSION: Coherent mapping combined with RM was superior to coherent mapping alone in identifying the mechanism of scar-related ATs post-cardiac surgery and non-anatomic reentrant ATs.

Dual-Specificity Phosphatase 4 Promotes Malignant Features in Colorectal Cancer Through Cyclic-AMP Response Element Binding Protein/Protein Kinase CAMP-Activated Catalytic Subunit Beta Activation.

INTRODUCTION: Previous studies have demonstrated that Dual-specificity phosphatase 4 (DUSP4) plays an important role in the progression of different tumor types. However, the role and mechanism of DUSP4 in colorectal cancer (CRC) remain unclear. AIMS: We investigate the role and mechanisms of DUSP4 in CRC. METHODS: Immunohistochemistry was used to investigate DUSP4 expression in CRC tissues. Cell proliferation, apoptosis and migration assays were used to validate DUSP4 function in vitro and in vivo. RNA-sequence assay was used to identify the target genes of DUSP4. Human phosphokinase array and inhibitor assays were used to explore the downstream signaling of DUSP4. RESULTS: DUSP4 expression was upregulated in CRC tissues relative to normal colorectal tissues, and DUSP4 expression showed a significant positive correlation with CRC stage. Consistently, we found that DUSP4 was highly expressed in colorectal cancer cells compared to normal cells. DUSP4 knockdown inhibits CRC cell proliferation, migration and promotes apoptosis. Furthermore, the ectopic expression of DUSP4 enhanced CRC cell proliferation, migration and diminished apoptosis in vitro and in vivo. Human phosphokinase array data showed that ectopic expression of DUSP4 promotes CREB activation. RNA-sequencing data showed that PRKACB acts as a downstream target gene of DUSP4/CREB and enhances CREB activation through PKA/cAMP signaling. In addition, xenograft model results demonstrated that DUSP4 promotes colorectal tumor progression via PRKACB/CREB activation in vivo. CONCLUSION: These findings suggest that DUSP4 promotes CRC progression. Therefore, it may be a promising therapeutic target for CRC.

Phosphorylation of TGIF2 represents a therapeutic target that drives EMT and metastasis of lung adenocarcinoma.

BACKGROUND: TGF-ß-induced factor homeobox 2 (TGIF2) is a transcription regulator that is phosphorylated by EGFR/ERK signaling. However, the functions of phosphorylated (p)-TGIF2 in cancer are largely unknown. Here, we investigated the roles of p-TGIF2 in promoting epithelial-mesenchymal transition (EMT) and metastasis in lung adenocarcinoma (LUAD). METHODS: In vitro and in vivo experiments were conducted to investigate the role of TGIF2 in LUAD EMT and metastasis. Dual-luciferase reporter and ChIP assays were employed to observe the direct transcriptional regulation of E-cadherin by TGIF2 and HDAC1. Co-immunoprecipitation was performed to identify the interaction between TGIF2 and HDAC1. RESULTS: Downregulating the expression of TGIF2 inhibited LUAD cell migration, EMT and metastasis in vitro and in vivo. Phosphorylation of TGIF2 by EGFR/ERK signaling was required for TGIF2-promoted LUAD EMT and metastasis since phosphorylation-deficient TGIF2 mutant lost these functions. Phosphorylation of TGIF2 was necessary to recruit HDAC1 to the E-cadherin promoter sequence and subsequently suppress E-cadherin transcription. Meanwhile, inhibition of HDAC1 repressed the TGIF2 phosphorylation-induced migration and EMT of LUAD cells. In xenograft mouse models, both inhibition of ERK and HDAC1 could significantly inhibited TGIF2-enhanced metastasis. Furthermore, TGIF2-positive staining was significantly correlated with E-cadherin-negative staining in human lung cancer specimens. CONCLUSIONS: Our study reveals the novel function of p-TGIF2 in promoting EMT and metastasis in LUAD; p-TGIF2 could be a potential therapeutic target to inhibit LUAD metastasis.

Function and regulation of RGS family members in solid tumours: a comprehensive review.

G protein-coupled receptors (GPCRs) play a key role in regulating the homeostasis of the internal environment and are closely associated with tumour progression as major mediators of cellular signalling. As a diverse and multifunctional group of proteins, the G protein signalling regulator (RGS) family was proven to be involved in the cellular transduction of GPCRs. Growing evidence has revealed dysregulation of RGS proteins as a common phenomenon and highlighted the key roles of these proteins in human cancers. Furthermore, their differential expression may be a potential biomarker for tumour diagnosis, treatment and prognosis. Most importantly, there are few systematic reviews on the functional/mechanistic characteristics and clinical application of RGS family members at present. In this review, we focus on the G-protein signalling regulator (RGS) family, which includes more than 20 family members. We analysed the classification, basic structure, and major functions of the RGS family members. Moreover, we summarize the expression changes of each RGS family member in various human cancers and their important roles in regulating cancer cell proliferation, stem cell maintenance, tumorigenesis and cancer metastasis. On this basis, we outline the molecular signalling pathways in which some RGS family members are involved in tumour progression. Finally, their potential application in the precise diagnosis, prognosis and treatment of different types of cancers and the main possible problems for clinical application at present are discussed. Our review provides a comprehensive understanding of the role and potential mechanisms of RGS in regulating tumour progression. Video Abstract.

TIFA promotes colorectal cancer cell proliferation in an RSK- and PRAS40-dependent manner.

Previous studies have reported that TIFA plays different roles in various tumor types. However, the function of TIFA in colorectal cancer (CRC) remains unclear. Here, we showed that the expression of TIFA was markedly increased in CRC versus normal tissue, and positively correlated with CRC TNM stages. In agreement, we found that the CRC cell lines show increased TIFA expression levels versus normal control. The knockdown of TIFA inhibited cell proliferation but had no effect on cell apoptosis in vitro or in vivo. Moreover, the ectopic expression of TIFA enhanced cell proliferation ability in vitro and in vivo. In contrast, the expression of mutant TIFA (T9A, oligomerization site mutation; D6, TRAF6 binding site deletion) abolished TIFA-mediated cell proliferation enhancement. Exploration of the underlying mechanism revealed that the protein synthesis-associated kinase RSK and PRAS40 activation were responsible for TIFA-mediated CRC progression. In summary, these findings suggest that TIFA plays a role in mediating CRC progression. This could provide a promising target for CRC therapy.

Ripple mapping-guided atrial tachycardia ablation following open-heart surgery.

Ripple mapping can make the visualization of activation conduction on a 3-dimensional voltage map and is useful tool for scar-related organized atrial tachycardia (AT). This study sought to assess the efficacy of ripple mapping for interpreting reentrant circuits and critical isthmus in postoperative ATs. 34 consecutive patients with a history of mitral valve surgery (mean age, 54.5 ± 12.4 years) underwent high density (HD) RM during ATs with CARTO3v4 CONFIDENSE system. The voltage activation threshold was determined by RM over a bipolar voltage map. The identification of underlying mechanisms and ablation setting was based on RM without reviewing activation mapping. A total of 41 ATs (35 spontaneous, 6 induced) were characterized. 39 reentry circuits were successfully mapped (cycle length, 256 ± 43 ms). Of the 41 ATs, 28 were confirmed by ripple mapping alone (68%), and 12 (29%) by ripple mapping and entrainment mapping. Of 12 ATs in the left atrium, 9 (75%) needed entrainment to confirm, compared with 5 (17.8%) in the right atrium. Primary endpoint after initial ablation set was achieved in 32 of the 34 patients (94.1%). Freedom from atrial arrhythmias was 79.4% after the follow-up of 12 ± 5 months. Of the seven patients with recurrence, three underwent the repeated catheter ablation. Ripple mapping precisely delineated reentrant circuits in post-cardiac surgery AT resulting in a high success rate of ablation. Entrainment maneuvers remain useful for elucidation of complex AT circuits.

Analysis of cranial type characteristics in term infants: a multi-center study.

BACKGROUND: Positional head deformity (PHD) is defined as a change in the shape of an infant's skull due to an external force. In certain cases, it can lead to cosmetic deformities or even neurological issues due to its impact on the developing nervous system. Therefore, we conducted this study to investigate the incidence and characteristics of PHD in term infants in China and preliminarily establish a localized diagnostic reference standard. METHODS: Overall, 4456 term infants from three medical institutions in Chongqing were and divided and analyzed according to their age. Cranial vault asymmetry (CVA) and cephalic index (CI) were calculated in all infants. The current international diagnostic criteria were used to understand PHD incidence and analyze the CVA and CI distribution. RESULTS: According to the current international standards, the total detection rate of PHD in Chongqing's term infants was 81.5%, with brachycephaly alone being the most frequent (39.4%), followed by brachycephaly with plagiocephaly (34.8%) and plagiocephaly alone (6.2%). The detection rates of dolichocephaly were low: alone, 0.9% and combined with plagiocephaly, 0.2%. According to age, plagiocephaly (44.5%) and brachycephaly (82.0%) were the most frequent in the 2-3-month group. The 75th/90th/97th and 3rd/10th/25th/75th/90th/97th percentiles of CVA and CIs were 0.4/0.7/1.0 and 76.4/78.8/82.3/91.1/94.6/99.2%, respectively. CONCLUSIONS: According to the current international standards, the PHD detection rate among term infants in Chongqing was high. Therefore, a new diagnostic standard for Chinese infants was proposed where CVA ≥ 0.4 cm indicates plagiocephaly, CI ≥ 91% indicates brachycephaly, and CI ≤ 82% indicates dolichocephaly.

Ibuprofen mediates histone modification to diminish cancer cell stemness properties via a COX2-dependent manner.

BACKGROUND: The anticancer potential of ibuprofen has created a broad interest to explore the clinical benefits of ibuprofen in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anticancer potential of ibuprofen remains limited. METHODS: Cancer stemness assays to validate ibuprofen function in vitro and in vivo. Histone modification assays to check the effect of ibuprofen on histone acetylation/methylation, as well as the activity of HDAC and KDM6A/B. Inhibitors' in vivo assays to evaluate therapeutic effects of various inhibitors' combination manners. RESULTS: In our in vitro studies, we report that ibuprofen diminishes cancer cell stemness properties that include reducing the ALDH + subpopulation, side population and sphere formation in three cancer types. In our in vivo studies, we report that ibuprofen decreases tumour growth, metastasis and prolongs survival. In addition, our results showed that ibuprofen inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a high-throughput siRNA platform. In regard to the underlying molecular mechanism of action, we report that ibuprofen reduces HDACs and histone demethylase (KDM6A/B) expression that mediates histone acetylation and methylation, and suppresses gene expression via a COX2-dependent way. In regard to therapeutic strategies, we report that ibuprofen combined HDAC/HDM inhibitors prevents cancer progression in vivo. CONCLUSIONS: The aforementioned findings suggest a molecular model that explains how ibuprofen diminishes cancer cell stemness properties. These may provide novel targets for therapeutic strategies involving ibuprofen in the prevention of cancer progression.

Prevalence of positional skull deformities in 530 premature infants with a corrected age of up to 6 months: a multicenter study.

BACKGROUND: Positional deformities (PD) are common during early infancy. Severe cases may result in facial abnormalities and be associated with delayed neurological development in infants. The earlier the detection of PD, the better the intervention effect and the lower the cost of treatment. Currently, there are many studies on PD in Europe and the United States. However, in China, there is little data on the basic metrics and incidence of PD. Premature infants have a high risk of PD. However, there are few studies on PD in premature infants globally, and none in Asia. This study aimed to investigate PD and its characteristics inpremature infants to help its early detection and intervention and thus improve the quality of life for premature infants. METHODS: We analyzed 530 preterm infants who visited the outpatient departments at Xinqiao Hospital of Army Medical University and Maternal and Child Health Care Hospitals of Wanzhou and Yongchuan Districts in Chongqing from September 1, 2016, to August 31, 2017. The head shape data measured by a simple manual method were recorded. The diagonal difference (DD) between the transcranial diagonals and the cranial index (CI) was calculated. PD and its incidences indifferent gestational ages and corrected age groups were analyzed. RESULTS: According to previously defined international diagnostic criteria, the incidence of plagiocephaly, brachycephaly, and dolichocephaly were 51.1, 85.1, and 3.0% respectively, and those of right and left plagiocephalywere69.4 and 30.6%, respectively. The incidence of PD was highest among infants with a gestational age of < 32 weeks and decreased as the gestational age increased. As the corrected age (CA) increased, the incidence of plagiocephaly and dolichocephaly decreased, and the incidence of brachycephaly increased. CONCLUSIONS: PD incidence is high among preterm infants. As gestational age decreased, PD incidence and severity increased. Therefore, healthcare providers should implement early PD detection and intervention to prevent the adverse outcomes. The extremely high incidence of brachycephaly and extremely low incidence of dolichocephaly in this study are likely to be due to the variance of cranial metrics caused by cultural differences. The Chinese standards for infant cranial measurements must be established.

PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner.

BACKGROUND/AIMS: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells. METHODS: The expression of PFKFB4 was first analyzed using the Cancer Genome Atlas (TCGA) dataset, and confirmed by immunohistochemical staining of tissue microarray and breast cancer tissues from patient samples. Gain- and loss-of- function approaches were used to investigate the effects of PFKFB4 on breast cancer cell migration in vitro. Orthotopic xenograft model and experimental metastasis model were used to assess the effects of PFKFB4 on breast cancer cell metastasis in vivo. ELISA and immunofluorescence staining were used to examine HA production. Quantitative RT-PCR and western blotting were used to explore the mRNA and protein levels of HAS2, respectively. RESULTS: We found that PFKFB4 enhances the migration/invasiveness of breast cancer cells in vitro as well as in vivo. Notably, the effects of PFKFB4 on migration are mediated by induction of HAS2 expression and HA production. Moreover, PFKFB4-induced HAS2 up-regulation depends upon the activation of p38 signaling. CONCLUSION: PFKFB4 promotes the metastasis of breast cancer cells via induction of HAS2 expression and HA production in a p38-dependent manner. Therefore, the PFKFB4/p38/HAS2 signaling pathway may serve as a potential therapeutic target for metastatic breast cancer.

ICAM3 mediates tumor metastasis via a LFA-1-ICAM3-ERM dependent manner.

ICAM3 was reported to promote metastasis in tumors. However, the underlying mechanism remains elusive. Here, we disclosed that the expression of ICAM3 was closely correlated with the TNM stage of human breast and lung cancer, as well as the dominant overexpression in high aggressive tumor cell lines (231 and A549 cells). Moreover, the knockdown of ICAM3 inhibited tumor metastasis whereas the ectopic expression of ICAM3 promoted tumor metastasis both in vitro and in vivo. In addition, exploration of the underlying mechanism demonstrated that ICAM3 not only binds to LFA-1 with its extracellular domain and structure protein ERM but also to lamellipodia with its intracellular domain which causes a tension that pulls cells apart (metastasis). Furthermore, ICAM3 extracellular or intracellular mutants alternatively abolished ICAM3 mediated tumor metastasis in vitro and in vivo. As a therapy strategy, LFA-1 antibody or Lifitegrast restrained tumor metastasis via targeting ICAM3-LFA-1 interaction. In summary, the aforementioned findings suggest a model of ICAM3 in mediating tumor metastasis. This may provide a promising target or strategy for the prevention of tumor metastasis.

Low dosage of arsenic trioxide (As2O3) inhibits angiogenesis in epithelial ovarian cancer without cell apoptosis.

Arsenic trioxide (As2O3) induces cell apoptosis and reduces the invasive and metastatic activities in various cancer types. However, the role of As2O3 in ovarian cancer angiogenesis remains unclear. In this study, we investigated the role of As2O3 in ovarian cancer angiogenesis and found that a low concentration of As2O3 causes no effects on epithelial ovarian cancer cell viability or apoptosis. Moreover, we found that As2O3-treated epithelial ovarian cancer cells demonstrate a reduced tube formation of endothelial cells in Matrigel. In addition, As2O3-treated epithelial ovarian cancer cells show a decreased VEGFA, VEGFR2 and CD31 mRNA expression. As per the underlying mechanisms involved in As2O3 treatment, we found that As2O3 inhibits VEGFA and VEGFR2 expression that thereby inhibits the VEGFA-VEGFR2-PI3K/ERK signaling pathway. This leads to a suppression in both VEGFA synthesis and angiogenesis-related gene expression. A decreased VEGFA synthesis and secretion also inhibits the VEGFA-VEGFR2-PI3K/ERK signaling pathway in human umbilical vein endothelial cells (HUVECs). In summary, our results may provide strategies for the use of As2O3 in the prevention of tumor angiogenesis.

Sox2 Communicates with Tregs Through CCL1 to Promote the Stemness Property of Breast Cancer Cells.

As an important component of the tumor microenvironment, CD4+ CD25+ Tregs reduce antitumor immunity, promote angiogenesis and metastasis in breast cancer. However, their function in regulating the "stemness" of tumor cells and the communication between Tregs and cancer stem cells (CSCs) remain elusive. Here, we disclose that the primarily cultured Tregs isolated from breast-tumor-bearing Foxp3-EGFP mouse upregulate the stemness property of breast cancer cells. Tregs increased the side-population and the Aldehyde dehydrogenase-bright population of mouse breast cancer cells, promoted their sphere formation in a paracrine manner, and enhanced the expression of stemness genes, such as Sox2 and so forth. In addition, Tregs increased tumorigenesis, metastasis, and chemoresistance of breast cancer cells. Furthermore, Sox2-overexpression tumor cells activated NF-κB-CCL1 signaling to recruit Tregs through reducing the binding of H3K27Me3 on promoter regions of p65 and Ccl1. These findings reveal the functional interaction between Tregs and CSCs and indicate that targeting on the communication between them is a promising strategy in breast cancer therapy. Stem Cells 2017;35:2351-2365.

Efficacy of sole pulmonary vein isolation in patients with nonparoxysmal atrial fibrillation without significant left atrium scar.

BACKGROUND: Catheter ablation strategies for nonparoxysmal atrial fibrillation (NPAF) are in varied forms. The mechanisms that circumferential pulmonary vein isolation (CPVI) alone could achieve success in some of the patients with NPAF are not well studied. This study sought to assess the clinical outcome of only CPVI approach in NPAF patients without significant left atrium scar. METHODS AND RESULTS: A total of 241 consecutive patients with NPAF undergoing an initial ablation procedure were studied. After CPVI, cavotricuspid isthmus ablation and direct current cardioversion, high-density atrial voltage mapping was performed during sinus rhythm. Transitional-voltage zone (TZ) was defined as 0.4-1.3 mV, and low-voltage zone (LVZ) as <0.4 mV. No LVZs were identified in 101 patients (41.9%), and only CPVI was performed. Among the patients without LVZs, single-procedure freedom from atrial fibrillation (AF)/atrial tachycardia was achieved in 73 patients (72%), while 28 patients (28%) had AF recurrence with mean follow-up of 29 ± 14 months. TZ index (TZi) was deduced by calculating the ratio of all TZ points over the total number of points and was found to be a univariate predictor of recurrence after a single procedure (P  =  0.047). CONCLUSIONS: The CPVI alone strategy for patients with NPAF can be performed in highly selective patients without LVZs. TZi may reflect healthy extent of left atrium, which has trend toward the association with AF recurrence.

Ifit1 Protects Against Lipopolysaccharide and D-galactosamine-Induced Fatal Hepatitis by Inhibiting Activation of the JNK Pathway.

Treatment of mice with lipopolysaccharide (LPS) and the liver-specific transcriptional inhibitor D-(+)-galactosamine (GalN) induces fatal hepatitis, which is mediated by tumor necrosis factor α (TNF-α) and characterized by massive hepatic apoptosis. Previous studies suggest that GalN increases the sensitivity to LPS/TNF-α, probably by blocking the transcription of protective factors, but the identity of most of these factors is still unclear. Here, we report that Ifit1 protects against LPS/GalN-induced fatal hepatitis. Forced expression of Ifit1 in hepatocytes significantly diminished TNF-α-mediated apoptosis. Moreover, targeted expression of Ifit1 in the liver by recombinant adeno-associated virus serotype 8 protected mice from LPS/GalN-induced lethal hepatitis, which was associated with the inhibition of TNF-α-mediated activation of the c-Jun N-terminal kinase (JNK)-Bim cascade. Furthermore, Ifit1 bound to a scaffolding protein Axin and inhibited its function to mediate JNK activation. Together, our data demonstrate that Ifit1 is a novel protective factor that inhibits LPS/GalN-induced (TNF-α-mediated) fatal hepatitis, suggesting that Ifit1 is a potential therapeutic target for treatment of inflammatory liver diseases.

Erratum: PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer: Erratum.

[This corrects the article DOI: 10.7150/jca.66773.].

RV1+RV3 Index to Differentiate Idiopathic Ventricular Arrhythmias Arising From Right Ventricular Outflow Tract and Aortic Sinus of Valsalva: A Multicenter Study.

BACKGROUND: This study aimed to investigate the predictive value of parameters of every precordial lead and their combinations in differentiating between idiopathic ventricular arrhythmias (IVAs) from the right ventricular outflow tract and aortic sinus of Valsalva (ASV). METHODS AND RESULTS: Between March 1, 2018, and December 1, 2021, consecutive patients receiving successful ablation of right ventricular outflow tract or ASV IVAs were enrolled. The amplitude and duration of the R wave and S wave were measured in every precordial lead during IVAs. These parameters were either summed, subtracted, multiplied, or divided to create different indexes. The index with the highest area under the curve to predict ASV IVAs was developed, compared with established indexes, and validated in an independent prospective multicenter cohort. A total of 150 patients (60 men; mean age, 45.3±16.4 years) were included in the derivation cohort. The RV1+RV3 index (summed R-wave amplitude in leads V1 and V3) had the highest area under the curve (0.942) among the established indexes. An RV1+RV3 index >1.3 mV could predict ASV IVAs with a sensitivity of 95% and a specificity of 83%. Its predictive performance was maintained in the validation cohort (N=109). In patients with V3 R/S transition, an RV1+RV3 index >1.3 mV could predict ASV IVAs, with an area under the curve of 0.892, 93% sensitivity, and 75% specificity. CONCLUSIONS: The RV1+RV3 index is a simple and novel criterion that accurately differentiates between right ventricular outflow tract and ASV IVAs. Its performance outperformed established indexes, making it a valuable tool in clinical practice.

CHDH, a key mitochondrial enzyme, plays a diagnostic role in metabolic disorders diseases and tumor progression.

Human choline dehydrogenase (CHDH) is a transmembrane protein located in mitochondria. CHDH has been shown to be one of the important catalytic enzymes that catalyze the oxidation of choline to betaine and is involved in mitochondrial autophagy after mitochondrial damage. In recent years, an increasing number of studies have focused on CHDH and found a close association with the pathogenesis of various diseases, including tumor prognosis. Here we summarized the genomic localization, protein structure and basic functions of CHDH and discuss the progress of CHDH research in metabolic disorders and other diseases. Moreover, we described the regulatory role of CHDH on the progression of different types of malignant tumors. In addition, major pathogenic mechanisms of CHDH in multiple diseases may be associated with single nucleotide polymorphism (SNP). We look forward to providing new strategies and basis for clinical diagnosis and prognosis prediction of diseases by diagnosing SNP loci of CHDH genes. Our work evaluates the feasibility of CHDH as a molecular marker relevant to the diagnosis of some metabolic disorders diseases and tumors, which may provide new targets for the treatment of related diseases and tumors.

TBX21 attenuates colorectal cancer progression via an ARHGAP29/RSK/GSK3ß dependent manner.

PURPOSE: Previous studies have shown that TBX21 (T-Box Transcription Factor 21) plays a vital role in coordinating multiple aspects of the immune response especially type 1 immune response as well as tumor progression. However, the function of TBX21 in colorectal cancer (CRC) remains unclear. METHODS: IHC to investigate TBX21 expression in CRC tissues. Cell proliferation and apoptosis assays to validate TBX21 function in vitro and in vivo. RNA-seq assay to explore target genes of TBX21. Human phospho-kinase array assay to explore down-stream signaling of TBX21. RESULTS: We disclosed that the expression of TBX21 was marked decreased in CRC versus normal tissue, and negatively correlated with CRC TNM stages. Surprisingly, we found that the CRC and normal cell lines show no TBX21 expression levels. Ectopic expression of TBX21 inhibited cell proliferation and promoted cell apoptosis in vitro. Moreover, RNA-sequence data first time showed that ARHGAP29 acts as the target gene of TBX21 to mediate down-stream signaling activation. Human phospho-kinase array data first time displayed that ectopic expression of TBX21 reduced kinase RSK and GSK3ß activation. In contrast, knocked down the expression of TBX21 or ARHGAP29 alternatively abolished TBX21 mediated cell proliferation suppression, cell apoptosis enhancement and RSK/GSK3ß activation. In addition, xenograft model studies demonstrated that TBX21 inhibits colorectal tumor progression via ARHGAP29/ RSK/ GSK3ß signaling in vivo. CONCLUSIONS: In summary, the aforementioned findings suggest a model of TBX21 in suppressing CRC progression. This may provide a promising target for CRC therapy.

XMU-MP-1 protects heart from ischemia/reperfusion injury in mice through modulating Mst1/AMPK pathway.

Up to now, there are few therapeutic approaches available to protect heart from ischemia/reperfusion (I/R) injury. The present work was designed to examine the protection of XMU-MP-1, an inhibitor of mammalian sterile 20-like kinase 1 (Mst1), against myocardial I/R injury in mice and investigate the underlying molecular mechanisms. The wild-type and Mst1 (-/-) mice were exposed to I/R injury and treated with XMU-MP-1 immediately after reperfusion. Treatment with XMU-MP-1 reduced infarct size, attenuated apoptosis and necrosis, and preserved cardiac function of I/R mice. XMU-MP-1 mitigated mitochondrial dysfunction in myocardium of I/R mice. In addition, XMU-MP-1 stimulated M2 macrophage polarization and suppressed inflammation in myocardium of I/R mice. Mst1 deficiency had similar benefits on myocardial I/R injury and XMU-MP-1 treatment did not provide further protection against I/R injury in Mst1 (-/-) mice. Both treatment with XMU-MP-1 and Mst1 deficiency promoted the activation of AMPKα in myocardium of I/R mice. More importantly, administration of Compound C (a specific AMPK signaling blocker) blunted the protective effects of XMU-MP-1 on myocardial I/R injury. Collectively, reperfusion therapy with XMU-MP-1 mitigated myocardial I/R injury and preserved myocardial function in mice through modulating Mst1/AMPK pathway.