The value of machine learning approaches in the diagnosis of early gastric cancer: a systematic review and meta-analysis.

BACKGROUND: The application of machine learning (ML) for identifying early gastric cancer (EGC) has drawn increasing attention. However, there lacks evidence-based support for its specific diagnostic performance. Hence, this systematic review and meta-analysis was implemented to assess the performance of image-based ML in EGC diagnosis. METHODS: We performed a comprehensive electronic search in PubMed, Embase, Cochrane Library, and Web of Science up to September 25, 2022. QUADAS-2 was selected to judge the risk of bias of included articles. We did the meta-analysis using a bivariant mixed-effect model. Sensitivity analysis and heterogeneity test were performed. RESULTS: Twenty-one articles were enrolled. The sensitivity (SEN), specificity (SPE), and SROC of ML-based models were 0.91 (95% CI: 0.87-0.94), 0.85 (95% CI: 0.81-0.89), and 0.94 (95% CI: 0.39-1.00) in the training set and 0.90 (95% CI: 0.86-0.93), 0.90 (95% CI: 0.86-0.92), and 0.96 (95% CI: 0.19-1.00) in the validation set. The SEN, SPE, and SROC of EGC diagnosis by non-specialist clinicians were 0.64 (95% CI: 0.56-0.71), 0.84 (95% CI: 0.77-0.89), and 0.80 (95% CI: 0.29-0.97), and those by specialist clinicians were 0.80 (95% CI: 0.74-0.85), 0.88 (95% CI: 0.85-0.91), and 0.91 (95% CI: 0.37-0.99). With the assistance of ML models, the SEN of non-specialist physicians in the diagnosis of EGC was significantly improved (0.76 vs 0.64). CONCLUSION: ML-based diagnostic models have greater performance in the identification of EGC. The diagnostic accuracy of non-specialist clinicians can be improved to the level of the specialists with the assistance of ML models. The results suggest that ML models can better assist less experienced clinicians in diagnosing EGC under endoscopy and have broad clinical application value.

A Cuproptosis-Related LncRNA Risk Model for Predicting Prognosis and Immunotherapeutic Efficacy in Patients with Hepatocellular Carcinoma.

Cuproptosis is a novel programmed cell death pathway that is initiated by direct binding of copper to lipoylated tricarboxylic acid (TCA) cycle proteins. Recent studies have demonstrated that cuproptosis-related genes regulate tumorigenesis. However, the potential role and clinical significance of cuproptosis-related long noncoding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) have not been established. We performed a bioinformatics analyses of RNA-sequencing data of HCC patients extracted from The Cancer Genome Atlas (TCGA) dataset to identify and validate a cuproptosis-related lncRNA prognostic signature. Furthermore, we analyzed the clinical significance of the prognostic signature of cuproptosis-related lncRNA in predicting the immunotherapeutic efficacy and the status of the tumor immune microenvironment. The RNA-sequencing data, genomic mutations, and clinical information were downloaded for 374 HCC samples and 50 normal liver samples from TCGA-Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. Co-expression analysis of Gene-lncRNA pairs with 49 known cuproptosis-related prognostic genes was used to define cuproptosis-related prognostic lncRNAs. We performed the LASSO algorithm and univariate and multivariate Cox regression analysis, respectively, to gradually identify the prognostic risk models of cuproptosis-related lncRNA based on the TCGA-LIHC dataset. Subsequently, the predictive performance of the model was evaluated using receiver operation characteristic (ROC) curves, Kaplan-Meier survival curves, and prognostic nomogram. The analysis of gene-lncRNA co-expression with 49 known cuproptosis-related genes identified 1359 cuproptosis-related lncRNAs in the TCGA-LIHC data set. A prognostic model was constructed with nine cuproptosis-related prognostic lncRNAs (AC007998.3, AC003086.1, AC009974.2, IQCH-AS1, LINC0256 1, AC105345.1, ZFPM2-AS1, AL353708.1 and WAC-AS1) using LASSO regression and Cox regression analyses. Risk scores were calculated for all HCC patient samples based on the four cuproptosis-related lncRNA prognostic models. All HCC patients were divided into high-risk and low-risk subgroups according to a 1:1 ratio column. The Kaplan-Meier survival curve analysis showed that the overall survival rate (OS) of the high-risk group patients was significantly lower than that of the low-risk group. The principal component analysis (PCA) confirmed that the prognostic lncRNA model accurately distinguished between high- and low-risk HCC patients. Furthermore, regression analysis as well as ROC curves confirmed the prognostic value of the risk score. A nomogram with risk scores and other clinicopathological characteristics was constructed. The nomogram accurately predicted the probability of 1-, 3-, and 5-year OS in HCC patients. Tumor mutation burden (TMB) scores were higher for high-risk patients than for low-risk patients. HCC patients in the low-risk group showed lower TIDE scores and greater sensitivity to antitumor drugs than those in the high-risk group. Tumor immune responses and tumor immune cell infiltration were significantly different between the high-risk and low-risk groups of patients with HCC. Our study identified a 9-cuproptosis-related lncRNA signature that accurately predicted prognosis, immunotherapeutic efficacy, and the status of the tumor immune microenvironment in HCC patients. Therefore, this cuproptosis-related lncRNA risk model is a potential prognostic biometric feature in HCC and shows high clinical value in identifying HCC patients who are potentially responsive to immunotherapy.

Isolation of Leclercia adecarboxylata Producing Carbapenemases in A Newborn Female.

Leclercia adecarboxylata is a Gram-negative bacterium belonging to the Enterobacteriaceae family. To our knowledge, this is the first report of a carbapenem-resistant L. adecarboxylata strain isolated from a healthy newborn. The L. adecarboxylata strain isolated in this study carried four plasmids that may serve as reservoirs for antibiotic resistance genes. Plasmids 2 and 4 did not harbor any antimicrobial resistance genes. Plasmid 3 is a novel plasmid containing three resistance genes. The bla IMP gene harbored in the strain was most similar to bla IMP-79 at the nucleotide level, with a similarity of 99.4% (737/741). This case highlights the importance of considering L. adecarboxylata as a potential cause of infections in children.

Construction and validation of a prognostic nomogram for predicting cancer-specific survival in patients with intermediate and advanced colon cancer after receiving surgery and chemotherapy.

BACKGROUND: Existing predictive models often focus solely on overall survival (OS), neglecting the bias that other causes of death might introduce into survival rate predictions. To date, there is no strict predictive model established for cancer-specific survival (CSS) in patients with intermediate and advanced colon cancer after receiving surgery and chemotherapy. METHODS: We extracted the data from the Surveillance, Epidemiology, and End Results (SEER) database on patients with stage-III and -IV colon cancer treated with surgery and chemotherapy between 2010 and 2015. The cancer-specific survival (CSS) was assessed using a competitive risk model, and the associated risk factors were identified via univariate and multivariate analyses. A nomogram predicting 1-, 3-, and 5-year CSS was constructed. The c-index, area under the curve (AUC), and calibration curve were adopted to assess the predictive performance of the model. Additionally, the model was externally validated. RESULTS: A total of 18 risk factors were identified by univariate and multivariate analyses for constructing the nomogram. The AUC values of the nomogram for the 1-, 3-, and 5-year CSS prediction were 0.831, 0.842, and 0.848 in the training set; 0.842, 0.853, and 0.849 in the internal validation set; and 0.815, 0.823, and 0.839 in the external validation set. The C-index were 0.826 (se: 0.001), 0.836 (se: 0.002) and 0.763 (se: 0.013), respectively. Moreover, the calibration curve showed great calibration. CONCLUSION: The model we have constructed is of great accuracy and reliability, and can help physicians develop treatment and follow-up strategies that are beneficial to the survival of the patients.

Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer's disease via cGAS-STING.

Alzheimer's disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear. In this study, we demonstrated that AD transgenic mice exhibited cognitive deficits accompanied by the elevated serum and brain inflammation. Treating with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) from the Chinese herb Polygonum multiflorum that has been well known for its unique anti-aging effect, learning-memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN-γ induced microglia activation showed that TSG reversed the polarization status of M1-type microglia to restore the quiescence, and cGAS-STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL-1ß, IL-6, TNF-α, IFN-α and IFN-ß, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN-γ-stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS-STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS-STING inhibitors. Taken together, our findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS-STING signaling pathway in AD.

Effect of COP1 in Promoting the Tumorigenesis of Gastric Cancer by Down-Regulation of CDH18 via PI3K/AKT Signal Pathway.

In recent years, the involvement of E3 ubiquitin ligase constitutive photomorphogenesis 1 (COP1) in the tumorigenesis of gastric cancer (GC) has been elucidated. However, the exact underlying mechanism remains to be clarified. In the present study, the expression profiles of COP1 in GC were derived from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases, followed by verification via immunohistochemical staining (IHC), Western blotting (WB), and quantitative real-time polymerase chain reaction (qRT-PCR) reaction assays on clinical samples. In vitro, the gain- and loss-of-function experiments of COP1 protein were conducted to explore its role in GC cell lines HGC-27 and SGC-7901. Furthermore, we screened the interaction protein of COP1 by yeast two-hybrid experiment and verified their combination by co-immunoprecipitation (co-IP). We preliminary explored the possible underlying mechanisms of COP1 protein in GC cell lines via WB. COP1 was upregulated in GC tissues compared with the corresponding non-carcinoma tissues. In vitro, the upregulation of COP1 protein promoted the proliferation and migration of GC cells. The yeast two-hybrid experiment and co-IP indicated that Cadherin 18 (CDH18) could constitute a complex with COP1. Moreover, cells with COP1 over-expression showed low levels of CDH18 expression, with the intracellular PI3K/AKT pathway activated and the malignancy of GC cell lines enhanced. Our findings demonstrated that COP1 promoted the GC tumorigenesis by downregulated CDH18 with the involvement of PI3K/AKT signaling pathway in cell lines, suggesting the potential of COP1 as a prognostic biomarker and therapeutic target for GC.

Tetrahydroxy stilbene glucoside alters neurogenesis and neuroinflammation to ameliorate radiation-associated cognitive disability via AMPK/Tet2.

Along with the extensive application of radiation in medical, military and other fields, human beings carry a greater risk of exposure to radiation environment that causes a range of physical injure, particularly to the brain in cognition. However, the radiation-associated cognitive disability is poorly understood and there is no effective prevention or long-term treatment. Here, we demonstrate that neurogenesis and neuroinflammation disorder are primarily involved in the pathophysiological basis of irradiation-induced cognitive decline. Furthermore, we discovered that tetrahydroxy stilbene glucoside (TSG), a natural active ingredient from Heshouwu that has been well known for its unique anti-aging effect as the Chinese herb, can be a promising mitigator to improve learning-memory ability by facilitating the neurogenesis in the proliferation and differentiation of the surviving neural progenitor cells via AMPK/Tet2, and attenuating the neuroinflammation in the microglial NLRP3 inflammasomes activation via AMPK in vivo. Additionally, TSG was also revealed to activate AMPK by molecular docking and kinase enzyme system assay in vitro. Taken together, our findings identify TSG, as the AMPK activator, prevents radiation-induced cognitive dysfunction by regulating neurogenesis and neuroinflammation via AMPK/Tet2 in rodents, and represents a very promising candidate for developing drugs that can be used for radiation-associated brain injury.

The involvement of Pellino-1 downregulation in the modulation of visceral hypersensitivity via the TLR4/NF-κB pathway in the rat fastigial nucleus.

Irritable bowel syndrome (IBS) is a common functional bowel disorder whose key characteristics include chronic visceral hypersensitivity (CVH) and abnormal brain-gut interactions. Pellino-1 is an E3 ubiquitin ligase, mediating the degradation or modification of targeted proteins. Some brain regions, such as the fastigial nucleus (FN), may play important roles in CVH; however, the molecular mechanism underlying this phenomenon is not clear. In this study, we assessed the roles of Pellino-1 within the FN in modulating VH by generating a colorectal distention (CRD) model in male Sprague-Dawley rats. Our results showed that the downregulation of Pellino-1 in the fastigial nucleus (FN) was involved in the modulation of visceral hypersensitivity. The expression of Pellino-1 was downregulated in the FN of adult CRD rats compared with control rats, whereas TLR4 and NF-κB were upregulated in the CRD model. To overexpress Pellino-1, a lentivirus specifically expressing Pellino-1 and green fluorescent protein was administered into the FN. The overexpression of Pellino-1 increased the visceral sensitivity of CRD rats, and the expression of TLR4 and NF-κB increased further. After administration of TAK-242 (a specific TLR4 inhibitor), the visceral response to overexpression of Pellino-1 was reversed. Overall, the findings indicated the involvement of the FN in the development of CVH; the downregulation of Pellino-1 in the FN acted through the TLR4/NF-κB pathway to protect against CVH in a CRD rat model.

Low serum pepsinogen II levels are closely linked with a risk of metabolic syndrome among healthy individuals with asymptomatic Helicobacter pylori infection: a cross-sectional study.

Aim:Helicobacter pylori (Hp) infection has a connection with metabolic syndrome (MetS). Pepsinogen II (PGII) is a marker for gastric epithelial function. The present research was aimed at determining the associations among serum PGII levels, Hp infection and MetS in healthy subjects. Methods: This cross-sectional study enrolled 1242 healthy people, including 545 subjects with asymptomatic Hp infection and 697 subjects without Hp infection. Based on the number of MetS components present, subjects with Hp infection were assigned to the following groups: group 1, no component (126 subjects); group 2, one or two components (260 subjects); and group 3, three or more components (159 subjects). Physical measurements and biochemical indices were recorded. Serum PGII levels were recorded using ELISA. SPSS and GraphPad Prism were used for statistical analyses. Results: Among subjects with Hp infection, serum PGII was evidently downregulated in group 3 compared with group 1 (14.95 ± 8.24 vs 17.97 ± 9.08 µg/l; p = 0.015). Serum PGII levels were correlated with an increased risk of MetS (odds ratio: 0.867; 95% CI: 0.772-0.974; p = 0.016), as indicated by the multivariate logistic regression analysis. Grouping subjects with Hp infection according to quartiles of serum PGII levels identified an evident difference in MetS prevalence among the four quartile-based groups (p = 0.047). Conclusions: Among healthy subjects with asymptomatic Hp infection, serum PGII levels were lower in those with MetS than in those without MetS. Serum PGII levels showed an independent and negative correlation with the risk of MetS in healthy subjects with Hp infection.

[WU Lian-zhong's experience in treating spasmodic torticollis by Kaiqiao Shunjin method].

Professor WU Lian-zhong's experience in treating spasmodic torticollis by Kaiqiao Shunjin method (resuscitation and regulating muscle) is summarized in this paper. The pathogenesis of spasmodic torticollis is the occluded brain orifices and delirium, qi disorder of meridian tendons, specifically divided into five categories: damp-heat, liver-yang hyperactivity, liver-kidney yin deficiency, deficiency of the governor vessel, excess of the governor vessel. The treatment should be based on the symptoms and the root causes, the symptoms should be the main treatment, and the root cause should be treated based on syndrome differentiation. The main treatment is Kaiqiao Shunjin method (resuscitation and regulating muscle), and to take the chief (five heart acupoints-Shuigou [GV 26], Laogong [PC 8], Yongquan [KI 1]), deputy (Yintang [GV 24+], Shangxing [GV 23] through Baihui [GV 20], Ximen [PC 4]), assistant (Fenglong [ST 40], Lianquan [CV 23], combined with tongue needle prick), envoy (Hanyan [GB 4]) as the basic main acupoints, at the same time cooperate with local acupoints to remove knots and accumulation. Finally, syndrome differentiation is adopted to dredge meridians and disperse knots, regulate the governor vessel, and nourish yin and dispel wind.

Differential Activation of pERK1/2 and c-Fos Following Injury to Different Regions of Primary Sensory Neuron.

Nerve injury causes hyperexcitability of the dorsal root ganglion (DRG) and spinal dorsal horn (DH) neurons, which results in neuropathic pain. We have previously demonstrated that partial dorsal rhizotomy (PDR) produced less severe pain-like behavior than chronic constriction injury (CCI) or chronic compression of DRG (CCD) and did not enhance DRG neuronal excitability. However, the mechanisms underlying such discrepancy remain unclear. This study was designed to compare the activation of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) in DRG and DH, and c-Fos in DH following treatments of CCI, CCD, and PDR. We confirmed that thermal hyperalgesia produced by PDR was less severe than that produced by CCI or CCD. We showed that pERK1/2 in DRG and DH was greatly activated by CCI or CCD, whereas PDR produced only transient and mild pERK1/2 activation. CCI, CCD, and PDR induced robust c-Fos expression in DH; nevertheless, c-Fos+ neurons following PDR were much fewer than that following CCI or CCD. Blocking retrograde axonal transport by colchicine proximal to the CCI injury site diminished thermal hyperalgesia and inhibited pERK1/2 and c-Fos activation. These findings demonstrate that less severe pain-like behavior produced by PDR than CCI or CCD attributes to less activation of pERK1/2 and c-Fos. Such neurochemical activation partially relies on retrograde axonal transport of certain "injury signals" from the peripheral injured site to DRG somata.

Protective effect of HCN2-induced SON sensitization on chronic visceral hypersensitivity in neonatal-CRD rat model.

Abnormal brain-gut interactions contribute to the development of chronic visceral hypersensitivity (CVH), which is the pivotal feature of irritable bowel syndrome (IBS). Despite the consensus with respect to the vital role of hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channels in promoting painful symptoms in the peripheral nervous system, we identified that the upregulation of HCN2 in supraoptic nucleus (SON) was involved in the modulation of CVH in rat model of neonatal colorectal distention (n-CRD). Specifically, colorectal distention (CRD) upregulated the expression of c-Fos in SON in adult CVH rats, indicating the involvement of SON sensitazation in visceral sensation. Moreover, the administration of ZD7288 (the pan-HCN channel inhibitor) rather than 8-Br-cAMP (the non-specific HCN channel agonist) aggravated the CVH symptoms and reduced the phosphorylation level of CaMKII-CREB cascade. Together, the findings indicated that the upregulation of supraoptic HCN2 contributed to the sensitization of SON, which had protective effects on the modulation of CVH with the involvement of CaMKII-CREB cascade in n-CRD rat model.

Tetrahydroxy Stilbene Glucoside Ameliorates Cognitive Impairments and Pathology in APP/PS1 Transgenic Mice.

Cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD), and amyloid-ß (Aß) deposition and senile plaques are the characteristic neuropathological hallmarks in AD brains. This study aimed to explore the effect and mechanism of tetrahydroxy stilbene glucoside (TSG) on cognitive function in APP/PS1 mice during long-term administration. Here, we treated APP/PS1 model mice of AD with different doses of TSG (50 mg/kg and 100 mg/kg) for 5 to 17 months by gavage, and we further observed whether TSG could ameliorate the cognitive decline in APP/PS1 mice using behavioral tests, and investigated the possible mechanisms by immunohistochemistry and Western blotting. Our results showed that TSG treatment rescued the spatial and non-spatial learning and memory impairments of APP/PS1 mice at Morris water maze test and novel object recognition test. Furthermore, Aß40/42 deposition in the cortex and hippocampus of APP/PS1 mice treated with TSG was significantly reduced compared to the wild type mice using the immunohistochemical technique. Finally, Western blotting showed that TSG primarily decreased the APP expression to avoid the Aß plaque deposition in the cortex and hippocampus of mice. These results reveal the beneficial effects of TSG in APP/PS1-AD mice, which may be associated with the reduction of Aß deposits in the brain.

The implication of transient receptor potential canonical 6 in BDNF-induced mechanical allodynia in rat model of diabetic neuropathic pain.

AIMS: Brain-derived neurotrophic factor (BDNF) is vital in the pathogenesis of mechanical allodynia with a paucity of reports available regarding diabetic neuropathy pain (DNP). Herein we identified the involvement of BDNF in driving mechanical allodynia in DNP rats via the activation of transient receptor potential canonical 6 (TRPC6) channel. MATERIALS AND METHODS: The DNP rat model was established via streptozotocin (STZ) injection, and allodynia was assessed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). The expression profiles of BDNF and TRPC6 in dorsal root ganglia (DRG) and spinal cord were illustrated by immunofluorescence and Western blotting. Intrathecal administration of K252a or TrkB-Fc was performed to inhibit BNDF/TrkB expression, and respective injection of GsMTX-4, BTP2 and TRPC6 antisense oligodeoxynucleotides (TRPC6-AS) was likewise conducted to inhibit TRPC6 expression in DNP rats. Calcium influx in DRG was monitored by calcium imaging. KEY FINDINGS: The time-dependent increase of BDNF and TRPC6 expression in DRG and spinal cord was observed since the 7th post-STZ day, correlated with the development of mechanical allodynia in DNP rats. Intrathecal administration of K252a, TrkB-Fc, GsMTX-4 and BTP2 prevented mechanical allodynia in DNP rats. Pre-treatment of TRPC6-AS reversed the BDNF-induced pain-like responses in DNP rats rather than the naïve rats. In addition, the TRPC6-AS reversed BDNF-induced increase of calcium influx in DRG neurons in DNP rats. SIGNIFICANCE: The intrathecal inhibition of TRPC6 alleviated the BDNF-induced mechanical allodynia in DNP rat model. This finding may validate the application of TRPC6 antagonists as interesting strategy for DNP management.

Regulation of ARL2 in colorectal cancer cell proliferation and tumorigenicity, and its negative association with AXL.

Colorectal cancer (CRC) is the third most common malignant disease in adults. ADP ribosylation factor-like GTPase 2 (ARL2) is crucial for controlling the dynamics of microtubules and mitochondrial functions. However, the biological function of ARL2 in CRC remains unclear. The present study was performed to identify the expression level and functional role of ARL2 in CRC. A total of 19 CRC and 3 normal healthy colorectal tissues were collected. Furthermore, ARL2 expression was analyzed in healthy colorectal and CRC tissues by immunohistochemistry (IHC). ARL2 overexpression and knockdown was achieved using lentiviral vectors and plasmid transfection in HCT8 and HCT116 cells. The protein and mRNA expression levels of ARL2 and AXL were analyzed using western blot and reverse transcription-quantitative PCR in ARL2 knockdown and ARL2 overexpressing HCT8 and HCT116 cells. Cell Counting Kit-8, colony formation, wound healing, and Matrigel assays were used to investigate the biological functions of ARL2. Taken together, ARL2 protein expression level was upregulated in CRC tissues. Furthermore, ARL2 overexpression decreased proliferation and weakened the colony-formation abilities of the CRC cells, as well as their migratory and invasive abilities. ARL2 interference enhanced proliferation and colony-formation rates of the CRC cells, as well as their migratory and invasive abilities. ARL2 regulated CRC proliferation and tumorigenicity and was negatively associated with AXL. The results of the present study suggested that the proliferation, migration and tumorigenicity of the CRC cells could be inhibited by ARL2 overexpression. The latter may be used as a predicted and potential therapeutic target for CRC.

Inhibition of Bcl2L12 Attenuates Eosinophilia-Related Inflammation in the Heart.

Background: The eosinophilic inflammation plays a critical role in myocarditis (Mcd); its underlying mechanism remains to be further elucidated. This study aims to investigate the role of Bcl2-like protein 12 (Bcl2L12) in inducing the defects of apoptosis in eosinophils (Eos) of the heart tissues. Methods: Human explant heart samples were collected. Eosinophilia and myocarditis (Mcd)-like inflammation were induced in the mouse heart by immunizing with murine cardiac α-myosin heavy chain (MyHCα) peptides. Results: Markedly more Eos were observed in heart tissues from patients with Mcd than those from patients with dilated cardiomyopathy. Eos isolated from Mcd hearts showed the signs of apoptosis defects. The Eo counts in the Mcd heart tissues were positively correlated with the Bcl2L12 expression in Eos isolated from the heart tissues. Exposure to interleukin 5 in the culture induced the expression of Bcl2L12 in Eos. Bcl2L12 bound c-Myc, the transcription factor of Fas ligand (FasL), to prevent c-Myc from binding to the FasL promoter, to restrict the FasL gene transcription in Eos. Inhibition of Bcl2L12 prevented the induction of eosinophilia and Mcd-like inflammation in the mouse heart. Conclusions: The Bcl2L12 expression contributes to apoptosis defects in Eos of the Mcd heart. Blocking Bcl2L12 prevents the eosinophilia induction and alleviates Mcd-like inflammation in mice.

Protective effect of microinjection of glutamate into hypothalamus paraventricular nucleus on chronic visceral hypersensitivity in rats.

Chronic visceral hypersensitivity (CVH) is a major pathophysiological feature of patients experiencing in irritable bowel syndrome (IBS) and other disorders with visceral pain. However, little is known about its regulation of the central nucleus. In this research, we investigated the protective effect of microinjection of glutamate into hypothalamus paraventricular nucleus (PVN) on CVH and its possible regulatory mechanism in rats. Visceral sensitivity was assessed by pain threshold, abdominal withdrawal reflex (AWR) score, and the abdominal external oblique muscle electromyography (EMG) amplitude. Pathological changes in colorectal mucosa were assessed using immunohistochemical, biochemical analysis and Western blot. Results showed that microinjection of different doses of glutamate into PVN reduced the visceral sensitivity in a dose-dependent manner. This effect can be reversed after chemical ablation of PVN or nucleus tractus solitarius (NTS) or pretreatment with the arginine vasopressin (AVP)-V1 receptor antagonist ([Deamino-pen1,val4,D-Arg8]-vasopressin) DPVDAV into NTS. The vagus discharge frequency was significantly reduced after the glutamate microinjection into PVN. Additionally, oxidation, proliferation and apoptosis in colorectal mucosa were related to the CVH regulations. These findings suggested that PVN and NTS are involved in the regulatory process of CVH and exert the protective effect on CVH, providing new ideas and therapeutic targets for CVH research.

KCNQ5 and C9orf50 Methylation in Stool DNA for Early Detection of Colorectal Cancer.

BACKGROUND: Aberrant DNA methylation has emerged as a class of promising biomarkers for early colorectal cancer (CRC) detection, but the performance of methylated C9orf50 and methylated KCNQ5 in stool DNA has never been evaluated. METHODS: Methylation specific quantitative PCR (qPCR) assays for methylated C9orf50 and methylated KCNQ5 were developed. The methylation levels of C9orf50 and KCNQ5 in 198 CRC patients, 20 advanced adenoma (AA) patients, 101 small polyp (SP) patients, and 141 no evidence of disease (NED) subjects were analyzed. RESULTS: The methylation levels of both KCNQ5 and C9orf50 genes were significantly higher in CRC and AA groups than those in SP and NED groups, but showed no significant difference among different stages of CRC. The sensitivities of methylated KCNQ5 and methylated C9orf50 for CRC detection were 77.3% (95% CI: 70.7-82.8%) and 85.9% (95% CI: 80.0-90.2%) with specificities of 91.5% (95% CI: 85.3-95.3%) and 95.0% (95% CI: 89.7-97.8%), respectively. When C9orf50 and methylated KCNQ5 were combined, the clinical performance for CRC detection was similar to that of methylated C9orf50 alone. CONCLUSIONS: Stool DNA based methylated C9orf50 test has the potential to become an alternative approach for CRC screening and prevention.

FN1, SPARC, and SERPINE1 are highly expressed and significantly related to a poor prognosis of gastric adenocarcinoma revealed by microarray and bioinformatics.

Gastric adenocarcinoma (GAC), also known as stomach adenocarcinoma (STAD), is one of the most lethal malignancies in the world. It is vital to classify and detect the hub genes and key pathways participated in the initiation and progression of GAC. In this study, we collected and sequenced 15 pairs of GAC tumor tissues and the adjacent normal tissues. Differentially expressed genes (DEGs) were analyzed and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analysis were used to annotate the unique biological significance and important pathways of enriched DEGs. Moreover, we constructed the protein-protein interaction (PPI) network by Cytoscape and conducted KEGG enrichment analysis of the prime module. We further applied the TCGA database to start the survival analysis of these hub genes by Kaplan-Meier estimates. Finally, we obtained total 233 DEGs consisted of 64 up-regulated genes and 169 down-regulated genes. GO enrichment analysis found that DEGs most significantly enriched in single organism process, extracellular region, and extracellular region part. KEGG pathway enrichment analysis suggested that DEGs most significantly enriched in Protein digestion and absorption, Gastric acid secretion, and ECM-receptor interaction. Furthermore, the PPI network showed that the top 10 hub genes in GAC were IL8, COL1A1, MMP9, SST, COL1A2, TIMP1, FN1, SPARC, ALDH1A1, and SERPINE1 respectively. The prime gene interaction module in PPI network was enriched in protein digestion and absorption, ECM receptor interaction, the PI3K-Akt signaling pathway, and pathway in cancer. Survival analysis based on the TCGA database found that the expression of the FN1, SERPINE1, and SPARC significantly predicted poor prognosis of GAC. Collectively, we identified several hub genes and key pathways associated with GAC initiation and progression by analyzing the microarray data on DEGs, which provided a detailed molecular mechanism underlying GAC occurrence and progression.

Histone acetyltransferase 1 up regulates Bcl2L12 expression in nasopharyngeal cancer cells.

The deregulation of Bcl2L12 expression in cancer has been recognized, but the causative factors are unknown. Histone acetyltransferases (HAT) play critical roles in the regulation gene transcription. This study tests a hypothesis that the aberrant activities of HAT induce deregulation of Bcl2L12 in nasopharyngeal cancer (NPC). In this study, human NPC tissues were collected from the clinic. The expression of Bcl2L12 and HATs in NPC cells was analyzed by real time RT-PCR and Western blotting. NPC cell apoptosis was analyzed by flow cytometry. The results showed that by screening the subtypes of HAT, the levels of HAT1 were uniquely higher in NPC as compared with non-cancer nasopharyngeal tissue. The levels of Bcl2L12 in NPC cells were positively correlated with HAT1. HAT1 involved in the STAT5 binding to the Bcl2L12 promoter. HAT1 increased the expression of Bcl2L12. Bcl2L12 mediated the effects of HAT1 on suppressing NPC cell apoptosis. Absorption of the HAT1 shRNA plasmid-carrying liposomes induced NPC cell apoptosis. In conclusion, inhibition of HAT1 can induce NPC cell apoptosis via increasing Bcl2L12 expression, which can be a potential therapy for NPC treatment.