YiQi GuBen formula alleviates airway inflammation and airway remodeling in OVA-induced asthma mice through TLR4/NF-κB signaling pathway.

BACKGROUND: We aim to investigate the effect of YiQi GuBen formula (YQGB) on airway inflammation and airway remodeling in the ovalbumin (OVA)-induced asthma model to further explore the potential mechanisms of YQGB in treating allergic asthma. METHODS: Mice were divided into five groups randomly (n = 10): the control group, OVA group, OVA + Dex (0.1 mg/kg) group, OVA + low-dose (1.1 g/kg) YQGB group, and OVA + high-dose (2.2 g/kg) YQGB group. Inflammatory cell count and IgE were detected in bronchoalveolar lavage fluid (BALF). Lung tissue histopathology was observed by using H&E, PAS, Masson, and immunohistochemistry staining. qRT-PCR and western blot were applied to analyze key genes and proteins associated with TLR4 and NF-κB signaling pathways. RESULTS: In OVA-induced asthma mice, YQGB decreased eosinophils and IgE in BALF. YQGB alleviated the OVA-induced inflammatory infiltration and declined IL-4, IL-5, IL-13, Eotaxin, ECP, GM-CSF, LTC4, and LTD4. YQGB attenuated the OVA-induced goblet cell metaplasia and mucus hypersecretion. YQGB mitigated the OVA-induced subepithelial fibrosis and lowered TGF-ß1, E-Cadherin, Vimentin, and Fibronectin. YQGB ameliorated the OVA-induced airway smooth muscle thickening and lessened α-SMA and PDGF levels. YQGB reduced the expression of TLR4, MyD88, TRAF6, IκBα, and p65 mRNAs, and IκBα and p-p65 protein levels were also reduced. CONCLUSION: YQGB exhibits the anti-asthma effect by reducing airway inflammation and airway remodeling through suppressing TLR4/NF-κB signaling pathway, and is worth promoting clinically.

Association between parental occupational exposure and the risk of asthma in offspring: A meta-analysis and systematic review.

BACKGROUND: Previous epidemiological studies have shown inconsistent results regarding the relation between the risk of asthma in offspring and parental occupational exposure. Therefore, we conducted a comprehensive and systematic collection of currently available epidemiological data to quantify the correlation between the 2. METHODS: Related studies published before March 2023 were identified through searches of the Cochrane Library, Embase, PubMed, and Web of Science databases. The quality of included studies was assessed using the Newcastle-Ottawa Scale, while pooled odds ratios (ORs) with 95% confidence intervals (CIs) were computed using fixed-effect or random-effects models. RESULTS: This systematic review included 10 cohort studies, with a total of 89,571 parent-child pairs included in the quantitative analysis. The results exhibited a substantial association between parental occupational exposure to allergens (OR = 1.11; 95% CI: 1.00, 1.23; P = .051) and irritants (OR = 1.19; 95% CI: 1.07, 1.32; P = .001) and an increased risk of asthma in offspring. This association was also observed in the analysis of wheezing (OR = 1.22; 95% CI: 1.11, 1.35; P < .001 and OR = 1.19; 95% CI: 1.08, 1.32; P = .001). Subgroup analysis demonstrated that maternal occupational exposure to allergens (OR = 1.07; 95% CI: 1.02, 1.12; P = .008) and irritants (OR = 1.13; 95% CI: 1.05, 1.21; P = .001) significantly increased the risk of childhood asthma. Furthermore, parental postnatal occupational exposure to allergens (OR = 1.26; 95% CI: 1.10, 1.46; P = .001) and irritants (OR = 1.26; 95% CI: 1.06, 1.49; P = .009) had a more pronounced impact on childhood asthma. Higher levels of exposure (OR = 1.26; 95% CI: 1.10, 1.46; P = .001 and OR = 1.30; 95% CI: 1.16, 1.47; P < .001) were recognized as significant risk factors for childhood asthma. CONCLUSION: Parental occupational exposure to allergens and irritants increases the risk of asthma and wheezing in offspring, with maternal exposure, postnatal exposure, and high-dose exposure being the primary risk factors for childhood asthma.

Angiotensin-(1-7) ameliorates intestinal barrier dysfunction by activating the Keap1/Nrf2/HO-1 signaling pathway in acute pancreatitis.

BACKGROUND: Intestinal barrier dysfunction is a serious complication associated with acute pancreatitis (AP). Angiotensin (Ang)-(1-7) plays a protective role in the intestinal barrier, but the underlying mechanism remains clear. This study investigated the impact of Ang-(1-7) on AP-induced intestinal dysfunction and its involvement in the Keap1/Nrf2/HO-1 pathway. METHODS AND RESULTS: We studied caerulein- and lipopolysaccharide (LPS)-induced AP in mice and an epithelial cell line (IEC-6) from the small intestinal crypt of rats. Ang-(1-7) was administered orally or via the tail vein. IEC-6 cells were divided into five groups: control; LPS; LPS + Ang-(1-7); LPS + Ang-(1-7) + ML385 (an Nrf2 inhibitor); and LPS + ML385. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. The expression of intestinal barrier-associated proteins and Keap1/Nrf2/HO-1 pathway constituents was assessed by RT-PCR and western blotting. The peroxide and antioxidant activities in the IEC-6 cells were measured. Compared to those in AP mice, Ang-(1-7) diminished the intestinal levels of proinflammatory factors (interleukin-1ß and tumor necrosis factor α) and serum levels of intestine permeability (D-lactate). Ang-(1-7) increased the expression of barrier-associated proteins (aquaporin-1, claudin-1, and occludin) compared to those in the AP and LPS group. Moreover, Ang-(1-7) promoted the Keap/Nrf2/HO-1 pathway, which resulted in significantly reduced malondialdehyde and increased superoxide dismutase levels.. However, ML385 abolished the effects of Ang-(1-7) on barrier-associated proteins and reversed the Keap1/Nrf2/HO-1 pathway. CONCLUSIONS: Ang-(1-7) reduces AP-induced intestinal inflammation and oxidative injuries by activating the Keap1/Nrf2/HO-1 pathway.

Diagnosis of endometrium hyperplasia and screening of endometrial intraepithelial neoplasia in histopathological images using a global-to-local multi-scale convolutional neural network.

BACKGROUND AND OBJECTIVE: Endometrial hyperplasia (EH), a uterine pathology characterized by an increased gland-to-stroma ratio compared to normal endometrium (NE), may precede the development of endometrial cancer (EC). Particularly, atypical EH also known as endometrial intraepithelial neoplasia (EIN), has been proven to be a precursor of EC. Thus, diagnosing different EH (EIN, hyperplasia without atypia (HwA) and NE) and screening EIN from non-EIN are crucial for the health of female reproductive system. Computer-aided-diagnosis (CAD) was used to diagnose endometrial histological images based on machine learning and deep learning. However, these studies perform single-scale image analysis and thus can only characterize partial endometrial features. Empirically, both global (cytological changes relative to background) and local features (gland-to-stromal ratio and lesion dimension) are helpful in identifying endometrial lesions. METHODS: We proposed a global-to-local multi-scale convolutional neural network (G2LNet) to diagnose different EH and to screen EIN in endometrial histological images stained by hematoxylin and eosin (H&E). The G2LNet first used a supervised model in the global part to extract contextual features of endometrial lesions, and simultaneously deployed multi-instance learning in the local part to obtain textural features from multiple image patches. The contextual and textural features were used together to diagnose different endometrial lesions after fusion by a convolutional block attention module. In addition, we visualized the salient regions on both the global image and local images to investigate the interpretability of the model in endometrial diagnosis. RESULTS: In the five-fold cross validation on 7812 H&E images from 467 endometrial specimens, G2LNet achieved an accuracy of 97.01% for EH diagnosis and an area-under-the-curve (AUC) of 0.9902 for EIN screening, significantly higher than state-of-the-arts. In external validation on 1631 H&E images from 135 specimens, G2LNet achieved an accuracy of 95.34% for EH diagnosis, which was comparable to that of a mid-level pathologist (95.71%). Specifically, G2LNet had advantages in diagnosing EIN, while humans performed better in identifying NE and HwA. CONCLUSIONS: The developed G2LNet that integrated both the global (contextual) and local (textural) features may help pathologists diagnose endometrial lesions in clinical practices, especially to improve the accuracy and efficiency of screening for precancerous lesions.

Gluconate-Lactobionate-Dextran Perfusion Solutions Attenuate Ischemic Injury and Improve Function in a Murine Cardiac Transplant Model.

Static cold storage is the cheapest and easiest method and current gold standard to store and preserve donor organs. This study aimed to compare the preservative capacity of gluconate-lactobionate-dextran (Unisol) solutions to histidine-tryptophan-ketoglutarate (HTK) solution. Murine syngeneic heterotopic heart transplantations (Balb/c-Balb/c) were carried out after 18 h of static cold storage. Cardiac grafts were either flushed and stored with Unisol-based solutions with high-(UHK) and low-potassium (ULK) ± glutathione, or HTK. Cardiac grafts were assessed for rebeating and functionality, histomorphologic alterations, and cytokine expression. Unisol-based solutions demonstrated a faster rebeating time (UHK 56 s, UHK + Glut 44 s, ULK 45 s, ULK + Glut 47 s) compared to HTK (119.5 s) along with a better contractility early after reperfusion and at the endpoint on POD 3. Ischemic injury led to a significantly increased leukocyte recruitment, with similar degrees of tissue damage and inflammatory infiltrate in all groups, yet the number of apoptotic cells tended to be lower in ULK compared to HTK. In UHK- and ULK-treated animals, a trend toward decreased expression of proinflammatory markers was seen when compared to HTK. Unisol-based solutions showed an improved preservative capacity compared with the gold standard HTK early after cardiac transplantation. Supplemented glutathione did not further improve tissue-protective properties.

KPNA2 promotes renal cell carcinoma proliferation and metastasis via NPM.

Karyopherin α2 (KPNA2), involved in nucleocytoplasmic transport, has been reported to be up-regulated in tumorigenesis. However, comprehensive studies of KPNA2 functions in renal cell carcinoma (RCC) are still lacking. In this study, we aim to investigate the roles of KPNA2 in kidney tumour development. Our results showed that down-regulation of KPNA2 inhibited the proliferation and invasion of kidney tumour cell cells in vitro, while the cell cycle arrest and cellular apoptosis were induced once KPNA2 was silenced. Repression of KPNA2 was proved to be efficient to repress tumorigenesis and development of kidney tumour in in nude mice. Furthermore, one related participator, NPM, was identified based on Co-IP/MS and bioinformatics analyses. The up-regulation of NPM attenuates the efficiency of knockdown KPNA2. These results indicated that KPNA2 may regulate NPM to play a crucial role for kidney tumour development.

Upregulation of microRNA miR-141-3p and its prospective targets in endometrial carcinoma: a comprehensive study.

The clinicopathological value of microRNA-141-3p (miR-141-3p) and its prospective target genes in endometrial carcinoma (EC) remains unclear. The present study determined the expression level of miR-141-3p in EC via quantitative real-time PCR (RT-qPCR). RT-qPCR showed a markedly higher expression level of miR-141-3p in EC tissues than in non-EC endometrium tissues (P < 0.0001). The microarray and miRNA-seq data revealed upregulation of miR-141-3p. Integrated analysis based on 675 cases of EC and 63 controls gave a standardized mean difference of 1.737, confirmed the upregulation of miR-141-3p. The Kaplan-Meier survival curve showed that a higher expression of miR-141-3p positively corelated with a poorer prognosis. Combining the predicted targets and downregulated genes in EC, we obtained 271 target genes for miR-141-3p in EC. Two potential targets, PPP1R12A and PPP1R12B, were downregulated at both the mRNA and protein levels. This study indicates that the overexpression of miR-141-3p may play an important part in the carcinogenesis of EC. The overexpression of miR-141-3p may be a risk factor for the prognosis of patients with EC.

Pazopanib in patients with metastatic renal cell carcinoma: a single-center, real-world, retrospective Chinese study.

BACKGROUND: The efficacy and safety of pazopanib in patients diagnosed with metastatic renal cell carcinoma (mRCC) have been demonstrated by a Chinese subgroup analysis of the COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial. However, the real-world data are still unknown. This single-center, retrospective study was designed to verify the real-world effects of pazopanib in Chinese patients with mRCC. METHODS: Patients with mRCC and a clinical decision to initiate pazopanib as first-line therapy were eligible. The primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and safety being evaluated as secondary endpoints. The effectiveness according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model, number of risk factors in the intermediate risk group, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and the number and site of organ metastasis were also assessed. RESULTS: A total of 32 patients were enrolled, including 23 (71.9%) males and 9 (28.1%) females. The median age was 57 years (range 29-75 years). With a median follow-up time of 23.8 months, a median PFS of 18.3 months, and an ORR of 37.5%. Median OS was not reached, and the 1-, 2-, and 3-year overall survival rates were 90.6%, 78.1, and 65.6%, respectively. According to IMDC risk model, 37.5% were placed in the favorable risk (FR) subgroup, 56.2% (the majority) were placed in the intermediate risk (IR) subgroup, and 6.3% were placed in the poor risk (PR) subgroup. Compared with the IR and PR groups, the FR group achieved the best ORR (58.3%) and median PFS (22.1 months). Having 1 risk factor, ECOG PS <2, 1 organ metastasis site, and only lung metastasis associated with a higher ORR and better median PFS. The IMDC risk model and number of metastases were associated with PFS. The most common adverse events were change in hair color (69.0%), diarrhea (63%), and hypertension (50%). CONCLUSIONS: Pazopanib showed efficacy and safety in real-world Chinese mRCC patients.

PSD-95 protects the pancreas against pathological damage through p38 MAPK signaling pathway in acute pancreatitis.

Acute pancreatitis is one of the leading causes of gastrointestinal disorder-related hospitalizations, yet its pathogenesis remains to be fully elucidated. Postsynaptic density protein-95 (PSD-95) is closely associated with tissue inflammation and injury. We aimed to investigate the expression of PSD-95 in pancreatic acinar cells, and its function in regulating the inflammatory response and pancreatic pathological damage in acute pancreatitis. A mouse model of edematous acute pancreatitis was induced with caerulein and lipopolysaccharide in C57BL/6 mice. Tat-N-dimer was injected to inhibit the PSD-95 activity separately, or simultaneously with SB203580, inhibitor of p38 MAPK phosphorylation. Rat pancreatic acinar cells AR42J were cultured with 1 µM caerulein to build a cell model of acute pancreatitis. PSD-95-knockdown and negative control cell lines were constructed by lentiviral transfection of AR42J cells. Paraffin-embedded pancreatic tissue samples were processed for routine HE staining to evaluate the pathological changes of human and mouse pancreatic tissues. Serum amylase and inflammatory cytokine levels were detected with specific ELISA kits. Immunofluorescence, immunohistochemical, Western-blot, and qRT-PCR were used to detect the expression levels of PSD-95, p38, and phosphorylated p38. Our findings showed that PSD-95 is expressed in the pancreatic tissues of humans, C57BL/6 mice, and AR42J cells, primarily in the cytoplasm. PSD-95 expression increased at 2 h, reaching the peak at 6 h in mice and 12 h in AR42J cells. IL-6, IL-8, and TNF-α increased within 2 h of disease induction. The pancreatic histopathologic score was greater in the PSD-95 inhibition group compared with the control (P < 0.05), while it was lesser when phosphorylation of p38 MAPK was inhibited compared with the PSD-95 inhibition group (P < 0.05). Moreover, phosphorylation of p38 MAPK increased statistically after PSD-95 knocked-down. In conclusion, PSD-95 effectively influences the pathological damage of the pancreas in acute pancreatitis by affecting the phosphorylation of p38 MAPK.

Latissimus Dorsi Myocutaneous Flap Procedure in a Swine Model.

BACKGROUND: As surgical research expands in both breadth and scope, translational models become increasingly important. The accessibility, reproducibility, and clinical applicability of translational models is of vital importance to ensure adequate and accurate research. Though different flap models have been described, the literature lacks an in-depth, technical description of an easy large-animal preclinical model. We here describe the procedure for elevation of a latissimus dorsi flap in a swine. This flap contains muscle and skin that can be isolated on a vascular pedicle, transferred as a free flap, perfused, or innervated/denervated as dictated by the needs of the experiment. METHODS: Five different latissimus dorsi flaps were elevated in miniature swine. Careful attention was paid to anatomical landmarks and optimal placement of incision, dissection, and retraction. Temporary ischemia with vascular clamping was performed along with serial digital and infrared imaging both intra- and postoperatively. In three of the flaps with induced ischemia, the animal was observed for a 30-day follow up with daily photodocumentation and intermittent biopsy. RESULTS: A reproducible latissimus flap model was designed with optimized conditions. In the animals in which flaps were followed postoperatively, complete healing was seen within 30 days without evidence of procedure-related ischemia or loss of motor function. CONCLUSION: We have identified and described a pre-clinical large animal flap model that can be easily reproduced for translational studies of multiple scientific areas including flap-based repair, ischemia, ischemia reperfusion, and operative technique. This provides an important model for ready replication in preclinical studies of many varieties.

Inhibitory Effect of the Traditional Chinese Medicine Ephedra sinica granules on Streptococcus pneumoniae Pneumolysin.

Streptococcus pneumoniae (S. pneumoniae) is an opportunistic pathogen that causes pneumonia, meningitis and bacteremia in humans and animals. Pneumolysin (PLY), a major pore-forming toxin that is important for S. pneumoniae pathogenicity, is a promising target for the development of anti-infective agents. Ephedra sinica granules (ESG) is one of the oldest medical preparation with multiple biological activities (such as a divergent wind and cold effect); however, the detailed mechanism remains unknown. In this study, we found that ESG treatment significantly inhibited the oligomerization of PLY and then reduced the activity of PLY without affecting S. pneumoniae growth and PLY production. In a PLY and A549 cell co-incubation system, the addition of ESG resulted in significant protection against PLY-mediated cell injury. Furthermore, S. pneumoniae-infected mice showed decreased mortality, and alleviated tissue damage and inflammatory reactions following treatment with ESG. Our results indicate that ESG is a potential candidate treatment for S. pneumoniae infection that targets PLY. This finding partially elucidates the mechanism of the Chinese herbal formula ESG in the treatment of pneumococcal disease.

TNFSF14, a novel target of miR-326, facilitates airway remodeling in airway smooth muscle cells via inducing extracellular matrix protein deposition and proliferation.

As a common chronic respiratory disease, the incidence of asthma is increasing in recent years worldwide. Airway remodeling is the primary pathological basis of refractory asthma, but the studies about the underlying mechanism of airway remodeling was a lack. In the study, we aimed to investigate the effects and mechanisms of miR-326 on airway remodeling in airway smooth muscle cells (ASMCs). The results showed that transforming growth factor-ß1 (TGF-ß1) accelerated matrix protein deposition by increasing the expression levels of collagen I and fibronectin, and promoted proliferative ability of ASMCs. However, miR-326 was significantly downregulated in TGF-ß1-treated ASMCs. MiR-326 mimics robustly decreased the collagen I and fibronectin levels and inhibited cell proliferation of TGF-ß1-treated ASMCs. Luciferase assay investigated that tumor necrosis factor superfamily member 14 (TNFSF14) was a direct target of miR-326. The expression of TNFSF14 was negatively regulated by miR-326. Moreover, exogenous TNFSF14 effectively reversed the inhibitory effects of miR-326 overexpression on the expression levels of collagen I and fibronectin, and promoted cell proliferation of TGF-ß1-treated ASMCs. In conclusion, miR-326 suppressed matrix protein deposition and cell proliferation of TGF-ß1-treated ASMCs via inhibiting TNFSF14. MiR-326 might be a promising novel therapeutic target for asthma.

The roles of MRI-based prostate volume and associated zone-adjusted prostate-specific antigen concentrations in predicting prostate cancer and high-risk prostate cancer.

Prostate biopsies are frequently performed to screen for prostate cancer (PCa) with complications such as infections and bleeding. To reduce unnecessary biopsies, here we designed an improved predictive model of MRI-based prostate volume and associated zone-adjusted prostate-specific antigen (PSA) concentrations for diagnosing PCa and risk stratification. Multiparametric MRI administered to 422 consecutive patients before initial transrectal ultrasonography-guided 13-core prostate biopsies from January 2012 to March 2018 at Fujian Medical University Union Hospital. Univariate and multivariate logistic regression analyses and determination of the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was performed to evaluate and integrate the predictors of PCa and high-risk prostate cancer (HR-PCa). The detection rates of PCa was 43.84% (185/422). And the detection rates of HR-PCa was 71.35% (132/185) in PCa patients. Multivariate analysis revealed that prostate volume(PV), PSA density(PSAD), transitional zone volume(TZV), PSA density of the transitional zone(PSADTZ), and MR were independent predictors of PCa and HR-PCa. PSA, peripheral zone volume(PZV) and PSA density of the peripheral zone(PSADPZ) were independent predictors of PCa but not HR-PCa. The AUC of our best predictive model including PSA + PV + PSAD + MR + TZV or PSA + PV + PSAD + MR + PZV was 0.906 for PCa. The AUC of the best predictive model of PV + PSAD + MR + TZV was 0.893 for HR-PCa. In conclusion, our results will likely improve the detection rate of prostate cancer, avoiding unnecessary prostate biopsies, and for evaluating risk stratification.

CD117 expression is correlated with poor survival of patients and progression of lung carcinoma:a meta-analysis with a panel of 2645 patients.

The aim of this research was to investigate the clinical role and prognostic value of CD117 expression assessed immunohistochemically in lung carcinoma through a comprehensive meta-analysis in which 27 publications were acquired and 2645 patients were ultimately analysed. Statistical analysis and corresponding plots were performed using STATA version 12.0. Publication bias was assessed by Begg's funnel plots and Egger's test. Pooled HR and its 95% CI (HR = 1.53, 95% CI: 1.13-2.07, p = 0.007) for overall survival of patients indicated a poor prognostic value for CD117 expression in lung carcinoma, which was accompanied by heterogeneity and publication bias. In the subgroup analysis, there was strong evidence that could support an association between CD117 expression and poor prognosis in NSCLC patients (HR = 2.03, 95% CI: 1.41-2.90, p < 0.001; heterogeneity: I2 = 41.9%, c2 = 15.49, p = 0.078). Multivariate analysis also revealed consistent results in high-quality studies with reported HRs (HR = 2.16, 95% CI: 1.67-2.79, p < 0.001), and Asian patients (HR = 2.12, 95% CI: 1.45-3.10, p < 0.001). The correlations between CD117 expression and age, clinical stage, TNM stage, lymph node metastasis, or histology were not statistically significant. In conclusion, CD117 expression might be a potential marker for predicting poor prognosis, faster tumour growth, and early lymph node metastasis in NSCLC.

Clinical value of microRNA-198-5p downregulation in lung adenocarcinoma and its potential pathways.

Lung adenocarcinoma (LUAD), the main subtype of non-small cell lung cancer, is known to be regulated by various microRNAs (miRs/miRNAs); however, the role of miR-198-5p in LUAD has not been clarified. In the present study, the clinical value of miR-198-5p in LUAD and its potential molecular mechanism was evaluated. miR-198-5p expression was examined by reverse transcription-quantitative PCR (RT-qPCR) in 101 paired LUAD and adjacent normal lung tissues. Subsequently, the miR-198-5p expression level was determined from microarray data from the Gene Expression Omnibus, ArrayExpress and by meta-analyses. Furthermore, the target mRNAs of miR-198-5p from 12 miRNA-mRNA predictive tools were intersected with The Cancer Genome Atlas (TCGA)-based differentially expressed genes. In addition, Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to determine the possible mechanism of miR-198-5p in LUAD. The Search Tool for the Retrieval of Interacting Genes/Proteins database was employed to construct a protein-protein interaction network among the potential target genes of miR-198-5p. The results showed that miR-198-5p expression was lower in LUAD tissues than in adjacent non-cancerous lung tissues (4.469±2.495 vs. 5.301±2.502; P=0.015). Meta-analyses, including the data from the present study and online microarray data, also verified the downregulation of miR-198-5p in 584 cases of LUAD. The expression of miR-198-5p was associated with the age, blood vessel invasion, Tumor-Node-Metastasis stage, and lymph node metastasis of patients with LUAD and served as an independent prognostic factor for survival. The hub genes of miR-198-5p were upregulated in LUAD, according to TCGA and The Human Protein Atlas. For the KEGG pathway analysis, the most enriched KEGG pathway was the p53 signaling pathway (P=1.42×10-6). These findings indicated that the downregulation of miR-198-5p may play a pivotal role in the development of LUAD by targeting various signaling pathways.

Down-regulation of microRNA-144-3p and its clinical value in non-small cell lung cancer: a comprehensive analysis based on microarray, miRNA-sequencing, and quantitative real-time PCR data.

BACKGROUND: Previous studies have shown that miR-144-3p might be a potential biomarker in non-small cell lung cancer (NSCLC). Nevertheless, the comprehensive mechanism behind the effects of miR-144-3p on the origin, differentiation, and apoptosis of NSCLC, as well as the relationship between miR-144-3p and clinical parameters, has been rarely reported. METHODS: We investigated the correlations between miR-144-3p expression and clinical characteristics through data collected from Gene Expression Omnibus (GEO) microarrays, the relevant literature, The Cancer Genome Atlas (TCGA), and real-time quantitative real-time PCR (RT-qPCR) analyses to determine the clinical role of miR-144-3p in NSCLC. Furthermore, we investigated the biological function of miR-144-3p by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Protein-protein interaction (PPI) network was created to identify the hub genes. RESULTS: From the comprehensive meta-analysis, the combined SMD of miR-144-3p was - 0.95 with 95% CI of (- 1.37, - 0.52), indicating that less miR-144-3p was expressed in the NSCLC tissue than in the normal tissue. MiR-144-3p expression was significantly correlated with stage, lymph node metastasis and vascular invasion (all P <  0.05). As for the bioinformatics analyses, a total of 37 genes were chosen as the potential targets of miR-144-3p in NSCLC. These promising target genes were highly enriched in various key pathways such as the protein digestion and absorption and the thyroid hormone signaling pathways. Additionally, PPI revealed five genes-C12orf5, CEP55, E2F8, STIL, and TOP2A-as hub genes with the threshold value of 6. CONCLUSIONS: The current study validated that miR-144-3p was lowly expressed in NSCLC. More importantly, miR-144-3p might function as a latent tumor biomarker in the prognosis prediction for NSCLC. The results of bioinformatics analyses may present a new method for investigating the pathogenesis of NSCLC.

The expression, significance and function of cancer susceptibility candidate 9 in lung squamous cell carcinoma: A bioinformatics and in vitro investigation.

The cancer susceptibility candidate 9 (CASC9) gene has been reported to exert an oncogenic effect in several types of cancer. However, its role in lung squamous cell carcinoma (LUSC) is unknown. Therefore, the present study examined the expression of CASC9 in LUSC and non­cancer tissues by reverse transcription­quantitative polymerase chain reaction assays and by data mining of high­throughput public databases, including The Cancer Genome Atlas, the Gene Expression Omnibus, ArrayExpress and the Cancer Cell Line Encyclopedia. In vitro experiments were conducted to investigate the effects of CASC9 on the viability and the proliferation of LUSC cells. Furthermore, consulting the alteration status of CASC9 in LUSC from cBioPortal, functional enrichment analysis of co­expressed genes, prediction of potential transcription factors, and inspection of adjacent protein­coding genes were conducted to explore the potential molecular mechanism of CASC9 in LUSC. The results revealed that CASC9 was overexpressed in LUSC tissue, and significantly associated with the malignant progression of LUSC. In vitro experiments demonstrated that CASC9 knockdown by RNA interference attenuated the viability and proliferation of LUSC cells. Multiple copies of CASC9 gene were detected in 4 of 179 available sequenced LUSC cases. A functional enrichment analysis of 200 co­expressed genes indicated that these genes were significantly associated with terms, including 'cell­cell junction organization', 'desmosome organization', 'epidermis development', 'Hippo signaling pathway', 'pathogenic Escherichia coli infection' and 'PID HIF1 TF pathway'. Three genes, Fos­related antigen 2 (FOSL2), SWI/SNF complex subunit SMARCC2, and transcription factor COE1 (EBF1), were predicted by lncRNAMap to be associated with CASC9. Among these, the expression of FOSL2 and EBF1 was positively and negatively correlated with the expression of CASC9, respectively. Two adjacent protein­coding genes, cysteine­rich secretory protein LCCL domain­containing 1 and hepatocyte nuclear factor 4­Î³, were also positively correlated with CASC9 expression. In conclusion, the present data suggest that CASC9 serves as an oncogene in LUSC and may be a promising target for alternative therapeutic options for patients with this condition.

Comprehensive clinical implications of homeobox A10 in 3,199 cases of non-small cell lung cancer tissue samples combining qRT-PCR, RNA sequencing and microarray data.

In the current study, we proposed to explore the potential role and related signaling pathways of Homobox A10 (HOXA10) in non-small cell lung cancer (NSCLC). HOXA10 levels in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were detected by qRT-PCR and the expression of HOXA10 was significantly up-regulated in the NSCLC tissue of all 55 pairs (P = 0.037). Overexpression of HOXA10 was closely correlated with the clinical stage of LUSC (P = 0.011). HOXA10 expression in RNA sequencing data based on 1, 077 cases exhibited concordant significant up-regulation in NSCLC, LUAD and LUSC (P < 0.001). In NSCLC, HOXA10 expression was closely correlated to patient T stage (P = 0.006). In LUAD, HOXA10 expression was compactly correlated to patient N stage (P = 0.02). Some of the microarrays from Gene Expression Omnibus (GEO) and ArrayExpress showed consistent over-expression of HOXA10 levels in NSCLCs. More importantly, the combined SMD value was 0.052 (95% CI: 0.29-0.75, P < 0.001) generated by meta-analysis from 47 datasets based on 4, 616 cases of NSCLC. The area under the curve (AUC) of SROC supported the over-expression of HOXA10 in NSCLC as being 0.88 (95% CI: 0.81-0.93), with sensitivity and specificity of 0.88 (95% CI: 0.81-0.93) and 0.56 (95% CI: 0.44-0.66), respectively. In addition, 111 co-expressed genes were collected from cBioPortal and enriched in "cell cycle", "cell adhesion molecules", "p53 signaling", and "adherens junction". Interestingly, an up-regulation trend of HOXA10 protein expression was also observed in NSCLC through tissue chips and immunohistochemistry. In conclusion, the overexpression of HOXA10 may play a pivotal role in the tumorigenesis of NSCLC, and this effect is observed more obviously in LUSC than in LUAD.

Development of a prognostic index based on an immunogenomic landscape analysis of papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is the most common subtype of thyroid cancer, and inflammation relates significantly to its initiation and prognosis. Systematic exploration of the immunogenomic landscape therein to assist in PTC prognosis is therefore urgent. The Cancer Genome Atlas (TCGA) project provides a large number of genetic PTC samples that enable a comprehensive and reliable immunogenomic study. METHODS: We integrated the expression profiles of immune-related genes (IRGs) and progression-free intervals (PFIs) in survival in 493 PTC patients based on the TCGA dataset. Differentially-expressed and survival-associated IRGs in PTC patients were estimated a computational difference algorithm and COX regression analysis. The potential molecular mechanisms and properties of these PTC-specific IRGs were also explored with the help of computational biology. A new prognostic index based on immune-related genes was developed by using multivariable COX analysis. RESULTS: A total of 46 differentially expressed immune-related genes were significantly correlated with clinical outcome of PTC patients. Functional enrichment analysis revealed that these genes were actively involved in a cytokine-cytokine receptor interaction KEGG pathway. A prognostic signature based on RGs (AGTR1, CTGF, FAM3B, IL11, IL17C, PTH2R and SPAG11A) performed moderately in prognostic predictions and correlated with age, tumor stage, metastasis, number of lesions, and tumor burden. Intriguingly, the prognostic index based on IRGs reflected infiltration by several types of immune cells. CONCLUSIONS: Together, our results screened several IRGs of clinical significance, revealed drivers of the immune repertoire, and demonstrated the importance of a personalized, IRG-based immune signature in the recognition, surveillance, and prognosis of PTC.

The clinicopathological significance of decreased miR-125b-5p in hepatocellular carcinoma: evidence based on RT-qPCR, microRNA-microarray, and microRNA-sequencing.

The aim of the study was to comprehensively evaluate the clinical value of miR-125b-5p in hepatocellular carcinoma (HCC) and its potential molecular mechanisms. MiR-125b-5p expression was remarkably lower as examined by real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) in 95 paired HCC and nonmalignant liver tissues in house (P<0.001), which was in accord with the results from miRNA-sequencing data with 371 cases of HCC. miRNA-chips from Gene Expression Omnibus (GEO) and ArrayExpress were screened. Among the seven included miRNA-chips, the relative expression of miR-125b-5p expression levels showed decreasing trends in HCC tissue samples compared with non-cancerous liver tissue samples. Altogether, A total of 655 cases of HCC tissues and 334 non-HCC liver tissues were included in the final meta-analysis. We observed that the expression of miR-125b-5p indeed decreased markedly in HCC tissues compared with the non-HCC tissues (SMD: -1.414, 95% CI: -1.894 to -0.935, P<0.001). The area under the SROC curve of lower expression of miR-125b-5p was 0.91 (95% CI: 0.89 to 0.94). A Kaplan-Meier survival analysis indicated that the lower expression or the absence of miR-125b-5p may be a risk factor for the poor outcome of HCC patients. Furthermore, the potential target genes of miR-125b-5p from 11 miRNA target prediction databases were intersected with 1,486 differentially expressed genes (DEGs) as calculated by RNA-sequencing data. Finally, a total of 330 GEGs were collected and enriched in the pathways of lysosome, focal adhesion, and pathways in cancer. In conclusion, this study utilizes a variety of research methods to confirm the lower level of miR-125b-5p in HCC tissues. This lower expression level of miR-125b-5p is closely related to increased disease progression in HCC patients.